@article {pmid38492251, year = {2024}, author = {Keeling, PJ and Mtawali, M and Trznadel, M and Livingston, SJ and Wakeman, KC}, title = {Parallel functional reduction in the mitochondria of apicomplexan parasites.}, journal = {European journal of protistology}, volume = {94}, number = {}, pages = {126065}, doi = {10.1016/j.ejop.2024.126065}, pmid = {38492251}, issn = {1618-0429}, abstract = {Extreme functional reduction of mitochondria has taken place in parallel in many distantly related lineages of eukaryotes, leading to a number of recurring metabolic states with variously lost electron transport chain (ETC) complexes, loss of the tricarboxylic acid (TCA) cycle, and/or loss of the mitochondrial genome. The resulting mitochondria-related organelles (MROs) are generally structurally reduced and in the most extreme cases barely recognizable features of the cell with no role in energy metabolism whatsoever (e.g., mitosomes, which generally only make iron-sulfur clusters). Recently, a wide diversity of MROs were discovered to be hiding in plain sight: in gregarine apicomplexans. This diverse group of invertebrate parasites has been known and observed for centuries, but until recent applications of culture-free genomics, their mitochondria were unremarkable. The genomics, however, showed that mitochondrial function has reduced in parallel in multiple gregarine lineages to several different endpoints, including the most reduced mitosomes. Here we review this remarkable case of parallel evolution of MROs, and some of the interesting questions this work raises.}, } @article {pmid38475850, year = {2024}, author = {Vesala, L and Basikhina, Y and Tuomela, T and Nurminen, A and Siukola, E and Vale, PF and Salminen, TS}, title = {Mitochondrial perturbation in immune cells enhances cell-mediated innate immunity in Drosophila.}, journal = {BMC biology}, volume = {22}, number = {1}, pages = {60}, pmid = {38475850}, issn = {1741-7007}, support = {RPG-2018-369//Leverhulme Trust/ ; 322732//Academy of Finland/ ; 328979//Academy of Finland/ ; 353367//Academy of Finland/ ; 3122800849//Sigrid Juséliuksen Säätiö/ ; }, abstract = {BACKGROUND: Mitochondria participate in various cellular processes including energy metabolism, apoptosis, autophagy, production of reactive oxygen species, stress responses, inflammation and immunity. However, the role of mitochondrial metabolism in immune cells and tissues shaping the innate immune responses are not yet fully understood. We investigated the effects of tissue-specific mitochondrial perturbation on the immune responses at the organismal level. Genes for oxidative phosphorylation (OXPHOS) complexes cI-cV were knocked down in the fruit fly Drosophila melanogaster, targeting the two main immune tissues, the fat body and the immune cells (hemocytes).

RESULTS: While OXPHOS perturbation in the fat body was detrimental, hemocyte-specific perturbation led to an enhanced immunocompetence. This was accompanied by the formation of melanized hemocyte aggregates (melanotic nodules), a sign of activation of cell-mediated innate immunity. Furthermore, the hemocyte-specific OXPHOS perturbation induced immune activation of hemocytes, resulting in an infection-like hemocyte profile and an enhanced immune response against parasitoid wasp infection. In addition, OXPHOS perturbation in hemocytes resulted in mitochondrial membrane depolarization and upregulation of genes associated with the mitochondrial unfolded protein response.

CONCLUSIONS: Overall, we show that while the effects of mitochondrial perturbation on immune responses are highly tissue-specific, mild mitochondrial dysfunction can be beneficial in immune-challenged individuals and contributes to variation in infection outcomes among individuals.}, } @article {pmid38307786, year = {2024}, author = {Muñoz-Gómez, SA}, title = {The energetic costs of cellular complexity in evolution.}, journal = {Trends in microbiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tim.2024.01.003}, pmid = {38307786}, issn = {1878-4380}, abstract = {The evolutionary history of cells has been marked by drastic increases in complexity. Some hypothesize that such cellular complexification requires a massive energy flux as the origin of new features is hypothetically more energetically costly than their evolutionary maintenance. However, it remains unclear how increases in cellular complexity demand more energy. I propose that the early evolution of new genes with weak functions imposes higher energetic costs by overexpression before their functions are evolutionarily refined. In the long term, the accumulation of new genes deviates resources away from growth and reproduction. Accrued cellular complexity further requires additional infrastructure for its maintenance. Altogether, this suggests that larger and more complex cells are defined by increased survival but lower reproductive capacity.}, } @article {pmid38258637, year = {2024}, author = {Li, X and Li, W and Huo, J and Li, L and Chen, B and Guo, Z and Ma, Z}, title = {[Identification and expression analysis of citrate synthase 3 gene family members in apple].}, journal = {Sheng wu gong cheng xue bao = Chinese journal of biotechnology}, volume = {40}, number = {1}, pages = {137-149}, doi = {10.13345/j.cjb.230166}, pmid = {38258637}, issn = {1872-2075}, mesh = {*Citric Acid ; *Malus/genetics ; Citrate (si)-Synthase ; Phylogeny ; Citrates ; }, abstract = {As one of the key enzymes in cell metabolism, the activity of citrate synthase 3 (CS3) regulates the substance and energy metabolism of organisms. The protein members of CS3 family were identified from the whole genome of apple, and bioinformatics analysis was performed and expression patterns were analyzed to provide a theoretical basis for studying the potential function of CS3 gene in apple. BLASTp was used to identify members of the apple CS3 family based on the GDR database, and the basic information of CS3 protein sequence, subcellular localization, domain composition, phylogenetic relationship and chromosome localization were analyzed by Pfam, SMART, MEGA5.0, clustalx.exe, ExPASy Proteomics Server, MEGAX, SOPMA, MEME, WoLF PSORT and other software. The tissue expression and inducible expression characteristics of 6 CS3 genes in apple were determined by acid content and real-time fluorescence quantitative polymerase chain reaction (qRT-PCR). Apple CS3 gene family contains 6 members, and these CS3 proteins contain 473-608 amino acid residues, with isoelectric point distribution between 7.21 and 8.82. Subcellular localization results showed that CS3 protein was located in mitochondria and chloroplasts, respectively. Phylogenetic analysis divided them into 3 categories, and the number of genes in each subfamily was 2. Chromosome localization analysis showed that CS3 gene was distributed on different chromosomes of apple. The secondary structure of protein is mainly α-helix, followed by random curling, and the proportion of β-angle is the smallest. The 6 members were all expressed in different apple tissues. The overall expression trend from high to low was the highest relative expression content of MdCS3.4, followed by MdCS3.6, and the relative expression level of other members was in the order of MdCS3.3 > MdCS3.2 > MdCS3.1 > MdCS3.5. qRT-PCR results showed that MdCS3.1 and MdCS3.3 genes had the highest relative expression in the pulp of 'Chengji No. 1' with low acid content, and MdCS3.2 and MdCS3.3 genes in the pulp of 'Asda' with higher acid content had the highest relative expression. Therefore, in this study, the relative expression of CS3 gene in apple cultivars with different acid content in different apple varieties was detected, and its role in apple fruit acid synthesis was analyzed. The experimental results showed that the relative expression of CS3 gene in different apple varieties was different, which provided a reference for the subsequent study of the quality formation mechanism of apple.}, } @article {pmid38186275, year = {2024}, author = {Prokkola, JM and Chew, KK and Anttila, K and Maamela, KS and Yildiz, A and Åsheim, ER and Primmer, CR and Aykanat, T}, title = {Tissue-specific metabolic enzyme levels covary with whole-animal metabolic rates and life-history loci via epistatic effects.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {379}, number = {1896}, pages = {20220482}, pmid = {38186275}, issn = {1471-2970}, mesh = {Animals ; Humans ; Anaerobiosis ; Biological Evolution ; Genotype ; Heart ; *Muscles ; *Salmo salar ; Transcription Factors ; Energy Metabolism/physiology ; }, abstract = {Metabolic rates, including standard (SMR) and maximum (MMR) metabolic rate have often been linked with life-history strategies. Variation in context- and tissue-level metabolism underlying SMR and MMR may thus provide a physiological basis for life-history variation. This raises a hypothesis that tissue-specific metabolism covaries with whole-animal metabolic rates and is genetically linked to life history. In Atlantic salmon (Salmo salar), variation in two loci, vgll3 and six6, affects life history via age-at-maturity as well as MMR. Here, using individuals with known SMR and MMR with different vgll3 and six6 genotype combinations, we measured proxies of mitochondrial density and anaerobic metabolism, i.e. maximal activities of the mitochondrial citrate synthase (CS) and lactate dehydrogenase (LDH) enzymes, in four tissues (heart, intestine, liver, white muscle) across low- and high-food regimes. We found enzymatic activities were related to metabolic rates, mainly SMR, in the intestine and heart. Individual loci were not associated with the enzymatic activities, but we found epistatic effects and genotype-by-environment interactions in CS activity in the heart and epistasis in LDH activity in the intestine. These effects suggest that mitochondrial density and anaerobic capacity in the heart and intestine may partly mediate variation in metabolic rates and life history via age-at-maturity. This article is part of the theme issue 'The evolutionary significance of variation in metabolic rates'.}, } @article {pmid38149397, year = {2023}, author = {Shen, Q and Yuan, Y and Jin, J}, title = {[Relationship between Notch signaling pathway and mitochondrial energy metabolism].}, journal = {Zhonghua wei zhong bing ji jiu yi xue}, volume = {35}, number = {12}, pages = {1321-1326}, doi = {10.3760/cma.j.cn121430-20230719-00532}, pmid = {38149397}, issn = {2095-4352}, abstract = {Notch signaling pathway is a highly conserved signaling pathway in the process of evolution. It is composed of three parts: Notch receptor, ligand and effector molecules responsible for intracellular signal transduction. It plays an important role in cell proliferation, differentiation, development, migration, apoptosis and other processes, and has a regulatory effect on tissue homeostasis and homeostasis. Mitochondria are the sites of oxidative metabolism in eukaryotes, where sugars, fats and proteins are finally oxidized to release energy. In recent years, the regulation of Notch signaling pathway on mitochondrial energy metabolism has attracted more and more attention. A large number of data have shown that Notch signaling pathway has a significant effect on mitochondrial energy metabolism, but the relationship between Notch signaling pathway and mitochondrial energy metabolism needs to be specifically and systematically discussed. In this paper, the relationship between Notch signaling pathway and mitochondrial energy metabolism is reviewed, in order to improve the understanding of them and provide new ideas for the treatment of related diseases.}, } @article {pmid38112480, year = {2023}, author = {He, Z and Fang, Y and Zhang, F and Liu, Y and Cheng, X and Wang, J and Li, D and Chen, D and Wu, F}, title = {Adenine nucleotide translocase 2 (Ant2) is required for individualization of spermatogenesis of Drosophila melanogaster.}, journal = {Insect science}, volume = {}, number = {}, pages = {}, doi = {10.1111/1744-7917.13309}, pmid = {38112480}, issn = {1744-7917}, support = {CARS-18-SYZ10//China Agricultural Research System of MOF and MARA/ ; 2021-620-000-001-009//Hubei Province Agricultural Science and Technology Innovation Center Project/ ; 2022BBA0079//Hubei Province key Research and Development Project/ ; }, abstract = {Successful completion of spermatogenesis is crucial for the perpetuation of the species. In Drosophila, spermatid individualization, a process involving changes in mitochondrial structure and function is critical to produce functional mature sperm. Ant2, encoding a mitochondrial adenine nucleotide translocase, is highly expressed in male testes and plays a role in energy metabolism in the mitochondria. However, its molecular function remains unclear. Here, we identified an important role of Ant2 in spermatid individualization. In Ant2 knockdown testes, spermatid individualization complexes composed of F-actin cones exhibited a diffuse distribution, and mature sperms were absent in the seminal vesicle, thus leading to male sterility. The most striking effects in Ant2-knockdown spermatids were decrease in tubulin polyglycylation and disruption of proper mitochondria derivatives function. Excessive apoptotic cells were also observed in Ant2-knockdown testes. To further investigate the phenotype of Ant2 knockdown in testes at the molecular level, complementary transcriptome and proteome analyses were performed. At the mRNA level, 868 differentially expressed genes were identified, of which 229 genes were upregulated and 639 were downregulated induced via Ant2 knockdown. iTRAQ-labeling proteome analysis revealed 350 differentially expressed proteins, of which 117 proteins were upregulated and 233 were downregulated. The expression of glutathione transferase (GstD5, GstE5, GstE8, and GstD3), proteins involved in reproduction were significantly regulated at both the mRNA and protein levels. These results indicate that Ant2 is crucial for spermatid maturation by affecting mitochondrial morphogenesis.}, } @article {pmid37039888, year = {2023}, author = {Zuccoli, GS and Nascimento, JM and Moraes-Vieira, PM and Rehen, SK and Martins-de-Souza, D}, title = {Mitochondrial, cell cycle control and neuritogenesis alterations in an iPSC-based neurodevelopmental model for schizophrenia.}, journal = {European archives of psychiatry and clinical neuroscience}, volume = {273}, number = {8}, pages = {1649-1664}, pmid = {37039888}, issn = {1433-8491}, support = {2016/04912-2//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2018/14666-4//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2014/21035-0//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2015/15626-8//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2017/25588-1//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2019/00098-7//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2018/01410-1//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; }, mesh = {Adult ; Humans ; *Schizophrenia/metabolism ; *Induced Pluripotent Stem Cells/metabolism ; Cell Differentiation/genetics ; Reactive Oxygen Species/metabolism ; Proteomics ; Cell Cycle Checkpoints ; Mitochondria/metabolism ; }, abstract = {Schizophrenia is a severe psychiatric disorder of neurodevelopmental origin that affects around 1% of the world's population. Proteomic studies and other approaches have provided evidence of compromised cellular processes in the disorder, including mitochondrial function. Most of the studies so far have been conducted on postmortem brain tissue from patients, and therefore, do not allow the evaluation of the neurodevelopmental aspect of the disorder. To circumvent that, we studied the mitochondrial and nuclear proteomes of neural stem cells (NSCs) and neurons derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients versus healthy controls to assess possible alterations related to energy metabolism and mitochondrial function during neurodevelopment in the disorder. Our results revealed differentially expressed proteins in pathways related to mitochondrial function, cell cycle control, DNA repair and neuritogenesis and their possible implication in key process of neurodevelopment, such as neuronal differentiation and axonal guidance signaling. Moreover, functional analysis of NSCs revealed alterations in mitochondrial oxygen consumption in schizophrenia-derived cells and a tendency of higher levels of intracellular reactive oxygen species (ROS). Hence, this study shows evidence that alterations in important cellular processes are present during neurodevelopment and could be involved with the establishment of schizophrenia, as well as the phenotypic traits observed in adult patients. Neural stem cells (NSCs) and neurons were derived from induced pluripotent stem cells (iPSCs) from schizophrenia patients and controls. Proteomic analyses were performed on the enriched mitochondrial and nuclear fractions of NSCs and neurons. Whole-cell proteomic analysis was also performed in neurons. Our results revealed alteration in proteins related to mitochondrial function, cell cycle control, among others. We also performed energy pathway analysis and reactive oxygen species (ROS) analysis of NSCs, which revealed alterations in mitochondrial oxygen consumption and a tendency of higher levels of intracellular ROS in schizophrenia-derived cells.}, } @article {pmid38052127, year = {2023}, author = {Fernández Miyakawa, ME and Casanova, NA and Kogut, MH}, title = {How did antibiotic growth promoters increase growth and feed efficiency in poultry?.}, journal = {Poultry science}, volume = {103}, number = {2}, pages = {103278}, doi = {10.1016/j.psj.2023.103278}, pmid = {38052127}, issn = {1525-3171}, abstract = {It has been hypothesized that reducing the bioenergetic costs of gut inflammation as an explanation for the effect of antibiotic growth promoters (AGPs) on animal efficiency, framing some observations but not explaining the increase in growth rate or the prevention of infectious diseases. The host's ability to adapt to alterations in environmental conditions and to maintain health involves managing all physiological interactions that regulate homeostasis. Thus, metabolic pathways are vital in regulating physiological health as the energetic demands of the host guides most biological functions. Mitochondria are not only the metabolic heart of the cell because of their role in energy metabolism and oxidative phosphorylation, but also a central hub of signal transduction pathways that receive messages about the health and nutritional states of cells and tissues. In response, mitochondria direct cellular and tissue physiological alterations throughout the host. The endosymbiotic theory suggests that mitochondria evolved from prokaryotes, emphasizing the idea that these organelles can be affected by some antibiotics. Indeed, therapeutic levels of several antibiotics can be toxic to mitochondria, but subtherapeutic levels may improve mitochondrial function and defense mechanisms by inducing an adaptive response of the cell, resulting in mitokine production which coordinates an array of adaptive responses of the host to the stressor(s). This adaptive stress response is also observed in several bacteria species, suggesting that this protective mechanism has been preserved during evolution. Concordantly, gut microbiome modulation by subinhibitory concentration of AGPs could be the result of direct stimulation rather than inhibition of determined microbial species. In eukaryotes, these adaptive responses of the mitochondria to internal and external environmental conditions, can promote growth rate of the organism as an evolutionary strategy to overcome potential negative conditions. We hypothesize that direct and indirect subtherapeutic AGP regulation of mitochondria functional output can regulate homeostatic control mechanisms in a manner similar to those involved with disease tolerance.}, } @article {pmid38047232, year = {2023}, author = {Charrasse, S and Poquillon, T and Saint-Omer, C and Pastore, M and Bordignon, B and Frye, RE and Reynes, C and Racine, V and Aouacheria, A}, title = {Quantitative assessment of mitochondrial morphology relevant for studies on cellular health and environmental toxicity.}, journal = {Computational and structural biotechnology journal}, volume = {21}, number = {}, pages = {5609-5619}, pmid = {38047232}, issn = {2001-0370}, abstract = {Mitochondria are essential organelles that play crucial roles in cellular energy metabolism, calcium signaling and apoptosis. Their importance in tissue homeostasis and stress responses, combined to their ability to transition between various structural and functional states, make them excellent organelles for monitoring cellular health. Quantitative assessment of mitochondrial morphology can therefore provide valuable insights into environmentally-induced cell damage. High-content screening (HCS) provides a powerful tool for analyzing organelles and cellular substructures. We developed a fully automated and miniaturized HCS wet-plus-dry pipeline (MITOMATICS) exploiting mitochondrial morphology as a marker for monitoring cellular health or damage. MITOMATICS uses an in-house, proprietary software (MitoRadar) to enable fast, exhaustive and cost-effective analysis of mitochondrial morphology and its inherent diversity in live cells. We applied our pipeline and big data analytics software to assess the mitotoxicity of selected chemicals, using the mitochondrial uncoupler CCCP as an internal control. Six different pesticides (inhibiting complexes I, II and III of the mitochondrial respiratory chain) were tested as individual compounds and five other pesticides present locally in Occitanie (Southern France) were assessed in combination to determine acute mitotoxicity. Our results show that the assayed pesticides exhibit specific signatures when used as single compounds or chemical mixtures and that they function synergistically to impact mitochondrial architecture. Study of environment-induced mitochondrial damage has the potential to open new fields in mechanistic toxicology, currently underexplored by regulatory toxicology and exposome research. Such exploration could inform health policy guidelines and foster pharmacological intervention, water, air and soil pollution control and food safety.}, } @article {pmid36736695, year = {2023}, author = {Fähnrich, A and Stephan, I and Hirose, M and Haarich, F and Awadelkareem, MA and Ibrahim, S and Busch, H and Wohlers, I}, title = {North and East African mitochondrial genetic variation needs further characterization towards precision medicine.}, journal = {Journal of advanced research}, volume = {54}, number = {}, pages = {59-76}, doi = {10.1016/j.jare.2023.01.021}, pmid = {36736695}, issn = {2090-1224}, mesh = {Humans ; *DNA, Mitochondrial/genetics ; *East African People/genetics ; Genetic Variation/genetics ; Haplotypes ; Phylogeny ; Precision Medicine ; Sequence Analysis, DNA ; *North African People/genetics ; }, abstract = {INTRODUCTION: Mitochondria are maternally inherited cell organelles with their own genome, and perform various functions in eukaryotic cells such as energy production and cellular homeostasis. Due to their inheritance and manifold biological roles in health and disease, mitochondrial genetics serves a dual purpose of tracing the history as well as disease susceptibility of human populations across the globe. This work requires a comprehensive catalogue of commonly observed genetic variations in the mitochondrial DNAs for all regions throughout the world. So far, however, certain regions, such as North and East Africa have been understudied.

OBJECTIVES: To address this shortcoming, we have created the most comprehensive quality-controlled North and East African mitochondrial data set to date and use it for characterizing mitochondrial genetic variation in this region.

METHODS: We compiled 11 published cohorts with novel data for mitochondrial genomes from 159 Sudanese individuals. We combined these 641 mitochondrial sequences with sequences from the 1000 Genomes (n = 2504) and the Human Genome Diversity Project (n = 828) and used the tool haplocheck for extensive quality control and detection of in-sample contamination, as well as Nanopore long read sequencing for haplogroup validation of 18 samples.

RESULTS: Using a subset of high-coverage mitochondrial sequences, we predict 15 potentially novel haplogroups in North and East African subjects and observe likely phylogenetic deviations from the established PhyloTree reference for haplogroups L0a1 and L2a1.

CONCLUSION: Our findings demonstrate common hitherto unexplored variants in mitochondrial genomes of North and East Africa that lead to novel phylogenetic relationships between haplogroups present in these regions. These observations call for further in-depth population genetic studies in that region to enable the prospective use of mitochondrial genetic variation for precision medicine.}, } @article {pmid38002320, year = {2023}, author = {Nusir, A and Sinclair, P and Kabbani, N}, title = {Mitochondrial Proteomes in Neural Cells: A Systematic Review.}, journal = {Biomolecules}, volume = {13}, number = {11}, pages = {}, doi = {10.3390/biom13111638}, pmid = {38002320}, issn = {2218-273X}, abstract = {Mitochondria are ancient endosymbiotic double membrane organelles that support a wide range of eukaryotic cell functions through energy, metabolism, and cellular control. There are over 1000 known proteins that either reside within the mitochondria or are transiently associated with it. These mitochondrial proteins represent a functional subcellular protein network (mtProteome) that is encoded by mitochondrial and nuclear genomes and significantly varies between cell types and conditions. In neurons, the high metabolic demand and differential energy requirements at the synapses are met by specific modifications to the mtProteome, resulting in alterations in the expression and functional properties of the proteins involved in energy production and quality control, including fission and fusion. The composition of mtProteomes also impacts the localization of mitochondria in axons and dendrites with a growing number of neurodegenerative diseases associated with changes in mitochondrial proteins. This review summarizes the findings on the composition and properties of mtProteomes important for mitochondrial energy production, calcium and lipid signaling, and quality control in neural cells. We highlight strategies in mass spectrometry (MS) proteomic analysis of mtProteomes from cultured cells and tissue. The research into mtProteome composition and function provides opportunities in biomarker discovery and drug development for the treatment of metabolic and neurodegenerative disease.}, } @article {pmid37954502, year = {2022}, author = {Politis-Barber, V and Petrick, HL and Raajendiran, A and DesOrmeaux, GJ and Brunetta, HS and Dos Reis, LM and Mori, MA and Wright, DC and Watt, MJ and Holloway, GP}, title = {Ckmt1 is Dispensable for Mitochondrial Bioenergetics Within White/Beige Adipose Tissue.}, journal = {Function (Oxford, England)}, volume = {3}, number = {5}, pages = {zqac037}, pmid = {37954502}, issn = {2633-8823}, mesh = {Mice ; Humans ; Animals ; *Creatine/metabolism ; *Adipose Tissue, Beige/metabolism ; Adipose Tissue, White ; Energy Metabolism/genetics ; Creatine Kinase/metabolism ; Mitochondria/metabolism ; }, abstract = {Within brown adipose tissue (BAT), the brain isoform of creatine kinase (CKB) has been proposed to regulate the regeneration of ADP and phosphocreatine in a futile creatine cycle (FCC) that stimulates energy expenditure. However, the presence of FCC, and the specific creatine kinase isoforms regulating this theoretical model within white adipose tissue (WAT), remains to be fully elucidated. In the present study, creatine did not stimulate respiration in cultured adipocytes, isolated mitochondria or mouse permeabilized WAT. Additionally, while creatine kinase ubiquitous-type, mitochondrial (CKMT1) mRNA and protein were detected in human WAT, shRNA-mediated reductions in Ckmt1 did not decrease submaximal respiration in cultured adipocytes, and ablation of CKMT1 in mice did not alter energy expenditure, mitochondrial responses to pharmacological β3-adrenergic activation (CL 316, 243) or exacerbate the detrimental metabolic effects of consuming a high-fat diet. Taken together, these findings solidify CKMT1 as dispensable in the regulation of energy expenditure, and unlike in BAT, they do not support the presence of FCC within WAT.}, } @article {pmid37955101, year = {2023}, author = {Da Costa, RT and Riggs, LM and Solesio, ME}, title = {Inorganic polyphosphate and the regulation of mitochondrial physiology.}, journal = {Biochemical Society transactions}, volume = {}, number = {}, pages = {}, doi = {10.1042/BST20230735}, pmid = {37955101}, issn = {1470-8752}, abstract = {Inorganic polyphosphate (polyP) is an ancient polymer that is well-conserved throughout evolution. It is formed by multiple subunits of orthophosphates linked together by phosphoanhydride bonds. The presence of these bonds, which are structurally similar to those found in ATP, and the high abundance of polyP in mammalian mitochondria, suggest that polyP could be involved in the regulation of the physiology of the organelle, especially in the energy metabolism. In fact, the scientific literature shows an unequivocal role for polyP not only in directly regulating oxidative a phosphorylation; but also in the regulation of reactive oxygen species metabolism, mitochondrial free calcium homeostasis, and the formation and opening of mitochondrial permeability transitions pore. All these processes are closely interconnected with the status of mitochondrial bioenergetics and therefore play a crucial role in maintaining mitochondrial and cell physiology. In this invited review, we discuss the main scientific literature regarding the regulatory role of polyP in mammalian mitochondrial physiology, placing a particular emphasis on its impact on energy metabolism. Although the effects of polyP on the physiology of the organelle are evident; numerous aspects, particularly within mammalian cells, remain unclear and require further investigation. These aspects encompass, for example, advancing the development of more precise analytical methods, unraveling the mechanism responsible for sensing polyP levels, and understanding the exact molecular mechanism that underlies the effects of polyP on mitochondrial physiology. By increasing our understanding of the biology of this ancient and understudied polymer, we could unravel new pharmacological targets in diseases where mitochondrial dysfunction, including energy metabolism dysregulation, has been broadly described.}, } @article {pmid37508434, year = {2023}, author = {Preziuso, A and Piccirillo, S and Cerqueni, G and Serfilippi, T and Terenzi, V and Vinciguerra, A and Orciani, M and Amoroso, S and Magi, S and Lariccia, V}, title = {Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer's Disease.}, journal = {Biology}, volume = {12}, number = {7}, pages = {}, doi = {10.3390/biology12071005}, pmid = {37508434}, issn = {2079-7737}, support = {2017YH3SXK//Ministry of Education, Universities and Research/ ; }, abstract = {Alzheimer's disease (AD) is a widespread neurodegenerative disorder, affecting a large number of elderly individuals worldwide. Mitochondrial dysfunction, metabolic alterations, and oxidative stress are regarded as cooperating drivers of the progression of AD. In particular, metabolic impairment amplifies the production of reactive oxygen species (ROS), resulting in detrimental alterations to intracellular Ca[2+] regulatory processes. The Na[+]/Ca[2+] exchanger (NCX) proteins are key pathophysiological determinants of Ca[2+] and Na[+] homeostasis, operating at both the plasma membrane and mitochondria levels. Our study aimed to explore the role of NCX1 and NCX3 in retinoic acid (RA) differentiated SH-SY5Y cells treated with glyceraldehyde (GA), to induce impairment of the default glucose metabolism that typically precedes Aβ deposition or Tau protein phosphorylation in AD. By using an RNA interference-mediated approach to silence either NCX1 or NCX3 expression, we found that, in GA-treated cells, the knocking-down of NCX3 ameliorated cell viability, increased the intracellular ATP production, and reduced the oxidative damage. Remarkably, NCX3 silencing also prevented the enhancement of Aβ and pTau levels and normalized the GA-induced decrease in NCX reverse-mode activity. By contrast, the knocking-down of NCX1 was totally ineffective in preventing GA-induced cytotoxicity except for the increase in ATP synthesis. These findings indicate that NCX3 and NCX1 may differently influence the evolution of AD pathology fostered by glucose metabolic dysfunction, thus providing a potential target for preventing AD.}, } @article {pmid37429000, year = {2023}, author = {Wan, H and Zhang, Y and Wu, L and Zhou, G and Pan, L and Fernie, AR and Ruan, YL}, title = {Evolution of cytosolic and organellar invertases empowered the colonization and thriving of land plants.}, journal = {Plant physiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/plphys/kiad401}, pmid = {37429000}, issn = {1532-2548}, abstract = {The molecular innovation underpinning efficient carbon and energy metabolism during evolution of land plants remains largely unknown. Invertase-mediated sucrose cleavage into hexoses is central to fuel growth. Why some cytoplasmic invertases (CINs) function in the cytosol, whereas others operate in chloroplasts and mitochondria, is puzzling. We attempted to shed light on this question from an evolutionary perspective. Our analyses indicated that plant CINs originated from an putatively orthologous ancestral gene in cyanobacteria and formed the plastidic CIN (α1 clade) through endo-symbiotic gene transfer, while its duplication in algae with a loss of its signal peptide produced the β clade CINs in the cytosol. The mitochondrial CINs (α2) derived from duplication of the plastidic CINs and co-evolved with vascular plants. Importantly, the copy number of mitochondrial and plastidic CINs increased upon the emergence of seed plants, corresponding with the rise of respiratory, photosynthetic and growth rates. The cytosolic CIN (β subfamily) kept expanding from algae to gymnosperm, indicating its role in supporting the increase in carbon use efficiency during evolution. Affinity purification mass spectrometry identified a cohort of proteins interacting with α1 and 2 CINs, which points to their roles in plastid and mitochondrial glycolysis, oxidative stress tolerance and the maintenance of subcellular sugar homeostasis. Collectively, the findings indicate evolutionary roles of α1 and α2 CINs in chloroplasts and mitochondria for achieving high photosynthetic and respiratory rates, respectively, which, together with the expanding of cytosolic CINs, likely underpin the colonization of land plants through fueling rapid growth and biomass production.}, } @article {pmid37239904, year = {2023}, author = {Rossi, F and Picone, G and Cappadone, C and Sorrentino, A and Columbaro, M and Farruggia, G and Catelli, E and Sciutto, G and Prati, S and Oliete, R and Pasini, A and Pereiro, E and Iotti, S and Malucelli, E}, title = {Shedding Light on Osteosarcoma Cell Differentiation: Impact on Biomineralization and Mitochondria Morphology.}, journal = {International journal of molecular sciences}, volume = {24}, number = {10}, pages = {}, doi = {10.3390/ijms24108559}, pmid = {37239904}, issn = {1422-0067}, abstract = {Osteosarcoma (OS) is the most common primary malignant bone tumor and its etiology has recently been associated with osteogenic differentiation dysfunctions. OS cells keep a capacity for uncontrolled proliferation showing a phenotype similar to undifferentiated osteoprogenitors with abnormal biomineralization. Within this context, both conventional and X-ray synchrotron-based techniques have been exploited to deeply characterize the genesis and evolution of mineral depositions in a human OS cell line (SaOS-2) exposed to an osteogenic cocktail for 4 and 10 days. A partial restoration of the physiological biomineralization, culminating with the formation of hydroxyapatite, was observed at 10 days after treatment together with a mitochondria-driven mechanism for calcium transportation within the cell. Interestingly, during differentiation, mitochondria showed a change in morphology from elongated to rounded, indicating a metabolic reprogramming of OS cells possibly linked to an increase in glycolysis contribution to energy metabolism. These findings add a dowel to the genesis of OS giving new insights on the development of therapeutic strategies able to restore the physiological mineralization in OS cells.}, } @article {pmid37042115, year = {2023}, author = {Metcalfe, NB and Bellman, J and Bize, P and Blier, PU and Crespel, A and Dawson, NJ and Dunn, RE and Halsey, LG and Hood, WR and Hopkins, M and Killen, SS and McLennan, D and Nadler, LE and Nati, JJH and Noakes, MJ and Norin, T and Ozanne, SE and Peaker, M and Pettersen, AK and Przybylska-Piech, A and Rathery, A and Récapet, C and Rodríguez, E and Salin, K and Stier, A and Thoral, E and Westerterp, KR and Westerterp-Plantenga, MS and Wojciechowski, MS and Monaghan, P}, title = {Solving the conundrum of intra-specific variation in metabolic rate: A multidisciplinary conceptual and methodological toolkit: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {}, number = {}, pages = {e2300026}, doi = {10.1002/bies.202300026}, pmid = {37042115}, issn = {1521-1878}, abstract = {Researchers from diverse disciplines, including organismal and cellular physiology, sports science, human nutrition, evolution and ecology, have sought to understand the causes and consequences of the surprising variation in metabolic rate found among and within individual animals of the same species. Research in this area has been hampered by differences in approach, terminology and methodology, and the context in which measurements are made. Recent advances provide important opportunities to identify and address the key questions in the field. By bringing together researchers from different areas of biology and biomedicine, we describe and evaluate these developments and the insights they could yield, highlighting the need for more standardisation across disciplines. We conclude with a list of important questions that can now be addressed by developing a common conceptual and methodological toolkit for studies on metabolic variation in animals.}, } @article {pmid36883279, year = {2023}, author = {García Pascual, B and Nordbotten, JM and Johnston, IG}, title = {Cellular and environmental dynamics influence species-specific extents of organelle gene retention.}, journal = {Proceedings. Biological sciences}, volume = {290}, number = {1994}, pages = {20222140}, doi = {10.1098/rspb.2022.2140}, pmid = {36883279}, issn = {1471-2954}, abstract = {Mitochondria and plastids rely on many nuclear-encoded genes, but retain small subsets of the genes they need to function in their own organelle DNA (oDNA). Different species retain different numbers of oDNA genes, and the reasons for these differences are not completely understood. Here, we use a mathematical model to explore the hypothesis that the energetic demands imposed by an organism's changing environment influence how many oDNA genes it retains. The model couples the physical biology of cell processes of gene expression and transport to a supply-and-demand model for the environmental dynamics to which an organism is exposed. The trade-off between fulfilling metabolic and bioenergetic environmental demands, and retaining genetic integrity, is quantified for a generic gene encoded either in oDNA or in nuclear DNA. Species in environments with high-amplitude, intermediate-frequency oscillations are predicted to retain the most organelle genes, whereas those in less dynamic or noisy environments the fewest. We discuss support for, and insight from, these predictions with oDNA data across eukaryotic taxa, including high oDNA gene counts in sessile organisms exposed to day-night and intertidal oscillations (including plants and algae) and low counts in parasites and fungi.}, } @article {pmid36795453, year = {2023}, author = {Dong, LF and Rohlena, J and Zobalova, R and Nahacka, Z and Rodriguez, AM and Berridge, MV and Neuzil, J}, title = {Mitochondria on the move: Horizontal mitochondrial transfer in disease and health.}, journal = {The Journal of cell biology}, volume = {222}, number = {3}, pages = {}, doi = {10.1083/jcb.202211044}, pmid = {36795453}, issn = {1540-8140}, mesh = {Animals ; Phylogeny ; *Mitochondria/metabolism ; *Neoplasms/genetics/metabolism ; Energy Metabolism ; Mammals ; }, abstract = {Mammalian genes were long thought to be constrained within somatic cells in most cell types. This concept was challenged recently when cellular organelles including mitochondria were shown to move between mammalian cells in culture via cytoplasmic bridges. Recent research in animals indicates transfer of mitochondria in cancer and during lung injury in vivo, with considerable functional consequences. Since these pioneering discoveries, many studies have confirmed horizontal mitochondrial transfer (HMT) in vivo, and its functional characteristics and consequences have been described. Additional support for this phenomenon has come from phylogenetic studies. Apparently, mitochondrial trafficking between cells occurs more frequently than previously thought and contributes to diverse processes including bioenergetic crosstalk and homeostasis, disease treatment and recovery, and development of resistance to cancer therapy. Here we highlight current knowledge of HMT between cells, focusing primarily on in vivo systems, and contend that this process is not only (patho)physiologically relevant, but also can be exploited for the design of novel therapeutic approaches.}, } @article {pmid36790303, year = {2023}, author = {Sokolova, IM}, title = {Ectotherm mitochondrial economy and responses to global warming.}, journal = {Acta physiologica (Oxford, England)}, volume = {}, number = {}, pages = {e13950}, doi = {10.1111/apha.13950}, pmid = {36790303}, issn = {1748-1716}, abstract = {Temperature is a key abiotic factor affecting ecology, biogeography and evolution of species. Alterations of energy metabolism play an important role in adaptations and plastic responses to temperature shifts on different time scales. Mitochondrial metabolism plays a key role in bioenergetics and redox balance making these organelles an important determinant of organismal performances such as growth, locomotion or development. Here I analyze the impacts of environmental temperature on the mitochondrial functions (including oxidative phosphorylation, proton leak, production of reactive oxygen species and ATP synthesis) of ectotherms and discuss the mechanisms underlying negative shifts in the mitochondrial energy economy caused by supraoptimal temperatures. Due to the differences in the thermal sensitivity of different mitochondrial processes, elevated temperatures (beyond the species- and population-specific optimal range) cause reallocation of the electron flux and the protonmotive force (Δp) in a way that decreases ATP synthesis efficiency, elevates the relative cost of the mitochondrial maintenance, causes excessive production of reactive oxygen species (ROS) and raises energy cost for antioxidant defense. These shifts in the mitochondrial energy economy might have negative consequences for the organismal fitness traits such as the thermal tolerance or growth. Correlation between the thermal sensitivity indices of the mitochondria and the whole organism indicate that these traits experience similar selective pressures but further investigations are needed to establish whether there is a cause-effect relationship between the mitochondrial failure and loss of organismal performance during temperature change.}, } @article {pmid36748090, year = {2023}, author = {Zhang, Y and Li, W and Bian, Y and Li, Y and Cong, L}, title = {Multifaceted roles of aerobic glycolysis and oxidative phosphorylation in hepatocellular carcinoma.}, journal = {PeerJ}, volume = {11}, number = {}, pages = {e14797}, pmid = {36748090}, issn = {2167-8359}, mesh = {Humans ; *Carcinoma, Hepatocellular/metabolism ; Oxidative Phosphorylation ; *Liver Neoplasms/metabolism ; Energy Metabolism ; Glycolysis ; }, abstract = {Liver cancer is a common malignancy with high morbidity and mortality rates. Changes in liver metabolism are key factors in the development of primary hepatic carcinoma, and mitochondrial dysfunction is closely related to the occurrence and development of tumours. Accordingly, the study of the metabolic mechanism of mitochondria in primary hepatic carcinomas has gained increasing attention. A growing body of research suggests that defects in mitochondrial respiration are not generally responsible for aerobic glycolysis, nor are they typically selected during tumour evolution. Conversely, the dysfunction of mitochondrial oxidative phosphorylation (OXPHOS) may promote the proliferation, metastasis, and invasion of primary hepatic carcinoma. This review presents the current paradigm of the roles of aerobic glycolysis and OXPHOS in the occurrence and development of hepatocellular carcinoma (HCC). Mitochondrial OXPHOS and cytoplasmic glycolysis cooperate to maintain the energy balance in HCC cells. Our study provides evidence for the targeting of mitochondrial metabolism as a potential therapy for HCC.}, } @article {pmid36646908, year = {2023}, author = {Muñoz-Gómez, SA}, title = {Energetics and evolution of anaerobic microbial eukaryotes.}, journal = {Nature microbiology}, volume = {}, number = {}, pages = {}, pmid = {36646908}, issn = {2058-5276}, abstract = {Mitochondria and aerobic respiration have been suggested to be required for the evolution of eukaryotic cell complexity. Aerobic respiration is several times more energetically efficient than fermentation. Moreover, aerobic respiration occurs at internalized mitochondrial membranes that are not constrained by a sublinear scaling with cell volume. However, diverse and complex anaerobic eukaryotes (for example, free-living and parasitic unicellular, and even small multicellular, eukaryotes) that exclusively rely on fermentation for energy generation have evolved repeatedly from aerobic ancestors. How do fermenting eukaryotes maintain their cell volumes and complexity while relying on such a low energy-yielding process? Here I propose that reduced rates of ATP generation in fermenting versus respiring eukaryotes are compensated for by longer cell cycles that satisfy lifetime energy demands. A literature survey and growth efficiency calculations show that fermenting eukaryotes divide approximately four to six times slower than aerobically respiring counterparts with similar cell volumes. Although ecological advantages such as competition avoidance offset lower growth rates and yields in the short term, fermenting eukaryotes inevitably have fewer physiological and ecological possibilities, which ultimately constrain their long-term evolutionary trajectories.}, } @article {pmid36634192, year = {2023}, author = {Osipova, E and Barsacchi, R and Brown, T and Sadanandan, K and Gaede, AH and Monte, A and Jarrells, J and Moebius, C and Pippel, M and Altshuler, DL and Winkler, S and Bickle, M and Baldwin, MW and Hiller, M}, title = {Loss of a gluconeogenic muscle enzyme contributed to adaptive metabolic traits in hummingbirds.}, journal = {Science (New York, N.Y.)}, volume = {379}, number = {6628}, pages = {185-190}, doi = {10.1126/science.abn7050}, pmid = {36634192}, issn = {1095-9203}, mesh = {Animals ; *Flight, Animal/physiology ; *Gluconeogenesis/genetics ; Birds/genetics ; Muscles ; Energy Metabolism ; }, abstract = {Hummingbirds possess distinct metabolic adaptations to fuel their energy-demanding hovering flight, but the underlying genomic changes are largely unknown. Here, we generated a chromosome-level genome assembly of the long-tailed hermit and screened for genes that have been specifically inactivated in the ancestral hummingbird lineage. We discovered that FBP2 (fructose-bisphosphatase 2), which encodes a gluconeogenic muscle enzyme, was lost during a time period when hovering flight evolved. We show that FBP2 knockdown in an avian muscle cell line up-regulates glycolysis and enhances mitochondrial respiration, coincident with an increased mitochondria number. Furthermore, genes involved in mitochondrial respiration and organization have up-regulated expression in hummingbird flight muscle. Together, these results suggest that FBP2 loss was likely a key step in the evolution of metabolic muscle adaptations required for true hovering flight.}, } @article {pmid36545736, year = {2022}, author = {He, L and Maheshwari, A}, title = {Mitochondria in Early Life.}, journal = {Current pediatric reviews}, volume = {}, number = {}, pages = {}, doi = {10.2174/1573396319666221221110728}, pmid = {36545736}, issn = {1875-6336}, abstract = {Mitochondria are highly-dynamic, membrane-bound organelles that generate most of the chemical energy needed to power the biochemical reactions in eukaryotic cells. These organelles also communicate with the nucleus and other cellular structures to help maintain somatic homeostasis, allow cellular adaptation to stress, and help maintain the developmental trajectory. Mitochondria also perform numerous other functions to support metabolic, energetic, and epigenetic regulation in our cells. There is increasing information on various disorders caused by defects in intrinsic mitochondrial or supporting nuclear genes in different organ systems. In this review, we have summarized the ultrastructural morphology, structural components, our current understanding of the evolution, biogenesis, dynamics, function, clinical manifestations of mitochondrial dysfunction, and future possibilities. The implications of deficits in mitochondrial dynamics and signaling for embryo viability and offspring health are also explored. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus.}, } @article {pmid36523555, year = {2022}, author = {Hogg, DW and Reid, AL and Dodsworth, TL and Chen, Y and Reid, RM and Xu, M and Husic, M and Biga, PR and Slee, A and Buck, LT and Barsyte-Lovejoy, D and Locke, M and Lovejoy, DA}, title = {Skeletal muscle metabolism and contraction performance regulation by teneurin C-terminal-associated peptide-1.}, journal = {Frontiers in physiology}, volume = {13}, number = {}, pages = {1031264}, pmid = {36523555}, issn = {1664-042X}, abstract = {Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism in rats. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 in the C2C12 mouse skeletal cell line shows that TCAP stimulates an LPHN-dependent cytosolic Ca[2+] signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism that regulates the energy requirements and performance of skeletal muscle.}, } @article {pmid36373631, year = {2022}, author = {Mencía, M}, title = {Acid digestion and symbiont: Proton sharing at the origin of mitochondriogenesis?: Proton production by a symbiotic bacterium may have been the origin of two hallmark eukaryotic features, acid digestion and mitochondria: Proton production by a symbiotic bacterium may have been the origin of two hallmark eukaryotic features, acid digestion and mitochondria.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {}, number = {}, pages = {e2200136}, doi = {10.1002/bies.202200136}, pmid = {36373631}, issn = {1521-1878}, abstract = {The initial relationships between organisms leading to endosymbiosis and the first eukaryote are currently a topic of hot debate. Here, I present a theory that offers a gradual scenario in which the origins of phagocytosis and mitochondria are intertwined in such a way that the evolution of one would not be possible without the other. In this scenario, the premitochondrial bacterial symbiont became initially associated with a protophagocytic host on the basis of cooperation to kill prey with symbiont-produced toxins and reactive oxygen species (ROS). Subsequently, the cooperation was focused on the digestion stage, through the acidification of the protophagocytic cavities via exportation of protons produced by the aerobic respiration of the symbiont. The host gained an improved phagocytic capacity and the symbiont received organic compounds from prey. As the host gradually lost its membrane energetics to develop lysosomal digestion, respiration was centralized in the premitochondrial symbiont for energy production for the consortium.}, } @article {pmid36355038, year = {2022}, author = {Raval, PK and Garg, SG and Gould, SB}, title = {Endosymbiotic selective pressure at the origin of eukaryotic cell biology.}, journal = {eLife}, volume = {11}, number = {}, pages = {}, pmid = {36355038}, issn = {2050-084X}, mesh = {*Eukaryotic Cells/physiology ; *Symbiosis/genetics ; Biological Evolution ; Eukaryota/genetics ; Archaea/genetics ; Cell Nucleus ; Meiosis ; Biology ; Phylogeny ; }, abstract = {The dichotomy that separates prokaryotic from eukaryotic cells runs deep. The transition from pro- to eukaryote evolution is poorly understood due to a lack of reliable intermediate forms and definitions regarding the nature of the first host that could no longer be considered a prokaryote, the first eukaryotic common ancestor, FECA. The last eukaryotic common ancestor, LECA, was a complex cell that united all traits characterising eukaryotic biology including a mitochondrion. The role of the endosymbiotic organelle in this radical transition towards complex life forms is, however, sometimes questioned. In particular the discovery of the asgard archaea has stimulated discussions regarding the pre-endosymbiotic complexity of FECA. Here we review differences and similarities among models that view eukaryotic traits as isolated coincidental events in asgard archaeal evolution or, on the contrary, as a result of and in response to endosymbiosis. Inspecting eukaryotic traits from the perspective of the endosymbiont uncovers that eukaryotic cell biology can be explained as having evolved as a solution to housing a semi-autonomous organelle and why the addition of another endosymbiont, the plastid, added no extra compartments. Mitochondria provided the selective pressures for the origin (and continued maintenance) of eukaryotic cell complexity. Moreover, they also provided the energetic benefit throughout eukaryogenesis for evolving thousands of gene families unique to eukaryotes. Hence, a synthesis of the current data lets us conclude that traits such as the Golgi apparatus, the nucleus, autophagosomes, and meiosis and sex evolved as a response to the selective pressures an endosymbiont imposes.}, } @article {pmid36324074, year = {2022}, author = {Zhao, B and Gao, S and Zhao, M and Lv, H and Song, J and Wang, H and Zeng, Q and Liu, J}, title = {Mitochondrial genomic analyses provide new insights into the "missing" atp8 and adaptive evolution of Mytilidae.}, journal = {BMC genomics}, volume = {23}, number = {1}, pages = {738}, pmid = {36324074}, issn = {1471-2164}, mesh = {Animals ; *Genome, Mitochondrial ; *Mytilidae/genetics ; Phylogeny ; Genes, Mitochondrial ; Mitochondrial Proton-Translocating ATPases/genetics ; Genomics/methods ; }, abstract = {BACKGROUND: Mytilidae, also known as marine mussels, are widely distributed in the oceans worldwide. Members of Mytilidae show a tremendous range of ecological adaptions, from the species distributed in freshwater to those that inhabit in deep-sea. Mitochondria play an important role in energy metabolism, which might contribute to the adaptation of Mytilidae to different environments. In addition, some bivalve species are thought to lack the mitochondrial protein-coding gene ATP synthase F0 subunit 8. Increasing studies indicated that the absence of atp8 may be caused by annotation difficulties for atp8 gene is characterized by highly divergent, variable length.

RESULTS: In this study, the complete mitochondrial genomes of three marine mussels (Xenostrobus securis, Bathymodiolus puteoserpentis, Gigantidas vrijenhoeki) were newly assembled, with the lengths of 14,972 bp, 20,482, and 17,786 bp, respectively. We annotated atp8 in the sequences that we assembled and the sequences lacking atp8. The newly annotated atp8 sequences all have one predicted transmembrane domain, a similar hydropathy profile, as well as the C-terminal region with positively charged amino acids. Furthermore, we reconstructed the phylogenetic trees and performed positive selection analysis. The results showed that the deep-sea bathymodiolines experienced more relaxed evolutionary constraints. And signatures of positive selection were detected in nad4 of Limnoperna fortunei, which may contribute to the survival and/or thriving of this species in freshwater.

CONCLUSIONS: Our analysis supported that atp8 may not be missing in the Mytilidae. And our results provided evidence that the mitochondrial genes may contribute to the adaptation of Mytilidae to different environments.}, } @article {pmid35920046, year = {2022}, author = {Paulino, MG and Rossi, PA and Venturini, FP and Tavares, D and Sakuragui, MM and Moraes, G and Terezan, AP and Fernandes, JB and Giani, A and Fernandes, MN}, title = {Liver dysfunction and energy storage mobilization in traíra, Hoplias malabaricus (Teleostei, Erythrinidae) induced by subchronic exposure to toxic cyanobacterial crude extract.}, journal = {Environmental toxicology}, volume = {37}, number = {11}, pages = {2683-2691}, doi = {10.1002/tox.23628}, pmid = {35920046}, issn = {1522-7278}, mesh = {Acid Phosphatase/metabolism ; Alanine Transaminase/metabolism ; Alkaline Phosphatase/metabolism ; Ammonia ; Animals ; Aspartate Aminotransferases/metabolism ; Bilirubin/metabolism ; *Characiformes ; Complex Mixtures/metabolism/toxicity ; *Cyanobacteria/metabolism ; Glucose/metabolism ; Glycogen/metabolism ; Lactates ; Lipids ; Liver/metabolism ; *Liver Diseases/metabolism ; Microcystins/metabolism/toxicity ; Pyruvates/metabolism ; }, abstract = {Microcystins (MC) are hepatotoxic for organisms. Liver MC accumulation and structural change are intensely studied, but the functional hepatic enzymes and energy metabolism have received little attention. This study investigated the liver and hepatocyte structures and the activity of key hepatic functional enzymes with emphasis on energetic metabolism changes after subchronic fish exposure to cyanobacterial crude extract (CE) containing MC. The Neotropical erythrinid fish, Hoplias malabaricus, were exposed intraperitoneally to CE containing 100 μg MC-LR eq kg[-1] for 30 days and, thereafter, the plasma, liver, and white muscle was sampled for analyses. Liver tissue lost cellular structure organization showing round hepatocytes, hyperemia, and biliary duct obstruction. At the ultrastructural level, the mitochondria and the endoplasmic reticulum exhibited disorganization. Direct and total bilirubin increased in plasma. In the liver, the activity of acid phosphatase (ACP) increased, and the aspartate aminotransferase (AST) decreased; AST increased in plasma. Alkaline phosphatase (ALP) and alanine aminotransferase (ALT) were unchanged in the liver, muscle, and plasma. Glycogen stores and the energetic metabolites as glucose, lactate, and pyruvate decrease in the liver; pyruvate decreased in plasma and lactate decreased in muscle. Ammonia levels increased and protein concentration decreased in plasma. CE alters liver morphology by causing hepatocyte intracellular disorder, obstructive cholestasis, and dysfunction in the activity of key liver enzymes. The increasing energy demand implies glucose mobilization and metabolic adjustments maintaining protein preservation and lipid recruitment to supply the needs for detoxification allowing fish survival.}, } @article {pmid35915152, year = {2022}, author = {Schavemaker, PE and Muñoz-Gómez, SA}, title = {The role of mitochondrial energetics in the origin and diversification of eukaryotes.}, journal = {Nature ecology & evolution}, volume = {6}, number = {9}, pages = {1307-1317}, pmid = {35915152}, issn = {2397-334X}, support = {R35 GM122566/GM/NIGMS NIH HHS/United States ; }, mesh = {*Biological Evolution ; DNA ; *Eukaryota/genetics ; Mitochondria/genetics/metabolism ; Prokaryotic Cells/metabolism ; }, abstract = {The origin of eukaryotic cell size and complexity is often thought to have required an energy excess supplied by mitochondria. Recent observations show energy demands to scale continuously with cell volume, suggesting that eukaryotes do not have higher energetic capacity. However, respiratory membrane area scales superlinearly with the cell surface area. Furthermore, the consequences of the contrasting genomic architectures between prokaryotes and eukaryotes have not been precisely quantified. Here, we investigated (1) the factors that affect the volumes at which prokaryotes become surface area-constrained, (2) the amount of energy divested to DNA due to contrasting genomic architectures and (3) the costs and benefits of respiring symbionts. Our analyses suggest that prokaryotes are not surface area-constrained at volumes of 10[0]‒10[3] µm[3], the genomic architecture of extant eukaryotes is only slightly advantageous at genomes sizes of 10[6]‒10[7] base pairs and a larger host cell may have derived a greater advantage (lower cost) from harbouring ATP-producing symbionts. This suggests that eukaryotes first evolved without the need for mitochondria since these ranges hypothetically encompass the last eukaryotic common ancestor and its relatives. Our analyses also show that larger and faster-dividing prokaryotes would have a shortage of respiratory membrane area and divest more energy into DNA. Thus, we argue that although mitochondria may not have been required by the first eukaryotes, eukaryote diversification was ultimately dependent on mitochondria.}, } @article {pmid35866365, year = {2022}, author = {McCall, CE and Zhu, X and Zabalawi, M and Long, D and Quinn, MA and Yoza, BK and Stacpoole, PW and Vachharajani, V}, title = {Sepsis, pyruvate, and mitochondria energy supply chain shortage.}, journal = {Journal of leukocyte biology}, volume = {112}, number = {6}, pages = {1509-1514}, doi = {10.1002/JLB.3MR0322-692RR}, pmid = {35866365}, issn = {1938-3673}, mesh = {Mice ; Humans ; Animals ; *Pyruvic Acid/metabolism ; Pyruvate Dehydrogenase Complex/metabolism ; *Sepsis ; Mitochondria/metabolism ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase ; Acetates/pharmacology ; }, abstract = {Balancing high energy-consuming danger resistance and low energy supply of disease tolerance is a universal survival principle that often fails during sepsis. Our research supports the concept that sepsis phosphorylates and deactivates mitochondrial pyruvate dehydrogenase complex control over the tricarboxylic cycle and the electron transport chain. StimulatIng mitochondrial energetics in septic mice and human sepsis cell models can be achieved by inhibiting pyruvate dehydrogenase kinases with the pyruvate structural analog dichloroacetate. Stimulating the pyruvate dehydrogenase complex by dichloroacetate reverses a disruption in the tricarboxylic cycle that induces itaconate, a key mediator of the disease tolerance pathway. Dichloroacetate treatment increases mitochondrial respiration and ATP synthesis, decreases oxidant stress, overcomes metabolic paralysis, regenerates tissue, organ, and innate and adaptive immune cells, and doubles the survival rate in a murine model of sepsis.}, } @article {pmid35409376, year = {2022}, author = {Kasperski, A}, title = {Life Entrapped in a Network of Atavistic Attractors: How to Find a Rescue.}, journal = {International journal of molecular sciences}, volume = {23}, number = {7}, pages = {}, pmid = {35409376}, issn = {1422-0067}, mesh = {Cell Physiological Phenomena ; Cell Transformation, Neoplastic/metabolism ; *Energy Metabolism ; Humans ; Mitochondria/metabolism ; *Neoplasms/metabolism ; }, abstract = {In view of unified cell bioenergetics, cell bioenergetic problems related to cell overenergization can cause excessive disturbances in current cell fate and, as a result, lead to a change of cell-fate. At the onset of the problem, cell overenergization of multicellular organisms (especially overenergization of mitochondria) is solved inter alia by activation and then stimulation of the reversible Crabtree effect by cells. Unfortunately, this apparently good solution can also lead to a much bigger problem when, despite the activation of the Crabtree effect, cell overenergization persists for a long time. In such a case, cancer transformation, along with the Warburg effect, may occur to further reduce or stop the charging of mitochondria by high-energy molecules. Understanding the phenomena of cancer transformation and cancer development has become a real challenge for humanity. To date, many models have been developed to understand cancer-related mechanisms. Nowadays, combining all these models into one coherent universal model of cancer transformation and development can be considered a new challenge. In this light, the aim of this article is to present such a potentially universal model supported by a proposed new model of cellular functionality evolution. The methods of fighting cancer resulting from unified cell bioenergetics and the two presented models are also considered.}, } @article {pmid35406135, year = {2022}, author = {Snell, TW and Carberry, J}, title = {Astaxanthin Bioactivity Is Determined by Stereoisomer Composition and Extraction Method.}, journal = {Nutrients}, volume = {14}, number = {7}, pages = {}, pmid = {35406135}, issn = {2072-6643}, mesh = {Animals ; *Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; Stereoisomerism ; *Xanthophylls/chemistry/pharmacology ; }, abstract = {Astaxanthin (ASX) is a natural product and one of the most powerful antioxidants known. It has significant effects on the metabolism of many animals, increasing fecundity, egg yolk volume, growth rates, immune responses, and disease resistance. A large part of the bioactivity of ASX is due to its targeting of mitochondria, where it inserts itself into cell membranes. Here, ASX stabilizes membranes and acts as a powerful antioxidant, protecting mitochondria from damage by reactive oxygen species (ROS). ROS are ubiquitous by-products of energy metabolism that must be tightly regulated by cells, lest they bind to and inactivate proteins, DNA and RNA, lipids, and signaling molecules. Most animals cannot synthesize ASX, so they need to acquire it in their diet. ASX is easily thermally denatured during extraction, and its high hydrophobicity limits its bioavailability. Our focus in this review is to contrast the bioactivity of different ASX stereoisomers and how extraction methods can denature ASX, compromising its bioavailability and bioactivity. We discuss the commercial sources of astaxanthin, structure of stereoisomers, relative bioavailability and bioactivity of ASX stereoisomers, mechanisms of ASX bioactivity, evolution of carotenoids, and why mitochondrial targeting makes ASX such an effective antioxidant.}, } @article {pmid35255175, year = {2022}, author = {Treidel, LA and Quintanilla Ramirez, GS and Chung, DJ and Menze, MA and Vázquez-Medina, JP and Williams, CM}, title = {Selection on dispersal drives evolution of metabolic capacities for energy production in female wing-polymorphic sand field crickets, Gryllus firmus.}, journal = {Journal of evolutionary biology}, volume = {35}, number = {4}, pages = {599-609}, pmid = {35255175}, issn = {1420-9101}, mesh = {Animals ; Energy Metabolism ; Female ; *Gryllidae/physiology ; Phenotype ; Wings, Animal/metabolism ; }, abstract = {Life history and metabolism covary, but the mechanisms and individual traits responsible for these linkages remain unresolved. Dispersal capability is a critical component of life history that is constrained by metabolic capacities for energy production. Conflicting relationships between metabolism and life histories may be explained by accounting for variation in dispersal and maximal metabolic rates. We used female wing-polymorphic sand field crickets, Gryllus firmus, selected either for long wings (LW, flight-capable) or short wings (SW, flightless) to test the hypothesis that selection on dispersal capability drives the evolution of metabolic capacities. While resting metabolic rates were similar, long-winged crickets reached higher maximal metabolic rates than short-winged crickets, resulting in improved running performance. We further provided insight into the mechanisms responsible for covariation between life history and metabolism by comparing mitochondrial content of tissues involved in powering locomotion and assessing the function of mitochondria isolated from long- and short-winged crickets. Our results demonstrated that larger metabolic capacities in long-winged crickets were underpinned by increases in mitochondrial content of dorsoventral flight muscle and enhanced bioenergetic capacities of mitochondria within the fat body, a tissue responsible for fuel storage and mobilization. Thus, selection on flight capability correlates with increases in maximal, but not resting metabolic rates, through modifications of tissues powering locomotion at the cellular and organelle levels. This allows organisms to meet high energetic demands of activity for life history. Dispersal capability should therefore explicitly be considered as a potential factor driving the evolution of metabolic capacities.}, } @article {pmid35122922, year = {2022}, author = {Baratange, C and Paris-Palacios, S and Bonnard, I and Delahaut, L and Grandjean, D and Wortham, L and Sayen, S and Gallorini, A and Michel, J and Renault, D and Breider, F and Loizeau, JL and Cosio, C}, title = {Metabolic, cellular and defense responses to single and co-exposure to carbamazepine and methylmercury in Dreissena polymorpha.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {300}, number = {}, pages = {118933}, doi = {10.1016/j.envpol.2022.118933}, pmid = {35122922}, issn = {1873-6424}, mesh = {Animals ; Carbamazepine/analysis/toxicity ; *Dreissena/metabolism ; Gills/metabolism ; *Methylmercury Compounds/metabolism/toxicity ; *Water Pollutants, Chemical/analysis ; }, abstract = {Carbamazepine (CBZ) and Hg are widespread and persistent micropollutants in aquatic environments. Both pollutants are known to trigger similar toxicity mechanisms, e.g. reactive oxygen species (ROS) production. Here, their effects were assessed in the zebra mussel Dreissena polymorpha, frequently used as a freshwater model in ecotoxicology and biomonitoring. Single and co-exposures to CBZ (3.9 μg L[-1]) and MeHg (280 ng L[-1]) were performed for 1 and 7 days. Metabolomics analyses evidenced that the co-exposure was the most disturbing after 7 days, reducing the amount of 25 metabolites involved in protein synthesis, energy metabolism, antioxidant response and osmoregulation, and significantly altering cells and organelles' structure supporting a reduction of functions of gills and digestive glands. CBZ alone after 7 days decreased the amount of α-aminobutyric acid and had a moderate effect on the structure of mitochondria in digestive glands. MeHg alone had no effect on mussels' metabolome, but caused a significant alteration of cells and organelles' structure in gills and digestive glands. Single exposures and the co-exposure increased antioxidant responses vs control in gills and digestive glands, without resulting in lipid peroxidation, suggesting an increased ROS production caused by both pollutants. Data globally supported that a higher number of hyperactive cells compensated cellular alterations in the digestive gland of mussels exposed to CBZ or MeHg alone, while CBZ + MeHg co-exposure overwhelmed this compensation after 7 days. Those effects were unpredictable based on cellular responses to CBZ and MeHg alone, highlighting the need to consider molecular toxicity pathways for a better anticipation of effects of pollutants in biota in complex environmental conditions.}, } @article {pmid35108076, year = {2022}, author = {Giannotti, D and Boscaro, V and Husnik, F and Vannini, C and Keeling, PJ}, title = {The "Other" Rickettsiales: an Overview of the Family "Candidatus Midichloriaceae".}, journal = {Applied and environmental microbiology}, volume = {88}, number = {6}, pages = {e0243221}, pmid = {35108076}, issn = {1098-5336}, mesh = {*Alphaproteobacteria/genetics ; Animals ; Bacteria ; Phylogeny ; *Rickettsiales ; Symbiosis ; }, abstract = {The family "Candidatus Midichloriaceae" constitutes the most diverse but least studied lineage within the important order of intracellular bacteria Rickettsiales. "Candidatus Midichloriaceae" endosymbionts are found in many hosts, including terrestrial arthropods, aquatic invertebrates, and protists. Representatives of the family are not documented to be pathogenic, but some are associated with diseased fish or corals. Different genera display a range of unusual features, such as full sets of flagellar genes without visible flagella or the ability to invade host mitochondria. Since studies on "Ca. Midichloriaceae" tend to focus on the host, the family is rarely addressed as a unit, and we therefore lack a coherent picture of its diversity. Here, we provide four new midichloriaceae genomes, and we survey molecular and ecological data from the entire family. Features like genome size, ecological context, and host transitions vary considerably even among closely related midichloriaceae, suggesting a high frequency of such shifts, incomplete sampling, or both. Important functional traits involved in energy metabolism, flagella, and secretion systems were independently reduced multiple times with no obvious correspondence to host or habitat, corroborating the idea that many features of these "professional symbionts" are largely independent of host identity. Finally, despite "Ca. Midichloriaceae" being predominantly studied in ticks, our analyses show that the clade is mainly aquatic, with a few terrestrial offshoots. This highlights the importance of considering aquatic hosts, and protists in particular, when reconstructing the evolution of these endosymbionts and by extension all Rickettsiales. IMPORTANCE Among endosymbiotic bacterial lineages, few are as intensely studied as Rickettsiales, which include the causative agents of spotted fever, typhus, and anaplasmosis. However, an important subgroup called "Candidatus Midichloriaceae" receives little attention despite accounting for a third of the diversity of Rickettsiales and harboring a wide range of bacteria with unique features, like the ability to infect mitochondria. Midichloriaceae are found in many hosts, from ticks to corals to unicellular protozoa, and studies on them tend to focus on the host groups. Here, for the first time since the establishment of this clade, we address the genomics, evolution, and ecology of "Ca. Midichloriaceae" as a whole, highlighting trends and patterns, the remaining gaps in our knowledge, and its importance for the understanding of symbiotic processes in intracellular bacteria.}, } @article {pmid35107193, year = {2022}, author = {Huisman, TAGM and Kralik, SF and Desai, NK and Serrallach, BL and Orman, G}, title = {Neuroimaging of primary mitochondrial disorders in children: A review.}, journal = {Journal of neuroimaging : official journal of the American Society of Neuroimaging}, volume = {32}, number = {2}, pages = {191-200}, doi = {10.1111/jon.12976}, pmid = {35107193}, issn = {1552-6569}, mesh = {Child ; Diagnosis, Differential ; Humans ; Mitochondria/metabolism ; *Mitochondrial Diseases/diagnostic imaging/genetics ; Neuroimaging/methods ; }, abstract = {Mitochondrial disorders represent a diverse and complex group of entities typified by defective energy metabolism. The mitochondrial oxidative phosphorylation system is typically impaired, which is the predominant source of energy production. Because mitochondria are present in nearly all organs, multiple systems may be affected including the central nervous system, skeletal muscles, kidneys, and liver. In particular, those organs that are metabolically active with high energy demands are explicitly vulnerable. Initial diagnostic work up relies on a detailed evaluation of clinical symptoms including physical examination as well as a comprehensive review of the evolution of symptoms over time, relation to possible "triggering" events (eg, fever, infection), blood workup, and family history. High-end neuroimaging plays a pivotal role in establishing diagnosis, narrowing differential diagnosis, monitoring disease progression, and predicting prognosis. The pattern and characteristics of the neuroimaging findings are often highly suggestive of a mitochondrial disorder; unfortunately, in many cases the wide variability of involved metabolic processes prevents a more specific subclassification. Consequently, additional diagnostic steps including muscle biopsy, metabolic workup, and genetic tests are necessary. In the current manuscript, basic concepts of energy production, genetics, and inheritance patterns are reviewed. In addition, the imaging findings of several illustrative mitochondrial disorders are presented to familiarize the involved physicians with pediatric mitochondrial disorders. In addition, the significance of spinal cord imaging and the value of "reversed image-based discovery" for the recognition and correct (re-)classification of mitochondrial disorders is discussed.}, } @article {pmid34930424, year = {2021}, author = {Kelly, S}, title = {The economics of organellar gene loss and endosymbiotic gene transfer.}, journal = {Genome biology}, volume = {22}, number = {1}, pages = {345}, pmid = {34930424}, issn = {1474-760X}, mesh = {Arabidopsis/genetics ; Bacteria/*genetics ; Cell Nucleus ; Chloroplasts ; Gene Transfer, Horizontal ; *Genome, Chloroplast ; *Genome, Mitochondrial ; Genome, Plant ; Host Microbial Interactions/genetics ; Mitochondria/genetics ; Proteomics ; Symbiosis/*genetics ; }, abstract = {BACKGROUND: The endosymbiosis of the bacterial progenitors of the mitochondrion and the chloroplast are landmark events in the evolution of life on Earth. While both organelles have retained substantial proteomic and biochemical complexity, this complexity is not reflected in the content of their genomes. Instead, the organellar genomes encode fewer than 5% of the genes found in living relatives of their ancestors. While many of the 95% of missing organellar genes have been discarded, others have been transferred to the host nuclear genome through a process known as endosymbiotic gene transfer.

RESULTS: Here, we demonstrate that the difference in the per-cell copy number of the organellar and nuclear genomes presents an energetic incentive to the cell to either delete organellar genes or transfer them to the nuclear genome. We show that, for the majority of transferred organellar genes, the energy saved by nuclear transfer exceeds the costs incurred from importing the encoded protein into the organelle where it can provide its function. Finally, we show that the net energy saved by endosymbiotic gene transfer can constitute an appreciable proportion of total cellular energy budgets and is therefore sufficient to impart a selectable advantage to the cell.

CONCLUSION: Thus, reduced cellular cost and improved energy efficiency likely played a role in the reductive evolution of mitochondrial and chloroplast genomes and the transfer of organellar genes to the nuclear genome.}, } @article {pmid34887560, year = {2021}, author = {Guberovic, I and Hurtado-Bagès, S and Rivera-Casas, C and Knobloch, G and Malinverni, R and Valero, V and Leger, MM and García, J and Basquin, J and Gómez de Cedrón, M and Frigolé-Vivas, M and Cheema, MS and Pérez, A and Ausió, J and Ramírez de Molina, A and Salvatella, X and Ruiz-Trillo, I and Eirin-Lopez, JM and Ladurner, AG and Buschbeck, M}, title = {Evolution of a histone variant involved in compartmental regulation of NAD metabolism.}, journal = {Nature structural & molecular biology}, volume = {28}, number = {12}, pages = {1009-1019}, pmid = {34887560}, issn = {1545-9985}, mesh = {Cell Nucleus/metabolism ; Chromatin/metabolism ; DNA Repair/genetics ; Energy Metabolism/*physiology ; Eukaryota/metabolism ; Histones/*genetics/*metabolism ; Humans ; NAD/*metabolism ; Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors ; }, abstract = {NAD metabolism is essential for all forms of life. Compartmental regulation of NAD[+] consumption, especially between the nucleus and the mitochondria, is required for energy homeostasis. However, how compartmental regulation evolved remains unclear. In the present study, we investigated the evolution of the macrodomain-containing histone variant macroH2A1.1, an integral chromatin component that limits nuclear NAD[+] consumption by inhibiting poly(ADP-ribose) polymerase 1 in vertebrate cells. We found that macroH2A originated in premetazoan protists. The crystal structure of the macroH2A macrodomain from the protist Capsaspora owczarzaki allowed us to identify highly conserved principles of ligand binding and pinpoint key residue substitutions, selected for during the evolution of the vertebrate stem lineage. Metabolic characterization of the Capsaspora lifecycle suggested that the metabolic function of macroH2A was associated with nonproliferative stages. Taken together, we provide insight into the evolution of a chromatin element involved in compartmental NAD regulation, relevant for understanding its metabolism and potential therapeutic applications.}, } @article {pmid34799698, year = {2021}, author = {Vowinckel, J and Hartl, J and Marx, H and Kerick, M and Runggatscher, K and Keller, MA and Mülleder, M and Day, J and Weber, M and Rinnerthaler, M and Yu, JSL and Aulakh, SK and Lehmann, A and Mattanovich, D and Timmermann, B and Zhang, N and Dunn, CD and MacRae, JI and Breitenbach, M and Ralser, M}, title = {The metabolic growth limitations of petite cells lacking the mitochondrial genome.}, journal = {Nature metabolism}, volume = {3}, number = {11}, pages = {1521-1535}, pmid = {34799698}, issn = {2522-5812}, support = {200829/WT_/Wellcome Trust/United Kingdom ; FC001134/MRC_/Medical Research Council/United Kingdom ; FC001134/ARC_/Arthritis Research UK/United Kingdom ; FC001134/CRUK_/Cancer Research UK/United Kingdom ; FC001134/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; 260809/ERC_/European Research Council/International ; }, mesh = {Amino Acids/metabolism ; Biomass ; Cell Proliferation ; Citric Acid Cycle ; *Energy Metabolism ; Fungal Proteins/chemistry/genetics/metabolism ; *Genome, Mitochondrial ; Membrane Potential, Mitochondrial ; Mitochondria/*genetics/*metabolism ; Mutation ; Phenotype ; Structure-Activity Relationship ; Yeasts/*genetics/*metabolism ; }, abstract = {Eukaryotic cells can survive the loss of their mitochondrial genome, but consequently suffer from severe growth defects. 'Petite yeasts', characterized by mitochondrial genome loss, are instrumental for studying mitochondrial function and physiology. However, the molecular cause of their reduced growth rate remains an open question. Here we show that petite cells suffer from an insufficient capacity to synthesize glutamate, glutamine, leucine and arginine, negatively impacting their growth. Using a combination of molecular genetics and omics approaches, we demonstrate the evolution of fast growth overcomes these amino acid deficiencies, by alleviating a perturbation in mitochondrial iron metabolism and by restoring a defect in the mitochondrial tricarboxylic acid cycle, caused by aconitase inhibition. Our results hence explain the slow growth of mitochondrial genome-deficient cells with a partial auxotrophy in four amino acids that results from distorted iron metabolism and an inhibited tricarboxylic acid cycle.}, } @article {pmid34547233, year = {2021}, author = {Trefts, E and Shaw, RJ}, title = {AMPK: restoring metabolic homeostasis over space and time.}, journal = {Molecular cell}, volume = {81}, number = {18}, pages = {3677-3690}, pmid = {34547233}, issn = {1097-4164}, support = {R01 DK080425/DK/NIDDK NIH HHS/United States ; R01 CA234047/CA/NCI NIH HHS/United States ; R35 CA220538/CA/NCI NIH HHS/United States ; F32 DK126418/DK/NIDDK NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; P01 CA120964/CA/NCI NIH HHS/United States ; R01 CA172229/CA/NCI NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases/genetics/*metabolism ; Animals ; Cytoplasm/metabolism ; Energy Metabolism ; Homeostasis ; Humans ; Mitochondria/metabolism ; Protein Domains ; Signal Transduction ; Structure-Activity Relationship ; }, abstract = {The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies.}, } @article {pmid34418213, year = {2021}, author = {Jakovlić, I and Zou, H and Chen, JH and Lei, HP and Wang, GT and Liu, J and Zhang, D}, title = {Slow crabs - fast genomes: Locomotory capacity predicts skew magnitude in crustacean mitogenomes.}, journal = {Molecular ecology}, volume = {30}, number = {21}, pages = {5488-5502}, doi = {10.1111/mec.16138}, pmid = {34418213}, issn = {1365-294X}, mesh = {Animals ; Base Composition ; *Brachyura ; Evolution, Molecular ; *Genome, Mitochondrial/genetics ; Mutation ; Phylogeny ; }, abstract = {Base composition skews (G-C/G+C) of mitochondrial genomes are believed to be primarily driven by mutational pressure, which is positively correlated with metabolic rate. In marine animals, metabolic rate is also positively correlated with locomotory capacity. Given the central role of mitochondria in energy metabolism, we hypothesised that selection for locomotory capacity should be positively correlated with the strength of purifying selection (dN/dS), and thus be negatively correlated with the skew magnitude. Therefore, these two models assume diametrically opposite associations between the metabolic rate and skew magnitude: positive correlation in the prevailing paradigm, and negative in our working hypothesis. We examined correlations between the skew magnitude, metabolic rate, locomotory capacity, and several other variables previously associated with mitochondrial evolution on 287 crustacean mitogenomes. Weakly locomotory taxa had higher skew magnitude and ω (dN/dS) values, but not the gene order rearrangement rate. Skew and ω magnitudes were correlated. Multilevel regression analyses indicated that three competing variables, body size, gene order rearrangement rate, and effective population size, had negligible impacts on the skew magnitude. In most crustacean lineages selection for locomotory capacity appears to be the primary factor determining the skew magnitude. Contrary to the prevailing paradigm, this implies that adaptive selection outweighs nonadaptive selection (mutation pressure) in crustaceans. However, we found indications that effective population size (nonadaptive factor) may outweigh the impact of locomotory capacity in sessile crustaceans (Thecostraca). In conclusion, skew magnitude is a product of the interplay between adaptive and nonadaptive factors, the balance of which varies among lineages.}, } @article {pmid34384891, year = {2021}, author = {Aboouf, MA and Armbruster, J and Thiersch, M and Gassmann, M and Gödecke, A and Gnaiger, E and Kristiansen, G and Bicker, A and Hankeln, T and Zhu, H and Gorr, TA}, title = {Myoglobin, expressed in brown adipose tissue of mice, regulates the content and activity of mitochondria and lipid droplets.}, journal = {Biochimica et biophysica acta. Molecular and cell biology of lipids}, volume = {1866}, number = {12}, pages = {159026}, doi = {10.1016/j.bbalip.2021.159026}, pmid = {34384891}, issn = {1879-2618}, mesh = {Adipocytes, Brown/metabolism ; Adipose Tissue, Brown/metabolism ; Animals ; Apoptosis Regulatory Proteins/genetics ; Disease Models, Animal ; Energy Metabolism/genetics ; Humans ; Lipid Droplets/*metabolism ; Mice ; Mice, Knockout ; Mitochondria/genetics/*metabolism ; Muscle, Skeletal/metabolism ; Myoglobin/*genetics/metabolism ; Oxygen/*metabolism ; PPAR alpha/genetics ; Palmitates/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics ; Proteins/genetics ; Thermogenesis/genetics ; Uncoupling Protein 1/genetics ; }, abstract = {The identification of novel physiological regulators that stimulate energy expenditure through brown adipose tissue (BAT) activity in substrate catalysis is of utmost importance to understand and treat metabolic diseases. Myoglobin (MB), known to store or transport oxygen in heart and skeletal muscles, has recently been found to bind fatty acids with physiological constants in its oxygenated form (i.e., MBO2). Here, we investigated the in vivo effect of MB expression on BAT activity. In particular, we studied mitochondrial function and lipid metabolism as essential determinants of energy expenditure in this tissue. We show in a MB-null (MBko) mouse model that MB expression in BAT impacts on the activity of brown adipocytes in a twofold manner: i) by elevating mitochondrial density plus maximal respiration capacity, and through that, by stimulating BAT oxidative metabolism along with the organelles` uncoupled respiration; and ii) by influencing the free fatty acids pool towards a palmitate-enriched composition and shifting the lipid droplet (LD) equilibrium towards higher counts of smaller droplets. These metabolic changes were accompanied by the up-regulated expression of thermogenesis markers UCP1, CIDEA, CIDEC, PGC1-α and PPAR-α in the BAT of MB wildtype (MBwt) mice. Along with the emergence of the "browning" BAT morphology, MBwt mice exhibited a leaner phenotype when compared to MBko littermates at 20 weeks of age. Our data shed novel insights into MB's role in linking oxygen and lipid-based thermogenic metabolism. The findings suggest potential new strategies of targeting the MB pathway to treat metabolic disorders related to diminishing energy expenditure.}, } @article {pmid34378417, year = {2021}, author = {Yap, KN and Zhang, Y}, title = {Revisiting the question of nucleated versus enucleated erythrocytes in birds and mammals.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {321}, number = {4}, pages = {R547-R557}, doi = {10.1152/ajpregu.00276.2020}, pmid = {34378417}, issn = {1522-1490}, mesh = {Animals ; *Biological Evolution ; Birds/*blood ; Cell Size ; *Energy Metabolism ; Erythroblasts/*metabolism ; Erythrocytes/*metabolism ; Hemoglobins/metabolism ; Organelles/*physiology ; Oxidative Stress ; Phylogeny ; Species Specificity ; }, abstract = {Erythrocyte enucleation is thought to have evolved in mammals to support their energetic cost of high metabolic activities. However, birds face similar selection pressure yet possess nucleated erythrocytes. Current hypotheses on the mammalian erythrocyte enucleation claim that the absence of cell organelles allows erythrocytes to 1) pack more hemoglobin into the cells to increase oxygen carrying capacity and 2) decrease erythrocyte size for increased surface area-to-volume ratio, and improved ability to traverse small capillaries. In this article, we first empirically tested current hypotheses using both conventional and phylogenetically informed analysis comparing literature values of mean cell hemoglobin concentration (MCHC) and mean cell volume (MCV) between 181 avian and 194 mammalian species. We found no difference in MCHC levels between birds and mammals using both conventional and phylogenetically corrected analysis. MCV was higher in birds than mammals according to conventional analysis, but the difference was lost when we controlled for phylogeny. These results suggested that avian and mammalian erythrocytes may employ different strategies to solve a common problem. To further investigate existing hypotheses or develop new hypothesis, we need to understand the functions of various organelles in avian erythrocytes. Consequently, we covered potential physiological functions of various cell organelles in avian erythrocytes based on current knowledge, while making explicit comparisons with their mammalian counterparts. Finally, we proposed by taking an integrative and comparative approach, using tools from molecular biology to evolutionary biology, would allow us to better understand the fundamental physiological functions of various components of avian and mammalian erythrocytes.}, } @article {pmid34188831, year = {2021}, author = {Yang, M and Dong, D and Li, X}, title = {The complete mitogenome of Phymorhynchus sp. (Neogastropoda, Conoidea, Raphitomidae) provides insights into the deep-sea adaptive evolution of Conoidea.}, journal = {Ecology and evolution}, volume = {11}, number = {12}, pages = {7518-7531}, pmid = {34188831}, issn = {2045-7758}, abstract = {The deep-sea environment is characterized by darkness, hypoxia, and high hydrostatic pressure. Mitochondria play a vital role in energy metabolism; thus, they may endure the selection process during the adaptive evolution of deep-sea organisms. In the present study, the mitogenome of Phymorhynchus sp. from the Haima methane seep was completely assembled and characterized. This mitogenome is 16,681 bp in length and contains 13 protein-coding genes, 2 rRNAs, and 22 tRNAs. The gene order and orientation were identical to those of most sequenced conoidean gastropods. Some special elements, such as tandem repeat sequences and AT-rich sequences, which are involved in the regulation of the replication and transcription of the mitogenome, were observed in the control region. Phylogenetic analysis revealed that Conoidea is divided into two separate clades with high nodal support. Positive selection analysis revealed evidence of adaptive changes in the mitogenomes of deep-sea conoidean gastropods. Eight residues located in atp6, cox1, cytb, nad1, nad4, and nad5 were determined to have undergone positive selection. This study explores the adaptive evolution of deep-sea conoidean gastropods and provides valuable clues at the mitochondrial level regarding the exceptional adaptive ability of organisms in deep-sea environments.}, } @article {pmid34118265, year = {2021}, author = {Manoj, KM and Bazhin, NM}, title = {The murburn precepts for aerobic respiration and redox homeostasis.}, journal = {Progress in biophysics and molecular biology}, volume = {167}, number = {}, pages = {104-120}, doi = {10.1016/j.pbiomolbio.2021.05.010}, pmid = {34118265}, issn = {1873-1732}, mesh = {*Adenosine Triphosphate/metabolism ; *Cell Respiration ; Energy Metabolism ; Homeostasis ; Oxidation-Reduction ; Oxidative Phosphorylation ; Respiration ; }, abstract = {Murburn concept is a new perspective to metabolism which posits that certain redox enzymes/proteins mediate catalysis outside their active site, via diffusible reactive oxygen species (DROS, usually deemed as toxic wastes). We have recently questioned the proton-centric chemiosmotic rotary ATP synthesis (CRAS) explanation for mitochondrial oxidative phosphorylation (mOxPhos) and proposed an oxygen-centric murburn model in lieu. Herein, the chemical equations and thermodynamic foundations for this new model of mOxPhos are detailed. Standard transformed Gibbs free energy values of respiratory reactions are calculated to address the spontaneity, control, and efficiency of oxidative phosphorylation. Unlike the deterministic/multi-molecular and 'irreducibly complex' CRAS model, the stochastic/bimolecular and parsimonious murburn reactions afford a more viable precept for the variable and non-integral stoichiometry, higher yield for NADH than FADH2, and origin/evolution of oxygen-centric cellular life. Also, we present tangible DROS-based explanations for the multiple roles of various reaction components, HCN > H2S order of cellular toxicity in aerobes, and explain why oxygen inhibits anaerobes. We highlight the thermodynamic significance of proton deficiency in NADH/mitochondria and link the 'oxygen → DROS → water' metabolic pathway to the macroscopic physiologies of ATP-synthesis, trans-membrane potential, thermogenesis, and homeostasis. We also provide arguments for the extension of the murburn bioenergetics model to life under anoxic and extreme/unique habitats. In the context of mOxPhos, our findings imply that DROS should be seen as an essential requisite for life, and not merely as pathophysiological manifestations.}, } @article {pmid34098144, year = {2021}, author = {Spinelli, S and Begani, G and Guida, L and Magnone, M and Galante, D and D'Arrigo, C and Scotti, C and Iamele, L and De Jonge, H and Zocchi, E and Sturla, L}, title = {LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway.}, journal = {Molecular metabolism}, volume = {53}, number = {}, pages = {101263}, pmid = {34098144}, issn = {2212-8778}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Abscisic Acid/*metabolism ; Glucose/metabolism ; HeLa Cells ; Humans ; Mitochondria/metabolism ; Muscle, Skeletal/cytology/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism ; Receptors, G-Protein-Coupled/genetics/*metabolism ; Sirtuin 1/*metabolism ; }, abstract = {OBJECTIVE: Abscisic acid (ABA) is a plant hormone also present and active in animals. In mammals, ABA regulates blood glucose levels by stimulating insulin-independent glucose uptake and metabolism in adipocytes and myocytes through its receptor LANCL2. The objective of this study was to investigate whether another member of the LANCL protein family, LANCL1, also behaves as an ABA receptor and, if so, which functional effects are mediated by LANCL1.

METHODS: ABA binding to human recombinant LANCL1 was explored by equilibrium-binding experiments with [[3]H]ABA, circular dichroism, and surface plasmon resonance. Rat L6 myoblasts overexpressing either LANCL1 or LANCL2, or silenced for the expression of both proteins, were used to investigate the basal and ABA-stimulated transport of a fluorescent glucose analog (NBDG) and the signaling pathway downstream of the LANCL proteins using Western blot and qPCR analysis. Finally, glucose tolerance and sensitivity to ABA were compared in LANCL2[-/-] and wild-type (WT) siblings.

RESULTS: Human recombinant LANCL1 binds ABA with a Kd between 1 and 10 μM, depending on the assay (i.e., in a concentration range that lies between the low and high-affinity ABA binding sites of LANCL2). In L6 myoblasts, LANCL1 and LANCL2 similarly, i) stimulate both basal and ABA-triggered NBDG uptake (4-fold), ii) activate the transcription and protein expression of the glucose transporters GLUT4 and GLUT1 (4-6-fold) and the signaling proteins AMPK/PGC-1α/Sirt1 (2-fold), iii) stimulate mitochondrial respiration (5-fold) and the expression of the skeletal muscle (SM) uncoupling proteins sarcolipin (3-fold) and UCP3 (12-fold). LANCL2[-/-] mice have a reduced glucose tolerance compared to WT. They spontaneously overexpress LANCL1 in the SM and respond to chronic ABA treatment (1 μg/kg body weight/day) with an improved glycemia response to glucose load and an increased SM transcription of GLUT4 and GLUT1 (20-fold) of the AMPK/PGC-1α/Sirt1 pathway and sarcolipin, UCP3, and NAMPT (4- to 6-fold).

CONCLUSIONS: LANCL1 behaves as an ABA receptor with a somewhat lower affinity for ABA than LANCL2 but with overlapping effector functions: stimulating glucose uptake and the expression of muscle glucose transporters and mitochondrial uncoupling and respiration via the AMPK/PGC-1α/Sirt1 pathway. Receptor redundancy may have been advantageous in animal evolution, given the role of the ABA/LANCL system in the insulin-independent stimulation of cell glucose uptake and energy metabolism.}, } @article {pmid33974849, year = {2021}, author = {Mathur, V and Wakeman, KC and Keeling, PJ}, title = {Parallel functional reduction in the mitochondria of apicomplexan parasites.}, journal = {Current biology : CB}, volume = {31}, number = {13}, pages = {2920-2928.e4}, doi = {10.1016/j.cub.2021.04.028}, pmid = {33974849}, issn = {1879-0445}, mesh = {Animals ; Energy Metabolism ; Genome, Mitochondrial ; Mitochondria/genetics/*metabolism ; Parasites/*cytology/genetics/*metabolism ; *Phylogeny ; Toxoplasma ; }, abstract = {Gregarines are an early-diverging lineage of apicomplexan parasites that hold many clues into the origin and evolution of the group, a remarkable transition from free-living phototrophic algae into obligate parasites of animals.[1] Using single-cell transcriptomics targeting understudied lineages to complement available sequencing data, we characterized the mitochondrial metabolic repertoire across the tree of apicomplexans. In contrast to the large suite of proteins involved in aerobic respiration in well-studied parasites like Toxoplasma or Plasmodium,[2] we find that gregarine trophozoites have significantly reduced energy metabolism: most lack respiratory complexes III and IV, and some lack the electron transport chains (ETCs) and tricarboxylic acid (TCA) cycle entirely. Phylogenomic analyses show that these reductions took place several times in parallel, resulting in a functional range from fully aerobic organelles to extremely reduced "mitosomes" restricted to Fe-S cluster biosynthesis. The mitochondrial genome has also been lost repeatedly: in species with severe functional reduction simply by gene loss but in one species with a complete ETC by relocating cox1 to the nuclear genome. Severe functional reduction of mitochondria is generally associated with structural reduction, resulting in small, nondescript mitochondrial-related organelles (MROs).[3] By contrast, gregarines retain distinctive mitochondria with tubular cristae, even the most functionally reduced cases that also lack genes associated with cristae formation. Overall, the parallel, severe reduction of gregarine mitochondria expands the diversity of organisms that contain MROs and further emphasizes the role of parallel transitions in apicomplexan evolution.}, } @article {pmid33863338, year = {2021}, author = {Salomaki, ED and Terpis, KX and Rueckert, S and Kotyk, M and Varadínová, ZK and Čepička, I and Lane, CE and Kolisko, M}, title = {Gregarine single-cell transcriptomics reveals differential mitochondrial remodeling and adaptation in apicomplexans.}, journal = {BMC biology}, volume = {19}, number = {1}, pages = {77}, pmid = {33863338}, issn = {1741-7007}, mesh = {Animals ; *Apicomplexa/genetics ; Humans ; *Mitochondria/genetics ; Phylogeny ; Single-Cell Analysis ; Transcriptome ; }, abstract = {BACKGROUND: Apicomplexa is a diverse phylum comprising unicellular endobiotic animal parasites and contains some of the most well-studied microbial eukaryotes including the devastating human pathogens Plasmodium falciparum and Cryptosporidium hominis. In contrast, data on the invertebrate-infecting gregarines remains sparse and their evolutionary relationship to other apicomplexans remains obscure. Most apicomplexans retain a highly modified plastid, while their mitochondria remain metabolically conserved. Cryptosporidium spp. inhabit an anaerobic host-gut environment and represent the known exception, having completely lost their plastid while retaining an extremely reduced mitochondrion that has lost its genome. Recent advances in single-cell sequencing have enabled the first broad genome-scale explorations of gregarines, providing evidence of differential plastid retention throughout the group. However, little is known about the retention and metabolic capacity of gregarine mitochondria.

RESULTS: Here, we sequenced transcriptomes from five species of gregarines isolated from cockroaches. We combined these data with those from other apicomplexans, performed detailed phylogenomic analyses, and characterized their mitochondrial metabolism. Our results support the placement of Cryptosporidium as the earliest diverging lineage of apicomplexans, which impacts our interpretation of evolutionary events within the phylum. By mapping in silico predictions of core mitochondrial pathways onto our phylogeny, we identified convergently reduced mitochondria. These data show that the electron transport chain has been independently lost three times across the phylum, twice within gregarines.

CONCLUSIONS: Apicomplexan lineages show variable functional restructuring of mitochondrial metabolism that appears to have been driven by adaptations to parasitism and anaerobiosis. Our findings indicate that apicomplexans are rife with convergent adaptations, with shared features including morphology, energy metabolism, and intracellularity.}, } @article {pmid33848308, year = {2021}, author = {de Meeûs d'Argenteuil, C and Boshuizen, B and Oosterlinck, M and van de Winkel, D and De Spiegelaere, W and de Bruijn, CM and Goethals, K and Vanderperren, K and Delesalle, CJG}, title = {Flexibility of equine bioenergetics and muscle plasticity in response to different types of training: An integrative approach, questioning existing paradigms.}, journal = {PloS one}, volume = {16}, number = {4}, pages = {e0249922}, pmid = {33848308}, issn = {1932-6203}, mesh = {Amino Acids, Aromatic/metabolism ; Amino Acids, Branched-Chain/metabolism ; Animals ; Citric Acid Cycle ; *Energy Metabolism ; Female ; Glycolysis ; Heart Rate ; Horses ; Lipid Peroxidation ; Male ; Metabolomics ; Mitochondria/metabolism ; Muscle Fibers, Skeletal/physiology ; Muscle, Skeletal/metabolism/pathology/*physiology ; Pentose Phosphate Pathway ; Physical Conditioning, Animal ; }, abstract = {Equine bioenergetics have predominantly been studied focusing on glycogen and fatty acids. Combining omics with conventional techniques allows for an integrative approach to broadly explore and identify important biomolecules. Friesian horses were aquatrained (n = 5) or dry treadmill trained (n = 7) (8 weeks) and monitored for: evolution of muscle diameter in response to aquatraining and dry treadmill training, fiber type composition and fiber cross-sectional area of the M. pectoralis, M. vastus lateralis and M. semitendinosus and untargeted metabolomics of the M. pectoralis and M. vastus lateralis in response to dry treadmill training. Aquatraining was superior to dry treadmill training to increase muscle diameter in the hindquarters, with maximum effect after 4 weeks. After dry treadmill training, the M. pectoralis showed increased muscle diameter, more type I fibers, decreased fiber mean cross sectional area, and an upregulated oxidative metabolic profile: increased β-oxidation (key metabolites: decreased long chain fatty acids and increased long chain acylcarnitines), TCA activity (intermediates including succinyl-carnitine and 2-methylcitrate), amino acid metabolism (glutamine, aromatic amino acids, serine, urea cycle metabolites such as proline, arginine and ornithine) and xenobiotic metabolism (especially p-cresol glucuronide). The M. vastus lateralis expanded its fast twitch profile, with decreased muscle diameter, type I fibers and an upregulation of glycolytic and pentose phosphate pathway activity, and increased branched-chain and aromatic amino acid metabolism (cis-urocanate, carnosine, homocarnosine, tyrosine, tryptophan, p-cresol-glucuronide, serine, methionine, cysteine, proline and ornithine). Trained Friesians showed increased collagen and elastin turn-over. Results show that branched-chain amino acids, aromatic amino acids and microbiome-derived xenobiotics need further study in horses. They feed the TCA cycle at steps further downstream from acetyl CoA and most likely, they are oxidized in type IIA fibers, the predominant fiber type of the horse. These study results underline the importance of reviewing existing paradigms on equine bioenergetics.}, } @article {pmid33671025, year = {2021}, author = {Ramzan, R and Kadenbach, B and Vogt, S}, title = {Multiple Mechanisms Regulate Eukaryotic Cytochrome C Oxidase.}, journal = {Cells}, volume = {10}, number = {3}, pages = {}, pmid = {33671025}, issn = {2073-4409}, mesh = {Animals ; Electron Transport Complex IV/*metabolism ; Eukaryota/*metabolism ; Rats ; }, abstract = {Cytochrome c oxidase (COX), the rate-limiting enzyme of mitochondrial respiration, is regulated by various mechanisms. Its regulation by ATP (adenosine triphosphate) appears of particular importance, since it evolved early during evolution and is still found in cyanobacteria, but not in other bacteria. Therefore the "allosteric ATP inhibition of COX" is described here in more detail. Most regulatory properties of COX are related to "supernumerary" subunits, which are largely absent in bacterial COX. The "allosteric ATP inhibition of COX" was also recently described in intact isolated rat heart mitochondria.}, } @article {pmid33658719, year = {2021}, author = {Graf, JS and Schorn, S and Kitzinger, K and Ahmerkamp, S and Woehle, C and Huettel, B and Schubert, CJ and Kuypers, MMM and Milucka, J}, title = {Anaerobic endosymbiont generates energy for ciliate host by denitrification.}, journal = {Nature}, volume = {591}, number = {7850}, pages = {445-450}, pmid = {33658719}, issn = {1476-4687}, mesh = {Adenosine Triphosphate/metabolism ; *Anaerobiosis ; Bacteria/genetics/*metabolism ; Biological Evolution ; Cell Respiration ; Ciliophora/chemistry/cytology/*metabolism ; Citric Acid Cycle/genetics ; *Denitrification ; Electron Transport/genetics ; *Energy Metabolism ; Genome, Bacterial/genetics ; *Host Microbial Interactions/genetics ; Mitochondria ; Nitrates/metabolism ; Oxygen/metabolism ; Phylogeny ; *Symbiosis ; }, abstract = {Mitochondria are specialized eukaryotic organelles that have a dedicated function in oxygen respiration and energy production. They evolved about 2 billion years ago from a free-living bacterial ancestor (probably an alphaproteobacterium), in a process known as endosymbiosis[1,2]. Many unicellular eukaryotes have since adapted to life in anoxic habitats and their mitochondria have undergone further reductive evolution[3]. As a result, obligate anaerobic eukaryotes with mitochondrial remnants derive their energy mostly from fermentation[4]. Here we describe 'Candidatus Azoamicus ciliaticola', which is an obligate endosymbiont of an anaerobic ciliate and has a dedicated role in respiration and providing energy for its eukaryotic host. 'Candidatus A. ciliaticola' contains a highly reduced 0.29-Mb genome that encodes core genes for central information processing, the electron transport chain, a truncated tricarboxylic acid cycle, ATP generation and iron-sulfur cluster biosynthesis. The genome encodes a respiratory denitrification pathway instead of aerobic terminal oxidases, which enables its host to breathe nitrate instead of oxygen. 'Candidatus A. ciliaticola' and its ciliate host represent an example of a symbiosis that is based on the transfer of energy in the form of ATP, rather than nutrition. This discovery raises the possibility that eukaryotes with mitochondrial remnants may secondarily acquire energy-providing endosymbionts to complement or replace functions of their mitochondria.}, } @article {pmid33594064, year = {2021}, author = {Uwizeye, C and Decelle, J and Jouneau, PH and Flori, S and Gallet, B and Keck, JB and Bo, DD and Moriscot, C and Seydoux, C and Chevalier, F and Schieber, NL and Templin, R and Allorent, G and Courtois, F and Curien, G and Schwab, Y and Schoehn, G and Zeeman, SC and Falconet, D and Finazzi, G}, title = {Morphological bases of phytoplankton energy management and physiological responses unveiled by 3D subcellular imaging.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {1049}, pmid = {33594064}, issn = {2041-1723}, mesh = {Acclimatization/radiation effects ; *Energy Metabolism/radiation effects ; *Imaging, Three-Dimensional ; Light ; Microalgae/metabolism/radiation effects/ultrastructure ; Mitochondria/metabolism/radiation effects/ultrastructure ; Phytoplankton/*cytology/*physiology/radiation effects/ultrastructure ; Plastids/metabolism ; Subcellular Fractions/metabolism ; }, abstract = {Eukaryotic phytoplankton have a small global biomass but play major roles in primary production and climate. Despite improved understanding of phytoplankton diversity and evolution, we largely ignore the cellular bases of their environmental plasticity. By comparative 3D morphometric analysis across seven distant phytoplankton taxa, we observe constant volume occupancy by the main organelles and preserved volumetric ratios between plastids and mitochondria. We hypothesise that phytoplankton subcellular topology is modulated by energy-management constraints. Consistent with this, shifting the diatom Phaeodactylum from low to high light enhances photosynthesis and respiration, increases cell-volume occupancy by mitochondria and the plastid CO2-fixing pyrenoid, and boosts plastid-mitochondria contacts. Changes in organelle architectures and interactions also accompany Nannochloropsis acclimation to different trophic lifestyles, along with respiratory and photosynthetic responses. By revealing evolutionarily-conserved topologies of energy-managing organelles, and their role in phytoplankton acclimation, this work deciphers phytoplankton responses at subcellular scales.}, } @article {pmid33495511, year = {2021}, author = {Subramanian, V and Rodemoyer, B and Shastri, V and Rasmussen, LJ and Desler, C and Schmidt, KH}, title = {Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {2157}, pmid = {33495511}, issn = {2045-2322}, support = {R01 GM081425/GM/NIGMS NIH HHS/United States ; R01 GM139296/GM/NIGMS NIH HHS/United States ; }, mesh = {Autophagy ; Bloom Syndrome/*enzymology/*pathology ; Cyclin B1/metabolism ; DNA Damage ; DNA Replication ; DNA-Binding Proteins/metabolism ; Energy Metabolism ; Fibroblasts/enzymology/pathology ; G1 Phase ; Humans ; Mitochondria/*metabolism/ultrastructure ; Mitochondrial Proteins/metabolism ; Mitosis ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; RecQ Helicases/*deficiency/metabolism ; Transcription Factors/metabolism ; Up-Regulation ; }, abstract = {Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.}, } @article {pmid33455045, year = {2021}, author = {Pamplona, R and Jové, M and Mota-Martorell, N and Barja, G}, title = {Is the NDUFV2 subunit of the hydrophilic complex I domain a key determinant of animal longevity?.}, journal = {The FEBS journal}, volume = {288}, number = {23}, pages = {6652-6673}, doi = {10.1111/febs.15714}, pmid = {33455045}, issn = {1742-4658}, mesh = {Aging/*genetics/metabolism ; Animals ; Biological Evolution ; Electron Transport/genetics ; Electron Transport Complex I/*genetics/metabolism ; Energy Metabolism/*genetics ; Free Radicals/metabolism ; Longevity/*genetics ; Mitochondria/*genetics/metabolism ; Oxygen Consumption/genetics ; Protein Subunits/genetics/metabolism ; }, abstract = {Complex I, a component of the electron transport chain, plays a central functional role in cell bioenergetics and the biology of free radicals. The structural and functional N module of complex I is one of the main sites of the generation of free radicals. The NDUFV2 subunit/N1a cluster is a component of this module. Furthermore, the rate of free radical production is linked to animal longevity. In this review, we explore the hypothesis that NDUFV2 is the only conserved core subunit designed with a regulatory function to ensure correct electron transfer and free radical production, that low gene expression and protein abundance of the NDUFV2 subunit is an evolutionary adaptation needed to achieve a longevity phenotype, and that these features are determinants of the lower free radical generation at the mitochondrial level and a slower rate of aging of long-lived animals.}, } @article {pmid33454277, year = {2021}, author = {Fuentealba, M and Fabian, DK and Dönertaş, HM and Thornton, JM and Partridge, L}, title = {Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice.}, journal = {Mechanisms of ageing and development}, volume = {194}, number = {}, pages = {111437}, pmid = {33454277}, issn = {1872-6216}, support = {WT098565/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Age Factors ; Aging/*genetics/metabolism ; Animals ; Databases, Genetic ; Disease Models, Animal ; Energy Metabolism/*genetics ; *Gene Expression Profiling ; Gene Regulatory Networks ; Mice, Mutant Strains ; Mitochondria/*genetics/metabolism ; Progeria/*genetics/metabolism ; *Transcriptome ; }, abstract = {Genetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, and provide a powerful context in which to unravel the molecular mechanisms at work. In this study, we analysed and compared gene expression data from 10 long-lived and 8 short-lived mouse models of ageing. Transcriptome-wide correlation analysis revealed that mutations with equivalent effects on lifespan induce more similar transcriptomic changes, especially if they target the same pathway. Using functional enrichment analysis, we identified 58 gene sets with consistent changes in long- and short-lived mice, 55 of which were up-regulated in long-lived mice and down-regulated in short-lived mice. Half of these sets represented genes involved in energy and lipid metabolism, among which Ppargc1a, Mif, Aldh5a1 and Idh1 were frequently observed. Based on the gene sets with consistent changes, and also the whole transcriptome, the gene expression changes during normal ageing resembled the transcriptome of short-lived models, suggesting that accelerated ageing models reproduce partially the molecular changes of ageing. Finally, we identified new genetic interventions that may ameliorate ageing, by comparing the transcriptomes of 51 mouse mutants not previously associated with ageing to expression signatures of long- and short-lived mice and ageing-related changes.}, } @article {pmid33436278, year = {2021}, author = {Koch, RE and Buchanan, KL and Casagrande, S and Crino, O and Dowling, DK and Hill, GE and Hood, WR and McKenzie, M and Mariette, MM and Noble, DWA and Pavlova, A and Seebacher, F and Sunnucks, P and Udino, E and White, CR and Salin, K and Stier, A}, title = {Integrating Mitochondrial Aerobic Metabolism into Ecology and Evolution.}, journal = {Trends in ecology & evolution}, volume = {36}, number = {4}, pages = {321-332}, doi = {10.1016/j.tree.2020.12.006}, pmid = {33436278}, issn = {1872-8383}, mesh = {Adaptation, Physiological ; Adenosine Triphosphate/metabolism ; *Energy Metabolism ; Humans ; *Mitochondria ; Reactive Oxygen Species/metabolism ; }, abstract = {Biologists have long appreciated the critical role that energy turnover plays in understanding variation in performance and fitness among individuals. Whole-organism metabolic studies have provided key insights into fundamental ecological and evolutionary processes. However, constraints operating at subcellular levels, such as those operating within the mitochondria, can also play important roles in optimizing metabolism over different energetic demands and time scales. Herein, we explore how mitochondrial aerobic metabolism influences different aspects of organismal performance, such as through changing adenosine triphosphate (ATP) and reactive oxygen species (ROS) production. We consider how such insights have advanced our understanding of the mechanisms underpinning key ecological and evolutionary processes, from variation in life-history traits to adaptation to changing thermal conditions, and we highlight key areas for future research.}, } @article {pmid33372159, year = {2021}, author = {Chen, C and Mahar, R and Merritt, ME and Denlinger, DL and Hahn, DA}, title = {ROS and hypoxia signaling regulate periodic metabolic arousal during insect dormancy to coordinate glucose, amino acid, and lipid metabolism.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {118}, number = {1}, pages = {}, pmid = {33372159}, issn = {1091-6490}, support = {P41 GM122698/GM/NIGMS NIH HHS/United States ; R01 DK105346/DK/NIDDK NIH HHS/United States ; }, mesh = {Amino Acids/metabolism ; Animals ; Cell Respiration ; Citric Acid Cycle ; Diapause/physiology ; Energy Metabolism ; Glucose/metabolism ; Glycolysis/physiology ; Hypoxia/*metabolism ; Insecta/metabolism ; Lipid Metabolism/physiology ; Lipids/physiology ; Mitochondria/metabolism ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Sarcophagidae/metabolism ; Signal Transduction ; Torpor/*physiology ; }, abstract = {Metabolic suppression is a hallmark of animal dormancy that promotes overall energy savings. Some diapausing insects and some mammalian hibernators have regular cyclic patterns of substantial metabolic depression alternating with periodic arousal where metabolic rates increase dramatically. Previous studies, largely in mammalian hibernators, have shown that periodic arousal is driven by an increase in aerobic mitochondrial metabolism and that many molecules related to energy metabolism fluctuate predictably across periodic arousal cycles. However, it is still not clear how these rapid metabolic shifts are regulated. We first found that diapausing flesh fly pupae primarily use anaerobic glycolysis during metabolic depression but engage in aerobic respiration through the tricarboxylic acid cycle during periodic arousal. Diapausing pupae also clear anaerobic by-products and regenerate many metabolic intermediates depleted in metabolic depression during arousal, consistent with patterns in mammalian hibernators. We found that decreased levels of reactive oxygen species (ROS) induced metabolic arousal and elevated ROS extended the duration of metabolic depression. Our data suggest ROS regulates the timing of metabolic arousal by changing the activity of two critical metabolic enzymes, pyruvate dehydrogenase and carnitine palmitoyltransferase I by modulating the levels of hypoxia inducible transcription factor (HIF) and phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). Our study shows that ROS signaling regulates periodic arousal in our insect diapasue system, suggesting the possible importance ROS for regulating other types of of metabolic cycles in dormancy as well.}, } @article {pmid33366868, year = {2020}, author = {Yang, RS and Chen, YT}, title = {The complete mitochondrial genome of the freshwater fairy shrimp Branchinella kugenumaensis Ishikawa 1894 (Crustacea: Anostraca: Thamnocephalidae).}, journal = {Mitochondrial DNA. Part B, Resources}, volume = {5}, number = {1}, pages = {1048-1049}, pmid = {33366868}, issn = {2380-2359}, abstract = {In this study, we determined and analyzed the complete mitochondrial genome of the freshwater fairy shrimp Branchinella kugenumaensis Ishikawa 1894 (Crustacea: Anostraca: Thamnocephalidae). The mitogenome is 15,127 bp in length, consisted of 37 genes that participate in protein production and energy metabolism of mitochondria. The gene order of the B. kugenumaensis mtDNA exhibits major rearrangements compared with the pancrustacean ancestral pattern or other known anostracan mitogenomes, representing a novel mitochondrial genomic organization within the Crustacea. A maximum-likelihood phylogenetic analysis based on concatenated nucleotide sequences of protein-coding genes places B. kugenumaensis next to Streptocephalus sirindhornae, inside the Anostraca clade. Our study will provide new evidence to the less sampled anostracan evolution and take a further step to the completion of the Branchiopoda tree of life.}, } @article {pmid33359769, year = {2021}, author = {Else, PL}, title = {Mammals to membranes: A reductionist story.}, journal = {Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology}, volume = {253}, number = {}, pages = {110552}, doi = {10.1016/j.cbpb.2020.110552}, pmid = {33359769}, issn = {1879-1107}, mesh = {Animals ; Cell Membrane/*metabolism ; Energy Metabolism ; Humans ; Mammals/*metabolism ; Oxygen Consumption ; }, abstract = {This is the story of a series of reductionist studies that started with an attempt to explain what underpins the high-level of aerobic metabolism in mammals (i.e. associated with the evolution of endothermy) and almost forty years later had led to investigations into the role of membrane lipids in determining metabolism. Initial studies showed that the increase in aerobic metabolism in mammals was driven by a combination of increases in mitochondrial volume and membrane densities, organ size and changes in the molecular activity of enzymes. The increase in the capacity to produce energy was matched by an increase in energy use, notably driven by increases in H[+], Na[+] and K[+] fluxes. In the case of increased Na[+] flux, it was found this was matched by increases in Na[+]-dependent metabolism at the tissue level and increases in enzyme activity at a cellular level but not by an increase in the number of sodium pumps. To maintain Na[+] gradient across cell membranes, increased Na[+] flux is not controlled by an increase in sodium pump number but rather by an increase in sodium pump molecular activity (i.e. an increase the substrate turnover rate of each sodium pump) in tissues of endotherms. This increase in molecular activity is coupled to an increase in the level of highly unsaturated polyunsaturated fatty acids (PUFA) in membranes, a mechanism similar to that used by ectotherms to ameliorate decreasing activities of metabolic processes in the cold. Determination of how changes in membrane fatty acid composition can change the activities of proteins in membranes will be the next step in this story.}, } @article {pmid33307391, year = {2021}, author = {Harshkova, D and Majewska, M and Pokora, W and Baścik-Remisiewicz, A and Tułodziecki, S and Aksmann, A}, title = {Diclofenac and atrazine restrict the growth of a synchronous Chlamydomonas reinhardtii population via various mechanisms.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {230}, number = {}, pages = {105698}, doi = {10.1016/j.aquatox.2020.105698}, pmid = {33307391}, issn = {1879-1514}, mesh = {Antioxidants/metabolism ; Atrazine/*toxicity ; Catalase/metabolism ; Chlamydomonas reinhardtii/*drug effects/*growth & development/metabolism ; Chlorophyll A/metabolism ; Chloroplasts/metabolism ; Diclofenac/*toxicity ; Electron Transport ; Hydrogen Peroxide/metabolism ; Mitochondria/drug effects/metabolism ; Oxidative Stress/drug effects ; Photosynthesis/drug effects ; Water Pollutants, Chemical/*toxicity ; }, abstract = {Non-steroidal anti-inflammatory drug diclofenac (DCF) is commonly found in freshwater bodies and can have adverse effects on non-target organisms. Among the studies on DCF toxicity, several ones have reported its harmful effects on plants and algae. To gain a better understanding of the mechanisms of DCF toxicity towards green algae, we used a synchronous Chlamydomonas reinhardtii cc-1690 culture and compared DCF (135 mg/L) effects with effects caused by atrazine (ATR; 77.6 μg/L), an herbicide with a well-known mechanism of toxic action. To achieve our goal, cell number and size, photosynthetic oxygen consumption/evolution, chlorophyll a fluorescence in vivo, H2O2 production by the cells, antioxidative enzymes encoding genes expression were analyzed during light phase of the cell cycle. We have found, that DCF and ATR affect C. reinhardtii through different mechanisms. ATR inhibited the photosynthetic electron transport chain and induced oxidative stress in chloroplast. Such chloroplastic energetics disruption indirectly influenced respiration, the intensification of which could partially mitigate low efficiency of photosynthetic energy production. As a result, ATR inhibited the growth of single cell leading to limitation in C. reinhardtii population development. In contrast to ATR-treated algae, in DCF-treated cells the fraction of active PSII reaction centers was diminished without drastic changes in electron transport or oxidative stress symptoms in chloroplast. However, significant increase in transcript level of gene encoding for mitochondria-located catalase indicates respiratory processes as a source of H2O2 overproduced in the DCF-treated cells. Because the single cell growth was not strongly affected by DCF, its adverse effect on progeny cell number seemed to be related rather to arresting of cell divisions. Concluding, although the DCF phytotoxic action appeared to be different from the action of the typical herbicide ATR, it can act as algal growth-inhibiting factor in the environment.}, } @article {pmid33301801, year = {2021}, author = {Cortassa, S and Juhaszova, M and Aon, MA and Zorov, DB and Sollott, SJ}, title = {Mitochondrial Ca[2+], redox environment and ROS emission in heart failure: Two sides of the same coin?.}, journal = {Journal of molecular and cellular cardiology}, volume = {151}, number = {}, pages = {113-125}, pmid = {33301801}, issn = {1095-8584}, support = {Z99 AG999999/ImNIH/Intramural NIH HHS/United States ; ZIA AG000250/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Calcium/*metabolism ; Heart Failure/*metabolism ; Humans ; Mitochondria, Heart/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Sodium/metabolism ; }, abstract = {Heart failure (HF) is a progressive, debilitating condition characterized, in part, by altered ionic equilibria, increased ROS production and impaired cellular energy metabolism, contributing to variable profiles of systolic and diastolic dysfunction with significant functional limitations and risk of premature death. We summarize current knowledge concerning changes of intracellular Na[+] and Ca[2+] control mechanisms during the disease progression and their consequences on mitochondrial Ca[2+] homeostasis and the shift in redox balance. Absent existing biological data, our computational modeling studies advance a new 'in silico' analysis to reconcile existing opposing views, based on different experimental HF models, regarding variations in mitochondrial Ca[2+] concentration that participate in triggering and perpetuating oxidative stress in the failing heart and their impact on cardiac energetics. In agreement with our hypothesis and the literature, model simulations demonstrate the possibility that the heart's redox status together with cytoplasmic Na[+] concentrations act as regulators of mitochondrial Ca[2+] levels in HF and of the bioenergetics response that will ultimately drive ATP supply and oxidative stress. The resulting model predictions propose future directions to study the evolution of HF as well as other types of heart disease, and to develop novel testable mechanistic hypotheses that may lead to improved therapeutics.}, } @article {pmid33221746, year = {2020}, author = {Xu, H and Zhou, W and Zhan, L and Sui, H and Zhang, L and Zhao, C and Lu, X}, title = {The ZiBuPiYin recipe regulates proteomic alterations in brain mitochondria-associated ER membranes caused by chronic psychological stress exposure: Implications for cognitive decline in Zucker diabetic fatty rats.}, journal = {Aging}, volume = {12}, number = {23}, pages = {23698-23726}, pmid = {33221746}, issn = {1945-4589}, mesh = {Animals ; Behavior, Animal/*drug effects ; Brain/*drug effects/metabolism ; Chronic Disease ; Cognition/*drug effects ; Cognitive Dysfunction/etiology/metabolism/*prevention & control/psychology ; Diabetes Mellitus/*drug therapy/metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal/*pharmacology ; Endoplasmic Reticulum/*drug effects/metabolism ; Exploratory Behavior/drug effects ; Male ; Memory/drug effects ; Mitochondria/*drug effects/metabolism ; Mitochondrial Membranes/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Protein Interaction Maps ; Proteome/*drug effects ; Proteomics ; Rats, Zucker ; Signal Transduction ; Spatial Learning/drug effects ; Stress, Psychological/complications/*drug therapy/metabolism/psychology ; }, abstract = {Chronic psychological stress (PS) cumulatively affects memory performance through the deleterious effects on hypothalamic-pituitary-adrenal axis regulation. Several functions damaged in cognitive impairment-related diseases are regulated by mitochondria-associated ER membranes (MAMs). To elucidate the role of ZiBuPiYin recipe (ZBPYR) in regulating the MAM proteome to improve PS-induced diabetes-associated cognitive decline (PSD), differentially expressed MAM proteins were identified among Zucker diabetic fatty rats, PSD rats, and PS combined with ZBPYR administration rats via iTRAQ with LC-MS/MS. Proteomic analysis revealed that the expressions of 85 and 33 proteins were altered by PS and ZBPYR treatment, respectively. Among these, 21 proteins were differentially expressed under both PS and ZBPYR treatments, whose functional categories included energy metabolism, lipid and protein metabolism, and synaptic dysfunction. Furthermore, calcium signaling and autophagy-related proteins may play roles in the pathogenesis of PSD and the mechanism of ZBPYR, respectively. Notably, KEGG pathway analysis suggested that 'Alzheimer's disease' and 'oxidative phosphorylation' pathways may be impaired in PSD pathogenesis, while ZBPYR could play a neuroprotective role through regulating the above pathways. Overall, exposure to chronic PS contributes to the evolution of diabetes-associated cognitive decline and ZBPYR might prevent and treat PSD by regulating the MAM proteome.}, } @article {pmid33203574, year = {2021}, author = {Lukeš, J and Kaur, B and Speijer, D}, title = {RNA Editing in Mitochondria and Plastids: Weird and Widespread.}, journal = {Trends in genetics : TIG}, volume = {37}, number = {2}, pages = {99-102}, doi = {10.1016/j.tig.2020.10.004}, pmid = {33203574}, issn = {0168-9525}, mesh = {Mitochondria/*genetics ; Mutation/genetics ; Mutation Rate ; Phylogeny ; Plastids/*genetics ; RNA Editing/*genetics ; Symbiosis/genetics ; }, abstract = {Though widespread, RNA editing is rare, except in endosymbiotic organelles. A combination of higher mutation rates, relaxation of energetic constraints, and high genetic drift is found within plastids and mitochondria and is conducive for evolution and expansion of editing processes, possibly starting as repair mechanisms. To illustrate this, we present an exhaustive phylogenetic overview of editing types.}, } @article {pmid33036486, year = {2020}, author = {Zhu, Y and Berkowitz, O and Selinski, J and Hartmann, A and Narsai, R and Wang, Y and Mao, P and Whelan, J}, title = {Conserved and Opposite Transcriptome Patterns during Germination in Hordeum vulgare and Arabidopsis thaliana.}, journal = {International journal of molecular sciences}, volume = {21}, number = {19}, pages = {}, pmid = {33036486}, issn = {1422-0067}, mesh = {Arabidopsis/*genetics ; Computational Biology/methods ; Evolution, Molecular ; *Gene Expression Profiling ; *Gene Expression Regulation, Plant ; Germination/*genetics ; Hordeum/*genetics ; Molecular Sequence Annotation ; Seeds/*genetics/metabolism ; *Transcriptome ; }, abstract = {Seed germination is a critical process for completion of the plant life cycle and for global food production. Comparing the germination transcriptomes of barley (Hordeum vulgare) to Arabidopsis thaliana revealed the overall pattern was conserved in terms of functional gene ontology; however, many oppositely responsive orthologous genes were identified. Conserved processes included a set of approximately 6000 genes that peaked early in germination and were enriched in processes associated with RNA metabolism, e.g., pentatricopeptide repeat (PPR)-containing proteins. Comparison of orthologous genes revealed more than 3000 orthogroups containing almost 4000 genes that displayed similar expression patterns including functions associated with mitochondrial tricarboxylic acid (TCA) cycle, carbohydrate and RNA/DNA metabolism, autophagy, protein modifications, and organellar function. Biochemical and proteomic analyses indicated mitochondrial biogenesis occurred early in germination, but detailed analyses revealed the timing involved in mitochondrial biogenesis may vary between species. More than 1800 orthogroups representing 2000 genes displayed opposite patterns in transcript abundance, representing functions of energy (carbohydrate) metabolism, photosynthesis, protein synthesis and degradation, and gene regulation. Differences in expression of basic-leucine zippers (bZIPs) and Apetala 2 (AP2)/ethylene-responsive element binding proteins (EREBPs) point to differences in regulatory processes at a high level, which provide opportunities to modify processes in order to enhance grain quality, germination, and storage as needed for different uses.}, } @article {pmid32992875, year = {2020}, author = {Tan, DX and Hardeland, R}, title = {Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {19}, pages = {}, pmid = {32992875}, issn = {1420-3049}, mesh = {COVID-19 ; Coronavirus Infections/*drug therapy/metabolism ; Drug Delivery Systems ; Humans ; Melatonin/metabolism/*therapeutic use ; Mitochondria/*drug effects/metabolism ; Pandemics ; Pneumonia, Viral/*drug therapy/metabolism ; Virus Diseases/*drug therapy/*immunology/metabolism ; }, abstract = {Fighting infectious diseases, particularly viral infections, is a demanding task for human health. Targeting the pathogens or targeting the host are different strategies, but with an identical purpose, i.e., to curb the pathogen's spreading and cure the illness. It appears that targeting a host to increase tolerance against pathogens can be of substantial advantage and is a strategy used in evolution. Practically, it has a broader protective spectrum than that of only targeting the specific pathogens, which differ in terms of susceptibility. Methods for host targeting applied in one pandemic can even be effective for upcoming pandemics with different pathogens. This is even more urgent if we consider the possible concomitance of two respiratory diseases with potential multi-organ afflictions such as Coronavirus disease 2019 (COVID-19) and seasonal flu. Melatonin is a molecule that can enhance the host's tolerance against pathogen invasions. Due to its antioxidant, anti-inflammatory, and immunoregulatory activities, melatonin has the capacity to reduce the severity and mortality of deadly virus infections including COVID-19. Melatonin is synthesized and functions in mitochondria, which play a critical role in viral infections. Not surprisingly, melatonin synthesis can become a target of viral strategies that manipulate the mitochondrial status. For example, a viral infection can switch energy metabolism from respiration to widely anaerobic glycolysis even if plenty of oxygen is available (the Warburg effect) when the host cell cannot generate acetyl-coenzyme A, a metabolite required for melatonin biosynthesis. Under some conditions, including aging, gender, predisposed health conditions, already compromised mitochondria, when exposed to further viral challenges, lose their capacity for producing sufficient amounts of melatonin. This leads to a reduced support of mitochondrial functions and makes these individuals more vulnerable to infectious diseases. Thus, the maintenance of mitochondrial function by melatonin supplementation can be expected to generate beneficial effects on the outcome of viral infectious diseases, particularly COVID-19.}, } @article {pmid32878185, year = {2020}, author = {Karakaidos, P and Rampias, T}, title = {Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity.}, journal = {Life (Basel, Switzerland)}, volume = {10}, number = {9}, pages = {}, pmid = {32878185}, issn = {2075-1729}, abstract = {In eukaryotic cells, mitochondria originated in an α-proteobacterial endosymbiont. Although these organelles harbor their own genome, the large majority of genes, originally encoded in the endosymbiont, were either lost or transferred to the nucleus. As a consequence, mitochondria have become semi-autonomous and most of their processes require the import of nuclear-encoded components to be functional. Therefore, the mitochondrial-specific translation has evolved to be coordinated by mitonuclear interactions to respond to the energetic demands of the cell, acquiring unique and mosaic features. However, mitochondrial-DNA-encoded genes are essential for the assembly of the respiratory chain complexes. Impaired mitochondrial function due to oxidative damage and mutations has been associated with numerous human pathologies, the aging process, and cancer. In this review, we highlight the unique features of mitochondrial protein synthesis and provide a comprehensive insight into the mitonuclear crosstalk and its co-evolution, as well as the vulnerabilities of the animal mitochondrial genome.}, } @article {pmid32817169, year = {2020}, author = {Srivastava, SR and Mahalakshmi, R}, title = {Evolutionary selection of a 19-stranded mitochondrial β-barrel scaffold bears structural and functional significance.}, journal = {The Journal of biological chemistry}, volume = {295}, number = {43}, pages = {14653-14665}, pmid = {32817169}, issn = {1083-351X}, support = {/WT_/Wellcome Trust/United Kingdom ; IA/I/14/1/501305/WTDBT_/DBT-Wellcome Trust India Alliance/India ; }, mesh = {Animals ; Evolution, Molecular ; Humans ; Lipid Bilayers/chemistry/*metabolism ; Mitochondria/chemistry/genetics/metabolism ; Models, Molecular ; Mutation ; Porins/chemistry/genetics/metabolism ; Protein Conformation, beta-Strand ; Protein Engineering ; Protein Stability ; Saccharomyces cerevisiae/chemistry/genetics/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism ; Thermodynamics ; Voltage-Dependent Anion Channel 2/chemistry/genetics/metabolism ; Voltage-Dependent Anion Channels/*chemistry/genetics/*metabolism ; }, abstract = {Transmembrane β-barrels of eukaryotic outer mitochondrial membranes (OMMs) are major channels of communication between the cytosol and mitochondria and are indispensable for cellular homeostasis. A structurally intriguing exception to all known transmembrane β-barrels is the unique odd-stranded, i.e. 19-stranded, structures found solely in the OMM. The molecular origins of this 19-stranded structure and its associated functional significance are unclear. In humans, the most abundant OMM transporter is the voltage-dependent anion channel. Here, using the human voltage-dependent anion channel as our template scaffold, we designed and engineered odd- and even-stranded structures of smaller (V2[16], V2[17], V2[18]) and larger (V2[20], V2[21]) barrel diameters. Determination of the structure, dynamics, and energetics of these engineered structures in bilayer membranes reveals that the 19-stranded barrel surprisingly holds modest to low stability in a lipid-dependent manner. However, we demonstrate that this structurally metastable protein possesses superior voltage-gated channel regulation, efficient mitochondrial targeting, and in vivo cell survival, with lipid-modulated stability, all of which supersede the occurrence of a metastable 19-stranded scaffold. We propose that the unique structural adaptation of these transmembrane transporters exclusively in mitochondria bears strong evolutionary basis and is functionally significant for homeostasis.}, } @article {pmid32709961, year = {2020}, author = {Cunnane, SC and Trushina, E and Morland, C and Prigione, A and Casadesus, G and Andrews, ZB and Beal, MF and Bergersen, LH and Brinton, RD and de la Monte, S and Eckert, A and Harvey, J and Jeggo, R and Jhamandas, JH and Kann, O and la Cour, CM and Martin, WF and Mithieux, G and Moreira, PI and Murphy, MP and Nave, KA and Nuriel, T and Oliet, SHR and Saudou, F and Mattson, MP and Swerdlow, RH and Millan, MJ}, title = {Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.}, journal = {Nature reviews. Drug discovery}, volume = {19}, number = {9}, pages = {609-633}, pmid = {32709961}, issn = {1474-1784}, support = {MC_UU_00015/3/MRC_/Medical Research Council/United Kingdom ; R15 AG050292/AG/NIA NIH HHS/United States ; R01 NS107265/NS/NINDS NIH HHS/United States ; R37 AG053589/AG/NIA NIH HHS/United States ; RF1 AG055549/AG/NIA NIH HHS/United States ; R01 AG060733/AG/NIA NIH HHS/United States ; RF1 AG059093/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; P01 AG026572/AG/NIA NIH HHS/United States ; R21 AG064479/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; MC_U105663142/MRC_/Medical Research Council/United Kingdom ; RF1 AG062135/AG/NIA NIH HHS/United States ; R01 AG057931/AG/NIA NIH HHS/United States ; R01 AG061194/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*physiology ; Animals ; Brain/*physiology ; Energy Metabolism/*physiology ; Glycolysis/physiology ; Humans ; Neurodegenerative Diseases/*physiopathology ; Oxidative Phosphorylation ; }, abstract = {The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner - a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.}, } @article {pmid35372951, year = {2020}, author = {Chevalier, RL}, title = {Bioenergetic Evolution Explains Prevalence of Low Nephron Number at Birth: Risk Factor for CKD.}, journal = {Kidney360}, volume = {1}, number = {8}, pages = {863-879}, pmid = {35372951}, issn = {2641-7650}, mesh = {Adult ; Energy Metabolism/genetics ; Female ; Humans ; Infant, Newborn ; Male ; *Nephrons ; Placenta/metabolism ; Pregnancy ; *Premature Birth/metabolism ; Prevalence ; *Renal Insufficiency, Chronic/epidemiology ; Risk Factors ; }, abstract = {There is greater than tenfold variation in nephron number of the human kidney at birth. Although low nephron number is a recognized risk factor for CKD, its determinants are poorly understood. Evolutionary medicine represents a new discipline that seeks evolutionary explanations for disease, broadening perspectives on research and public health initiatives. Evolution of the kidney, an organ rich in mitochondria, has been driven by natural selection for reproductive fitness constrained by energy availability. Over the past 2 million years, rapid growth of an energy-demanding brain in Homo sapiens enabled hominid adaptation to environmental extremes through selection for mutations in mitochondrial and nuclear DNA epigenetically regulated by allocation of energy to developing organs. Maternal undernutrition or hypoxia results in intrauterine growth restriction or preterm birth, resulting in low birth weight and low nephron number. Regulated through placental transfer, environmental oxygen and nutrients signal nephron progenitor cells to reprogram metabolism from glycolysis to oxidative phosphorylation. These processes are modulated by counterbalancing anabolic and catabolic metabolic pathways that evolved from prokaryote homologs and by hypoxia-driven and autophagy pathways that evolved in eukaryotes. Regulation of nephron differentiation by histone modifications and DNA methyltransferases provide epigenetic control of nephron number in response to energy available to the fetus. Developmental plasticity of nephrogenesis represents an evolved life history strategy that prioritizes energy to early brain growth with adequate kidney function through reproductive years, the trade-off being increasing prevalence of CKD delayed until later adulthood. The research implications of this evolutionary analysis are to identify regulatory pathways of energy allocation directing nephrogenesis while accounting for the different life history strategies of animal models such as the mouse. The clinical implications are to optimize nutrition and minimize hypoxic/toxic stressors in childbearing women and children in early postnatal development.}, } @article {pmid32612534, year = {2020}, author = {Noiret, A and Puch, L and Riffaud, C and Costantini, D and Riou, JF and Aujard, F and Terrien, J}, title = {Sex-Specific Response to Caloric Restriction After Reproductive Investment in Microcebus murinus: An Integrative Approach.}, journal = {Frontiers in physiology}, volume = {11}, number = {}, pages = {506}, pmid = {32612534}, issn = {1664-042X}, abstract = {In seasonal environments, males and females usually maintain high metabolic activity during the whole summer season, exhausting their energy reserves. In the global warming context, unpredictability of food availability during summer could dramatically challenge the energy budget of individuals. Therefore, one can predict that resilience to environmental stress would be dramatically endangered during summer. Here, we hypothesized that females could have greater capacity to survive harsh conditions than males, considering the temporal shift in their respective reproductive energy investment, which can challenge them differently, as well as enhanced flexibility in females' physiological regulation. We tackled this question on the gray mouse lemur (Microcebus murinus), focusing on the late summer period, after the reproductive effort. We monitored six males and six females before and after a 2-weeks 60% caloric restriction (CR), measuring different physiological and cellular parameters in an integrative and comparative multiscale approach. Before CR, females were heavier than males and mostly characterized by high levels of energy expenditure, a more energetic mitochondrial profile and a downregulation of blood antioxidants. We observed a similar energy balance between sexes due to CR, with a decrease in metabolic activity over time only in males. Oxidative damage to DNA was also reduced by different pathways between sexes, which may reflect variability in their physiological status and life-history traits at the end of summer. Finally, females' mitochondria seemed to exhibit greater flexibility and greater metabolic potential than males in response to CR. Our results showed strong differences between males and females in response to food shortage during late summer, underlining the necessity to consider sex as a factor for population dynamics in climate change models.}, } @article {pmid32534048, year = {2020}, author = {Vertika, S and Singh, KK and Rajender, S}, title = {Mitochondria, spermatogenesis, and male infertility - An update.}, journal = {Mitochondrion}, volume = {54}, number = {}, pages = {26-40}, doi = {10.1016/j.mito.2020.06.003}, pmid = {32534048}, issn = {1872-8278}, mesh = {DNA, Mitochondrial/genetics ; Energy Metabolism ; Humans ; Infertility, Male/*genetics/metabolism ; Male ; Mitochondria/genetics/*metabolism ; *Mutation ; Sperm Motility ; *Spermatogenesis ; Spermatozoa/metabolism/physiology ; }, abstract = {The incorporation of mitochondria in the eukaryotic cell is one of the most enigmatic events in the course of evolution. This important organelle was thought to be only the powerhouse of the cell, but was later learnt to perform many other indispensable functions in the cell. Two major contributions of mitochondria in spermatogenesis concern energy production and apoptosis. Apart from this, mitochondria also participate in a number of other processes affecting spermatogenesis and fertility. Mitochondria in sperm are arranged in the periphery of the tail microtubules to serve to energy demand for motility. Apart from this, the role of mitochondria in germ cell proliferation, mitotic regulation, and the elimination of germ cells by apoptosis are now well recognized. Eventually, mutations in the mitochondrial genome have been reported in male infertility, particularly in sluggish sperm (asthenozoospermia); however, heteroplasmy in the mtDNA and a complex interplay between the nucleus and mitochondria affect their penetrance. In this article, we have provided an update on the role of mitochondria in various events of spermatogenesis and male fertility and on the correlation of mitochondrial DNA mutations with male infertility.}, } @article {pmid32396817, year = {2020}, author = {Seebacher, F}, title = {Is Endothermy an Evolutionary By-Product?.}, journal = {Trends in ecology & evolution}, volume = {35}, number = {6}, pages = {503-511}, doi = {10.1016/j.tree.2020.02.006}, pmid = {32396817}, issn = {1872-8383}, mesh = {Acclimatization ; Adaptation, Physiological ; Animals ; Biological Evolution ; *Energy Metabolism ; *Vertebrates ; }, abstract = {Endothermy alters the energetic relationships between organisms and their environment and thereby influences fundamental niches. Endothermy is closely tied to energy metabolism. Regulation of energy balance is indispensable for all life and regulatory pathways increase in complexity from bacteria to vertebrates. Increasing complexity of metabolic networks also increase the probability for endothermic phenotypes to appear. Adaptive arguments are problematic epistemologically because the regulatory mechanisms enabling endothermy have not evolved for the 'purpose' of endothermy and the utility of current traits is likely to have changed over evolutionary time. It is most parsimonious to view endothermy as the evolutionary by-product of energy balance regulation rather than as an adaptation and interpret its evolution in the context of metabolic networks.}, } @article {pmid32390938, year = {2020}, author = {Meduri, GU and Chrousos, GP}, title = {General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections.}, journal = {Frontiers in endocrinology}, volume = {11}, number = {}, pages = {161}, pmid = {32390938}, issn = {1664-2392}, mesh = {Adaptation, Physiological/drug effects/*physiology ; Animals ; Avitaminosis/complications/genetics/metabolism ; *Critical Illness/rehabilitation ; *Energy Metabolism/drug effects/genetics ; Gene Expression Regulation/drug effects ; Glucocorticoids/deficiency/pharmacology ; Homeostasis/drug effects/*genetics ; Humans ; Mitochondria/drug effects/physiology ; Receptors, Glucocorticoid/*physiology ; }, abstract = {In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.}, } @article {pmid32387125, year = {2020}, author = {Gangloff, EJ and Schwartz, TS and Klabacka, R and Huebschman, N and Liu, AY and Bronikowski, AM}, title = {Mitochondria as central characters in a complex narrative: Linking genomics, energetics, pace-of-life, and aging in natural populations of garter snakes.}, journal = {Experimental gerontology}, volume = {137}, number = {}, pages = {110967}, doi = {10.1016/j.exger.2020.110967}, pmid = {32387125}, issn = {1873-6815}, mesh = {Aging/genetics ; Animals ; *Colubridae ; Genomics ; Humans ; Longevity/genetics ; Mitochondria/genetics ; }, abstract = {As a pacesetter for physiological processes, variation in metabolic rate can determine the shape of energetic trade-offs and thereby drive variation in life-history traits. In turn, such variation in metabolic performance and life-histories can have profound consequences for lifespan and lifetime fitness. Thus, the extent to which metabolic rate variation is due to phenotypic plasticity or fixed genetic differences among individuals or populations is likely to be shaped by natural selection. Here, we first present a generalized framework describing the central role of mitochondria in processes linking environmental, genomic, physiological, and aging variation. We then present a test of these relationships in an exemplary system: populations of garter snakes (Thamnophis elegans) exhibiting contrasting life-history strategies - fast-growing, early-reproducing, and fast-aging (FA) versus slow-growing, late-reproducing, and slow-aging (SA). Previous work has characterized divergences in mitochondrial function, reactive oxygen species processing, and whole-organism metabolic rate between these contrasting life-history ecotypes. Here, we report new data on cellular respiration and mitochondrial genomics and synthesize these results with previous work. We test hypotheses about the causes and implications of mitochondrial genome variation within this generalized framework. First, we demonstrate that snakes of the FA ecotype increase cellular metabolic rate across their lifespan, while the opposite pattern holds for SA snakes, implying that reduced energetic throughput is associated with a longer life. Second, we show that variants in mitochondrial genomes are segregating across the landscape in a manner suggesting selection on the physiological consequences of this variation in habitats varying in temperature, food availability, and rates of predation. Third, we demonstrate functional variation in whole-organism metabolic rate related to these mitochondrial genome sequence variants. With this synthesis of numerous datasets, we are able to further characterize how variation across levels of biological organization interact within this generalized framework and how this has resulted in the emergence of distinct life-history ecotypes that vary in their rates of aging and lifespan.}, } @article {pmid32372945, year = {2020}, author = {Scorziello, A and Borzacchiello, D and Sisalli, MJ and Di Martino, R and Morelli, M and Feliciello, A}, title = {Mitochondrial Homeostasis and Signaling in Parkinson's Disease.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {100}, pmid = {32372945}, issn = {1663-4365}, abstract = {The loss of dopaminergic (DA) neurons in the substantia nigra leads to a progressive, long-term decline of movement and other non-motor deficits. The symptoms of Parkinson's disease (PD) often appear later in the course of the disease, when most of the functional dopaminergic neurons have been lost. The late onset of the disease, the severity of the illness, and its impact on the global health system demand earlier diagnosis and better targeted therapy. PD etiology and pathogenesis are largely unknown. There are mutations in genes that have been linked to PD and, from these complex phenotypes, mitochondrial dysfunction emerged as central in the pathogenesis and evolution of PD. In fact, several PD-associated genes negatively impact on mitochondria physiology, supporting the notion that dysregulation of mitochondrial signaling and homeostasis is pathogenically relevant. Derangement of mitochondrial homeostatic controls can lead to oxidative stress and neuronal cell death. Restoring deranged signaling cascades to and from mitochondria in PD neurons may then represent a viable opportunity to reset energy metabolism and delay the death of dopaminergic neurons. Here, we will highlight the relevance of dysfunctional mitochondrial homeostasis and signaling in PD, the molecular mechanisms involved, and potential therapeutic approaches to restore mitochondrial activities in damaged neurons.}, } @article {pmid32360615, year = {2020}, author = {Aparicio-Trejo, OE and Avila-Rojas, SH and Tapia, E and Rojas-Morales, P and León-Contreras, JC and Martínez-Klimova, E and Hernández-Pando, R and Sánchez-Lozada, LG and Pedraza-Chaverri, J}, title = {Chronic impairment of mitochondrial bioenergetics and β-oxidation promotes experimental AKI-to-CKD transition induced by folic acid.}, journal = {Free radical biology & medicine}, volume = {154}, number = {}, pages = {18-32}, doi = {10.1016/j.freeradbiomed.2020.04.016}, pmid = {32360615}, issn = {1873-4596}, mesh = {*Acute Kidney Injury/chemically induced/drug therapy/prevention & control ; Disease Progression ; Energy Metabolism ; Folic Acid ; Humans ; Mitochondria/metabolism ; Oxidation-Reduction ; *Renal Insufficiency, Chronic/chemically induced/drug therapy/metabolism ; }, abstract = {Recent studies suggest that mitochondrial bioenergetics and oxidative stress alterations may be common mechanisms involved in the progression of renal damage. However, the evolution of the mitochondrial alterations over time and the possible effects that their prevention could have in the progression of renal damage are not clear. Folic acid (FA)-induced kidney damage is a widely used experimental model to induce acute kidney injury (AKI), which can evolve to chronic kidney disease (CKD). Therefore, it has been extensively applied to study the mechanisms involved in AKI-to-CKD transition. We previously demonstrated that one day after FA administration, N-acetyl-cysteine (NAC) pre-administration prevented the development of AKI induced by FA. Such therapeutic effect was related to mitochondrial preservation. In the present study, we characterized the temporal course of mitochondrial bioenergetics and redox state alterations along the progression of renal damage induced by FA. Mitochondrial function was studied at different time points and showed a sustained impairment in oxidative phosphorylation capacity and a decrease in β-oxidation, decoupling, mitochondrial membrane potential depolarization and a pro-oxidative state, attributed to the reduction in activity of complexes I and III and mitochondrial cristae effacement, thus favoring the transition from AKI to CKD. Furthermore, the mitochondrial protection by NAC administration before AKI prevented not only the long-term deterioration of mitochondrial function at the chronic stage, but also CKD development. Taken together, our results support the idea that the prevention of mitochondrial dysfunction during an AKI event can be a useful strategy to prevent the transition to CKD.}, } @article {pmid32330419, year = {2020}, author = {Rotterová, J and Salomaki, E and Pánek, T and Bourland, W and Žihala, D and Táborský, P and Edgcomb, VP and Beinart, RA and Kolísko, M and Čepička, I}, title = {Genomics of New Ciliate Lineages Provides Insight into the Evolution of Obligate Anaerobiosis.}, journal = {Current biology : CB}, volume = {30}, number = {11}, pages = {2037-2050.e6}, doi = {10.1016/j.cub.2020.03.064}, pmid = {32330419}, issn = {1879-0445}, mesh = {Anaerobiosis/*genetics/*physiology ; *Biological Evolution ; Ciliophora/*genetics/*physiology/ultrastructure ; *Genomics ; Mitochondria/physiology ; }, abstract = {Oxygen plays a crucial role in energetic metabolism of most eukaryotes. Yet adaptations to low-oxygen concentrations leading to anaerobiosis have independently arisen in many eukaryotic lineages, resulting in a broad spectrum of reduced and modified mitochondrion-related organelles (MROs). In this study, we present the discovery of two new class-level lineages of free-living marine anaerobic ciliates, Muranotrichea, cl. nov. and Parablepharismea, cl. nov., that, together with the class Armophorea, form a major clade of obligate anaerobes (APM ciliates) within the Spirotrichea, Armophorea, and Litostomatea (SAL) group. To deepen our understanding of the evolution of anaerobiosis in ciliates, we predicted the mitochondrial metabolism of cultured representatives from all three classes in the APM clade by using transcriptomic and metagenomic data and performed phylogenomic analyses to assess their evolutionary relationships. The predicted mitochondrial metabolism of representatives from the APM ciliates reveals functional adaptations of metabolic pathways that were present in their last common ancestor and likely led to the successful colonization and diversification of the group in various anoxic environments. Furthermore, we discuss the possible relationship of Parablepharismea to the uncultured deep-sea class Cariacotrichea on the basis of single-gene analyses. Like most anaerobic ciliates, all studied species of the APM clade host symbionts, which we propose to be a significant accelerating factor in the transitions to an obligately anaerobic lifestyle. Our results provide an insight into the evolutionary mechanisms of early transitions to anaerobiosis and shed light on fine-scale adaptations in MROs over a relatively short evolutionary time frame.}, } @article {pmid32295425, year = {2020}, author = {Rodríguez, M and Valez, V and Cimarra, C and Blasina, F and Radi, R}, title = {Hypoxic-Ischemic Encephalopathy and Mitochondrial Dysfunction: Facts, Unknowns, and Challenges.}, journal = {Antioxidants & redox signaling}, volume = {33}, number = {4}, pages = {247-262}, doi = {10.1089/ars.2020.8093}, pmid = {32295425}, issn = {1557-7716}, mesh = {Adenosine Triphosphate/metabolism ; *Disease Susceptibility ; Electron Transport Complex IV/metabolism ; Homeostasis ; Humans ; Hypoxia-Ischemia, Brain/*etiology/*metabolism/pathology/physiopathology ; Mitochondria/*metabolism ; Neurons/metabolism ; Oxidation-Reduction ; Oxidative Stress ; }, abstract = {Significance: Hypoxic-ischemic events due to intrapartum complications represent the second cause of neonatal mortality and initiate an acute brain disorder known as hypoxic-ischemic encephalopathy (HIE). In HIE, the brain undergoes primary and secondary energy failure phases separated by a latent phase in which partial neuronal recovery is observed. A hypoxic-ischemic event leads to oxygen restriction causing ATP depletion, neuronal oxidative stress, and cell death. Mitochondrial dysfunction and enhanced oxidant formation in brain cells are characteristic phenomena associated with energy failure. Recent Advances: Mitochondrial sources of oxidants in neurons include complex I of the mitochondrial respiratory chain, as a key contributor to O2[•-] production via succinate by a reverse electron transport mechanism. The reaction of O2[•-] with nitric oxide ([•]NO) yields peroxynitrite, a mitochondrial and cellular toxin. Quantitation of the redox state of cytochrome c oxidase, through broadband near-infrared spectroscopy, represents a promising monitoring approach to evaluate mitochondrial dysfunction in vivo in humans, in conjunction with the determination of cerebral oxygenation and their correlation with the severity of brain injury. Critical Issues: The energetic failure being a key phenomenon in HIE connected with the severity of the encephalopathy, measurement of mitochondrial dysfunction in vivo provides an approach to assess evolution, prognosis, and adequate therapies. Restoration of mitochondrial redox homeostasis constitutes a key therapeutic goal. Future Directions: While hypothermia is the only currently accepted therapy in clinical management to preserve mitochondrial function, other mitochondria-targeted and/or redox-based treatments are likely to synergize to ensure further efficacy.}, } @article {pmid32201093, year = {2020}, author = {de Brito Monteiro, L and Davanzo, GG and de Aguiar, CF and Corrêa da Silva, F and Andrade, JR and Campos Codo, A and Silva Pereira, JAD and Freitas, LP and Moraes-Vieira, PM}, title = {M-CSF- and L929-derived macrophages present distinct metabolic profiles with similar inflammatory outcomes.}, journal = {Immunobiology}, volume = {225}, number = {3}, pages = {151935}, doi = {10.1016/j.imbio.2020.151935}, pmid = {32201093}, issn = {1878-3279}, mesh = {Animals ; Biomarkers ; Cell Line ; Cytokines/metabolism ; Energy Metabolism ; Inflammation Mediators/metabolism ; Macrophage Colony-Stimulating Factor/*metabolism ; Macrophages/*immunology/*metabolism ; *Metabolome ; *Metabolomics/methods ; Mice ; }, abstract = {Macrophages are essential components of the immune system. Macrophages can be derived from the bone marrow of mice with either recombinant M-CSF or L929 supernatant. Recent literature considers recombinant M-CSF- and L929-derived macrophages as equals, even though L929-derived macrophages are exposed to other substances secreted in the L929 supernatant, and not only M-CSF. Thus, we decided to perform a comparative analysis of both inflammatory and metabolic profiles of macrophages differentiated under the aforementioned conditions, which is relevant for standardization and interpretation of in vitro studies. We observed that, when treated with LPS, L929macs secrete lower levels of proinflammatory cytokines (TNF-α, IL-6, IL12) and present higher glycolysis and oxygen consumption when compared with M-CSFmacs. L929macs also have increased mitochondrial mass, with higher percentage of dysfunctional mitochondria. This sort of information can help direct further studies towards a more specific approach for macrophage generation.}, } @article {pmid32112190, year = {2020}, author = {Lang, SA and McIlroy, P and Shain, DH}, title = {Structural Evolution of the Glacier Ice Worm Fo ATP Synthase Complex.}, journal = {The protein journal}, volume = {39}, number = {2}, pages = {152-159}, pmid = {32112190}, issn = {1875-8355}, support = {ARRA NIH R15GM093685/NH/NIH HHS/United States ; }, mesh = {ATP Synthetase Complexes/*chemistry/genetics ; Adaptation, Biological ; Animals ; Cold Temperature ; Energy Metabolism ; *Evolution, Molecular ; Oligochaeta/*enzymology/genetics ; Protein Domains ; }, abstract = {The segmented annelid worm, Mesenchytraeus solifugus, is a permanent resident of temperate, maritime glaciers in the Pacific northwestern region of North America, displaying atypically high intracellular ATP levels which have been linked to its unusual ability to thrive in hydrated glacier ice. We have shown previously that ice worms contain a highly basic, carboxy terminal extension on their ATP6 regulatory subunit, likely acquired by horizontal gene transfer from a microbial dietary source. Here we examine the full complement of F1F0 ATP synthase structural subunits with attention to non-conservative, ice worm-specific structural modifications. Our genomics analyses and molecular models identify putative proton shuttling domains on either side of the F0 hemichannel, which predictably function to enhance proton flow across the mitochondrial membrane. Other components of the ice worm ATP synthase complex have remained largely unchanged in the context of Metazoan evolution.}, } @article {pmid32041806, year = {2020}, author = {Boël, M and Romestaing, C and Duchamp, C and Veyrunes, F and Renaud, S and Roussel, D and Voituron, Y}, title = {Improved mitochondrial coupling as a response to high mass-specific metabolic rate in extremely small mammals.}, journal = {The Journal of experimental biology}, volume = {223}, number = {Pt 5}, pages = {}, doi = {10.1242/jeb.215558}, pmid = {32041806}, issn = {1477-9145}, mesh = {Animals ; Basal Metabolism ; *Body Weight ; Liver/metabolism ; Male ; Mice/*metabolism ; Mitochondria, Muscle/*metabolism ; Muscle, Skeletal/metabolism ; }, abstract = {Mass-specific metabolic rate negatively co-varies with body mass from the whole-animal to the mitochondrial levels. Mitochondria are the mainly consumers of oxygen inspired by mammals to generate ATP or compensate for energetic losses dissipated as the form of heat (proton leak) during oxidative phosphorylation. Consequently, ATP synthesis and proton leak compete for the same electrochemical gradient. Because proton leak co-varies negatively with body mass, it is unknown whether extremely small mammals further decouple their mitochondria to maintain their body temperature or whether they implement metabolic innovations to ensure cellular homeostasis. The present study investigated the impact of body mass variation on cellular and mitochondrial functioning in small mammals, comparing two extremely small African pygmy mice (Mus mattheyi, ∼5 g, and Mus minutoides, ∼7 g) with the larger house mouse (Mus musculus, ∼22 g). Oxygen consumption rates were measured from the animal to the mitochondrial levels. We also measured mitochondrial ATP synthesis in order to appreciate the mitochondrial efficiency (ATP/O). At the whole-animal scale, mass- and surface-specific metabolic rates co-varied negatively with body mass, whereas this was not necessarily the case at the cellular and mitochondrial levels. Mus mattheyi had generally the lowest cellular and mitochondrial fluxes, depending on the tissue considered (liver or skeletal muscle), as well as having more-efficient muscle mitochondria than the other two species. Mus mattheyi presents metabolic innovations to ensure its homeostasis, by generating more ATP per oxygen consumed.}, } @article {pmid31972373, year = {2020}, author = {Muthye, V and Kandoi, G and Lavrov, DV}, title = {MMPdb and MitoPredictor: Tools for facilitating comparative analysis of animal mitochondrial proteomes.}, journal = {Mitochondrion}, volume = {51}, number = {}, pages = {118-125}, doi = {10.1016/j.mito.2020.01.001}, pmid = {31972373}, issn = {1872-8278}, mesh = {Acanthamoeba castellanii ; Animals ; Caenorhabditis elegans ; *Databases, Protein ; Drosophila melanogaster ; Energy Metabolism/physiology ; Humans ; *Machine Learning ; Mice ; Mitochondria/*metabolism ; Mitochondrial Proteins/*metabolism ; Proteome/genetics ; Saccharomyces cerevisiae ; }, abstract = {Data on experimentally-characterized animal mitochondrial proteomes (mt-proteomes) are limited to a few model organisms and are scattered across multiple databases, impeding a comparative analysis. We developed two resources to address these problems. First, we re-analyzed proteomic data from six species with experimentally characterized mt-proteomes: animals (Homo sapiens, Mus musculus, Caenorhabditis elegans, and Drosophila melanogaster), and outgroups (Acanthamoeba castellanii and Saccharomyces cerevisiae) and created the Metazoan Mitochondrial Proteome Database (MMPdb) to host the results. Second, we developed a novel pipeline, "MitoPredictor" that uses a Random Forest classifier to infer mitochondrial localization of proteins based on orthology, mitochondrial targeting signal prediction, and protein domain analyses. Both tools generate an R Shiny applet that can be used to visualize and interact with the results and can be used on a personal computer. MMPdb is also available online at https://mmpdb.eeob.iastate.edu/.}, } @article {pmid31947741, year = {2020}, author = {Chevigny, N and Schatz-Daas, D and Lotfi, F and Gualberto, JM}, title = {DNA Repair and the Stability of the Plant Mitochondrial Genome.}, journal = {International journal of molecular sciences}, volume = {21}, number = {1}, pages = {}, pmid = {31947741}, issn = {1422-0067}, mesh = {*DNA Repair ; DNA, Mitochondrial/genetics ; DNA, Plant/genetics ; *Genome, Mitochondrial ; *Genome, Plant ; Genomic Instability ; Mitochondria/genetics ; Plants/*genetics ; }, abstract = {The mitochondrion stands at the center of cell energy metabolism. It contains its own genome, the mtDNA, that is a relic of its prokaryotic symbiotic ancestor. In plants, the mitochondrial genetic information influences important agronomic traits including fertility, plant vigor, chloroplast function, and cross-compatibility. Plant mtDNA has remarkable characteristics: It is much larger than the mtDNA of other eukaryotes and evolves very rapidly in structure. This is because of recombination activities that generate alternative mtDNA configurations, an important reservoir of genetic diversity that promotes rapid mtDNA evolution. On the other hand, the high incidence of ectopic recombination leads to mtDNA instability and the expression of gene chimeras, with potential deleterious effects. In contrast to the structural plasticity of the genome, in most plant species the mtDNA coding sequences evolve very slowly, even if the organization of the genome is highly variable. Repair mechanisms are probably responsible for such low mutation rates, in particular repair by homologous recombination. Herein we review some of the characteristics of plant organellar genomes and of the repair pathways found in plant mitochondria. We further discuss how homologous recombination is involved in the evolution of the plant mtDNA.}, } @article {pmid34005357, year = {2020}, author = {Mélanie, B and Caroline, R and Claude, D and Frédéric, V and Sabrina, R and Damien, R and Yann, V}, title = {Improved mitochondrial coupling as a response to high mass-specific metabolic rate in extremely small mammals.}, journal = {The Journal of experimental biology}, volume = {}, number = {}, pages = {}, doi = {10.1242/jeb.215558}, pmid = {34005357}, issn = {1477-9145}, abstract = {Mass-specific metabolic rate negatively co-varies with body mass from the whole-animal to the mitochondrial levels. Mitochondria are the mainly consumers of oxygen inspired by mammals to generate ATP or compensate energetic losses dissipated as the form of heat (proton leak) during oxidative phosphorylation. Consequently, ATP synthesis and proton leak thus compete for the same electrochemical gradient. Because proton leak co-varies negatively with body mass, it is unknown if extremely small mammals further decouple their mitochondria to maintain their body temperature or if they implement metabolic innovations to ensure cellular homeostasis. The present study investigates the impact of body mass variation on cellular and mitochondrial functioning in small mammals, comparing the two extremely small African pygmy mice (Mus mattheyi, approx. 5 g and Mus minutoides, approx. 7 g) with the larger house mouse (Mus musculus, approx. 22 g). Oxygen consumption rates were measured from the animal to the mitochondrial levels. We also measured mitochondrial ATP synthesis in order to appreciate the mitochondrial efficiency (ATP/O). At the whole-animal scale, mass- and surface-specific metabolic rates co-varied negatively with body mass, whereas this was not necessarily the case at cellular and mitochondrial levels. M. mattheyi had generally the lowest cellular and mitochondrial fluxes, depending on the tissue considered (liver or skeletal muscle), as well as having higher efficient muscle mitochondria than the other two species. M. mattheyi presents metabolic innovations to ensure its homeostasis, by generating more ATP per oxygen consumed.}, } @article {pmid31881988, year = {2019}, author = {Liu, Y and Qu, J and Zhang, L and Xu, X and Wei, G and Zhao, Z and Ren, M and Cao, M}, title = {Identification and characterization of the TCA cycle genes in maize.}, journal = {BMC plant biology}, volume = {19}, number = {1}, pages = {592}, pmid = {31881988}, issn = {1471-2229}, mesh = {Amino Acid Sequence ; Arabidopsis/genetics ; Citric Acid Cycle/*genetics ; Computational Biology ; *Genes, Plant ; Lycopersicon esculentum/genetics ; Phylogeny ; Plant Proteins/genetics ; Sequence Alignment ; Transcriptome ; Zea mays/*genetics/metabolism ; }, abstract = {BACKGROUND: The tricarboxylic acid (TCA) cycle is crucial for cellular energy metabolism and carbon skeleton supply. However, the detailed functions of the maize TCA cycle genes remain unclear.

RESULTS: In this study, 91 TCA genes were identified in maize by a homology search, and they were distributed on 10 chromosomes and 1 contig. Phylogenetic results showed that almost all maize TCA genes could be classified into eight major clades according to their enzyme families. Sequence alignment revealed that several genes in the same subunit shared high protein sequence similarity. The results of cis-acting element analysis suggested that several TCA genes might be involved in signal transduction and plant growth. Expression profile analysis showed that many maize TCA cycle genes were expressed in specific tissues, and replicate genes always shared similar expression patterns. Moreover, qPCR analysis revealed that some TCA genes were highly expressed in the anthers at the microspore meiosis phase. In addition, we predicted the potential interaction networks among the maize TCA genes. Next, we cloned five TCA genes located on different TCA enzyme complexes, Zm00001d008244 (isocitrate dehydrogenase, IDH), Zm00001d017258 (succinyl-CoA synthetase, SCoAL), Zm00001d025258 (α-ketoglutarate dehydrogenase, αKGDH), Zm00001d027558 (aconitase, ACO) and Zm00001d044042 (malate dehydrogenase, MDH). Confocal observation showed that their protein products were mainly localized to the mitochondria; however, Zm00001d025258 and Zm00001d027558 were also distributed in the nucleus, and Zm00001d017258 and Zm00001d044042 were also located in other unknown positions in the cytoplasm. Through the bimolecular fluorescent complimentary (BiFC) method, it was determined that Zm00001d027558 and Zm00001d044042 could form homologous dimers, and both homologous dimers were mainly distributed in the mitochondria. However, no heterodimers were detected between these five genes. Finally, Arabidopsis lines overexpressing the above five genes were constructed, and those transgenic lines exhibited altered primary root length, salt tolerance, and fertility.

CONCLUSION: Sequence compositions, duplication patterns, phylogenetic relationships, cis-elements, expression patterns, and interaction networks were investigated for all maize TCA cycle genes. Five maize TCA genes were overexpressed in Arabidopsis, and they could alter primary root length, salt tolerance, and fertility. In conclusion, our findings may help to reveal the molecular function of the TCA genes in maize.}, } @article {pmid31873127, year = {2019}, author = {Terrien, J and Seugnet, I and Seffou, B and Herrero, MJ and Bowers, J and Chamas, L and Decherf, S and Duvernois-Berthet, E and Djediat, C and Ducos, B and Demeneix, BA and Clerget-Froidevaux, MS}, title = {Reduced central and peripheral inflammatory responses and increased mitochondrial activity contribute to diet-induced obesity resistance in WSB/EiJ mice.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {19696}, pmid = {31873127}, issn = {2045-2322}, mesh = {Animals ; Cytokines/blood ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Energy Metabolism ; Hypothalamus/metabolism/pathology ; Inflammation/genetics/*metabolism ; Inflammation Mediators/metabolism ; Leptin/blood ; Lipid Metabolism ; Male ; Metabolic Networks and Pathways ; Mice ; Mice, Inbred C57BL ; Mitochondria/*metabolism/pathology ; Mitochondrial Dynamics ; Obesity/*etiology/genetics/*metabolism ; Paraventricular Hypothalamic Nucleus/metabolism/pathology ; Species Specificity ; Transcriptome ; }, abstract = {Energy imbalance due to excess of calories is considered to be a major player in the current worldwide obesity pandemic and could be accompanied by systemic and central inflammation and mitochondrial dysfunctions. This hypothesis was tested by comparing the wild-derived diet-induced obesity- (DIO-) resistant mouse strain WSB/EiJ to the obesity-prone C57BL/6J strain. We analysed circulating and hypothalamic markers of inflammatory status and hypothalamic mitochondrial activity in both strains exposed to high-fat diet (HFD). We further analysed the regulations of hypothalamic genes involved in inflammation and mitochondrial pathways by high throughput microfluidic qPCR on RNA extracted from laser micro-dissected arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei. HFD induced increased body weight gain, circulating levels of leptin, cholesterol, HDL and LDL in C57BL/6J whereas WSB/EiJ mice displayed a lower inflammatory status, both peripherally (lower levels of circulating cytokines) and centrally (less activated microglia in the hypothalamus) as well as more reactive mitochondria in the hypothalamus. The gene expression data analysis allowed identifying strain-specific hypothalamic metabolic pathways involved in the respective responses to HFD. Our results point to the involvement of hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.}, } @article {pmid31817290, year = {2019}, author = {Arnedo, M and Latorre-Pellicer, A and Lucia-Campos, C and Gil-Salvador, M and Antoñanzas-Peréz, R and Gómez-Puertas, P and Bueno-Lozano, G and Puisac, B and Pié, J}, title = {More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones.}, journal = {International journal of molecular sciences}, volume = {20}, number = {24}, pages = {}, pmid = {31817290}, issn = {1422-0067}, mesh = {Cytosol/*enzymology ; Energy Metabolism ; Evolution, Molecular ; Humans ; Isoenzymes/classification/genetics/metabolism ; Ketone Bodies/metabolism ; Liver/enzymology ; Mitochondria/*enzymology ; Oxo-Acid-Lyases/classification/genetics/*metabolism ; Peroxisomes/*enzymology ; }, abstract = {There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes.}, } @article {pmid31787042, year = {2020}, author = {Elbassiouny, AA and Lovejoy, NR and Chang, BSW}, title = {Convergent patterns of evolution of mitochondrial oxidative phosphorylation (OXPHOS) genes in electric fishes.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {375}, number = {1790}, pages = {20190179}, pmid = {31787042}, issn = {1471-2970}, mesh = {Animals ; Electric Fish/*genetics/metabolism ; *Evolution, Molecular ; Fish Proteins/*genetics/metabolism ; Genome, Mitochondrial ; Mitochondria/*metabolism ; *Multigene Family ; *Oxidative Phosphorylation ; Selection, Genetic ; }, abstract = {The ability to generate and detect electric fields has evolved in several groups of fishes as a means of communication, navigation and, occasionally, predation. The energetic burden required can account for up to 20% of electric fishes' daily energy expenditure. Despite this, molecular adaptations that enable electric fishes to meet the metabolic demands of bioelectrogenesis remain unknown. Here, we investigate the molecular evolution of the mitochondrial oxidative phosphorylation (OXPHOS) complexes in the two most diverse clades of weakly electric fishes-South American Gymnotiformes and African Mormyroidea, using codon-based likelihood approaches. Our analyses reveal that although mitochondrial OXPHOS genes are generally subject to strong purifying selection, this constraint is significantly reduced in electric compared to non-electric fishes, particularly for complexes IV and V. Moreover, analyses of concatenated mitochondrial genes show strong evidence for positive selection in complex I genes on the two branches associated with the independent evolutionary origins of electrogenesis. These results suggest that adaptive evolution of proton translocation in the OXPHOS cellular machinery may be associated with the evolution of bioelectrogenesis. Overall, we find striking evidence for remarkably similar effects of electrogenesis on the molecular evolution of mitochondrial OXPHOS genes in two independently derived clades of electrogenic fishes. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.}, } @article {pmid31787040, year = {2020}, author = {Bettinazzi, S and Nadarajah, S and Dalpé, A and Milani, L and Blier, PU and Breton, S}, title = {Linking paternally inherited mtDNA variants and sperm performance.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {375}, number = {1790}, pages = {20190177}, pmid = {31787040}, issn = {1471-2970}, mesh = {Animals ; Bivalvia/*genetics ; DNA, Mitochondrial/*genetics ; *Genetic Variation ; *Genotype ; Male ; *Maternal Inheritance ; Mercenaria/genetics ; Mytilus edulis/genetics ; *Paternal Inheritance ; Spermatozoa/*physiology ; }, abstract = {Providing robust links between mitochondrial genotype and phenotype is of major importance given that mitochondrial DNA (mtDNA) variants can affect reproductive success. Because of the strict maternal inheritance (SMI) of mitochondria in animals, haplotypes that negatively affect male fertility can become fixed in populations. This phenomenon is known as 'mother's curse'. Doubly uniparental inheritance (DUI) of mitochondria is a stable exception in bivalves, which entails two mtDNA lineages that evolve independently and are transmitted separately through oocytes and sperm. This makes the DUI mitochondrial lineages subject to different sex-specific selective sieves during mtDNA evolution, thus DUI is a unique model to evaluate how direct selection on sperm mitochondria could contribute to male reproductive fitness. In this study, we tested the impact of mtDNA variants on sperm performance and bioenergetics in DUI and SMI species. Analyses also involved measures of sperm performance following inhibition of main energy pathways and sperm response to oocyte presence. Compared to SMI, DUI sperm exhibited (i) low speed and linearity, (ii) a strict OXPHOS-dependent strategy of energy production, and (iii) a partial metabolic shift towards fermentation following egg detection. Discussion embraces the adaptive value of mtDNA variation and suggests a link between male-energetic adaptation, fertilization success and paternal mitochondria preservation. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.}, } @article {pmid31787037, year = {2020}, author = {Camus, MF and O'Leary, M and Reuter, M and Lane, N}, title = {Impact of mitonuclear interactions on life-history responses to diet.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {375}, number = {1790}, pages = {20190416}, pmid = {31787037}, issn = {1471-2970}, support = {BB/S003681/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Cell Nucleus/*genetics ; DNA, Mitochondrial/*genetics ; Diet ; Drosophila melanogaster/genetics/*physiology ; Female ; Fertility/*genetics ; Haplotypes ; Life History Traits ; Longevity/*genetics ; Male ; Mitochondria/*genetics ; }, abstract = {Mitochondria are central to both energy metabolism and biosynthesis. Mitochondrial function could therefore influence resource allocation. Critically, mitochondrial function depends on interactions between proteins encoded by the mitochondrial and nuclear genomes. Severe incompatibilities between these genomes can have pervasive effects on both fitness and longevity. How milder deficits in mitochondrial function affect life-history trade-offs is less well understood. Here, we analyse how mitonuclear interactions affect the trade-off between fecundity and longevity in Drosophila melanogaster. We consider a panel of 10 different mitochondrial DNA haplotypes against two contrasting nuclear backgrounds (w[1118] (WE) and Zim53 (ZIM)) in response to high-protein versus standard diet. We report strikingly different responses between the two nuclear backgrounds. WE females have higher fecundity and decreased longevity on high protein. ZIM females have much greater fecundity and shorter lifespan than WE flies on standard diet. High protein doubled their fecundity with no effect on longevity. Mitochondrial haplotype reflected nuclear life-history trade-offs, with a negative correlation between longevity and fecundity in WE flies and no correlation in ZIM flies. Mitonuclear interactions had substantial effects but did not reflect genetic distance between mitochondrial haplotypes. We conclude that mitonuclear interactions can have significant impact on life-history trade-offs, but their effects are not predictable by relatedness. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.}, } @article {pmid31726178, year = {2020}, author = {Shen, Y and Wang, X and Guo, S and Qiu, M and Hou, G and Tan, Z}, title = {Evolutionary genomics analysis of human nucleus-encoded mitochondrial genes: implications for the roles of energy production and metabolic pathways in the pathogenesis and pathophysiology of demyelinating diseases.}, journal = {Neuroscience letters}, volume = {715}, number = {}, pages = {134600}, doi = {10.1016/j.neulet.2019.134600}, pmid = {31726178}, issn = {1872-7972}, mesh = {Animals ; Cell Nucleus/genetics/*metabolism ; Demyelinating Diseases/genetics/*metabolism ; Energy Metabolism/*physiology ; Evolution, Molecular ; Genes, Mitochondrial/*physiology ; Genomics/*methods ; Humans ; Metabolic Networks and Pathways/*physiology ; Mice ; Myelin Sheath/genetics/*metabolism ; }, abstract = {The myelin sheath is a plasma membrane extension that lines nerve fibers to protect, support and insulate neurons. The myelination of axons in vertebrates enables fast, saltatory impulse propagation, and this process relies on organelles, especially on mitochondria to supply energy. Approximately 99% of mitochondrial proteins are encoded in the nucleus. Since mitochondria play a central role in the energy production and metabolic pathways, which are essential for myelinogenesis, studying these nucleus-encoded genes (nMGs) may provide new insights into the roles of energy metabolism in demyelinating diseases. In this work, a multiomics-based approach was employed to 1) construct a 1,740 human nMG subset with mitochondrial localization evidence obtained from the Integrated Mitochondrial Protein Index (IMPI) and MitoCarta databases, 2) conduct an evolutionary genomics analysis across mouse, rat, monkey, chimp, and human models, 3) examine dysmyelination phenotype-related genes (nMG subset genes with oligodendrocyte- and myelin-related phenotypes, OMP-nMGs) in MGI mouse lines and human patients, 4) determine the expression discrepancy of OMP-nMGs in brain tissues of cuprizone-treated mice, multiple sclerosis patients, and normal controls, and 5) conduct literature data mining to explore OMP-nMG-associated disease impacts. By contrasting OMP-nMGs with other genes, OMP-nMGs were found to be more ubiquitously expressed (59.1% vs. 16.1%), disease-associated (67.3% vs. 20.2%), and evolutionarily conserved within the human populations. Our multiomics-based analysis identified 110 OMP-nMGs implicated in energy production and lipid and glycan biosynthesis in the pathogenesis and pathophysiology of demyelinating disorders. Future targeted characterization of OMP-nMGs in abnormal myelination conditions may allow the discovery of novel nMG mediated mechanisms underlying myelinogenesis and related diseases.}, } @article {pmid31687086, year = {2019}, author = {Poljsak, B and Kovac, V and Dahmane, R and Levec, T and Starc, A}, title = {Cancer Etiology: A Metabolic Disease Originating from Life's Major Evolutionary Transition?.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {7831952}, pmid = {31687086}, issn = {1942-0994}, mesh = {Animals ; *Biological Evolution ; Drug Resistance, Neoplasm ; Energy Metabolism ; Humans ; Metabolic Diseases/*etiology ; Mitochondria/metabolism ; Neoplasms/*etiology ; }, abstract = {A clear understanding of the origins of cancer is the basis of successful strategies for effective cancer prevention and management. The origin of cancer at the molecular and cellular levels is not well understood. Is the primary cause of the origin of cancer the genomic instability or impaired energy metabolism? An attempt was made to present cancer etiology originating from life's major evolutionary transition. The first evolutionary transition went from simple to complex cells when eukaryotic cells with glycolytic energy production merged with the oxidative mitochondrion (The Endosymbiosis Theory first proposed by Lynn Margulis in the 1960s). The second transition went from single-celled to multicellular organisms once the cells obtained mitochondria, which enabled them to obtain a higher amount of energy. Evidence will be presented that these two transitions, as well as the decline of NAD+ and ATP levels, are the root of cancer diseases. Restoring redox homeostasis and reactivation of mitochondrial oxidative metabolism are important factors in cancer prevention.}, } @article {pmid31621967, year = {2020}, author = {Johnson, RJ and Stenvinkel, P and Andrews, P and Sánchez-Lozada, LG and Nakagawa, T and Gaucher, E and Andres-Hernando, A and Rodriguez-Iturbe, B and Jimenez, CR and Garcia, G and Kang, DH and Tolan, DR and Lanaspa, MA}, title = {Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts.}, journal = {Journal of internal medicine}, volume = {287}, number = {3}, pages = {252-262}, doi = {10.1111/joim.12993}, pmid = {31621967}, issn = {1365-2796}, support = {R01 AR069137/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; *Biological Evolution ; *Climate Change ; Diet ; *Droughts ; Energy Metabolism/*physiology ; Extinction, Biological ; Fructose/*metabolism ; Hominidae ; Humans ; Mutation ; }, abstract = {Mass extinctions occur frequently in natural history. While studies of animals that became extinct can be informative, it is the survivors that provide clues for mechanisms of adaptation when conditions are adverse. Here, we describe a survival pathway used by many species as a means for providing adequate fuel and water, while also providing protection from a decrease in oxygen availability. Fructose, whether supplied in the diet (primarily fruits and honey), or endogenously (via activation of the polyol pathway), preferentially shifts the organism towards the storing of fuel (fat, glycogen) that can be used to provide energy and water at a later date. Fructose causes sodium retention and raises blood pressure and likely helped survival in the setting of dehydration or salt deprivation. By shifting energy production from the mitochondria to glycolysis, fructose reduced oxygen demands to aid survival in situations where oxygen availability is low. The actions of fructose are driven in part by vasopressin and the generation of uric acid. Twice in history, mutations occurred during periods of mass extinction that enhanced the activity of fructose to generate fat, with the first being a mutation in vitamin C metabolism during the Cretaceous-Paleogene extinction (65 million years ago) and the second being a mutation in uricase that occurred during the Middle Miocene disruption (12-14 million years ago). Today, the excessive intake of fructose due to the availability of refined sugar and high-fructose corn syrup is driving 'burden of life style' diseases, including obesity, diabetes and high blood pressure.}, } @article {pmid31591397, year = {2019}, author = {Smith, SR and Dupont, CL and McCarthy, JK and Broddrick, JT and Oborník, M and Horák, A and Füssy, Z and Cihlář, J and Kleessen, S and Zheng, H and McCrow, JP and Hixson, KK and Araújo, WL and Nunes-Nesi, A and Fernie, A and Nikoloski, Z and Palsson, BO and Allen, AE}, title = {Evolution and regulation of nitrogen flux through compartmentalized metabolic networks in a marine diatom.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {4552}, pmid = {31591397}, issn = {2041-1723}, mesh = {Carbon/metabolism ; Chloroplasts/genetics/metabolism ; Diatoms/*genetics/*metabolism ; Evolution, Molecular ; Gene Expression Profiling/methods ; Gene Expression Regulation ; Metabolic Networks and Pathways/*genetics ; Metabolomics/methods ; Mitochondria/genetics/metabolism ; Models, Biological ; Nitrates/metabolism ; Nitrogen/*metabolism ; Proteomics/methods ; Seawater/microbiology ; Signal Transduction/genetics ; }, abstract = {Diatoms outcompete other phytoplankton for nitrate, yet little is known about the mechanisms underpinning this ability. Genomes and genome-enabled studies have shown that diatoms possess unique features of nitrogen metabolism however, the implications for nutrient utilization and growth are poorly understood. Using a combination of transcriptomics, proteomics, metabolomics, fluxomics, and flux balance analysis to examine short-term shifts in nitrogen utilization in the model pennate diatom in Phaeodactylum tricornutum, we obtained a systems-level understanding of assimilation and intracellular distribution of nitrogen. Chloroplasts and mitochondria are energetically integrated at the critical intersection of carbon and nitrogen metabolism in diatoms. Pathways involved in this integration are organelle-localized GS-GOGAT cycles, aspartate and alanine systems for amino moiety exchange, and a split-organelle arginine biosynthesis pathway that clarifies the role of the diatom urea cycle. This unique configuration allows diatoms to efficiently adjust to changing nitrogen status, conferring an ecological advantage over other phytoplankton taxa.}, } @article {pmid31543463, year = {2019}, author = {Guièze, R and Liu, VM and Rosebrock, D and Jourdain, AA and Hernández-Sánchez, M and Martinez Zurita, A and Sun, J and Ten Hacken, E and Baranowski, K and Thompson, PA and Heo, JM and Cartun, Z and Aygün, O and Iorgulescu, JB and Zhang, W and Notarangelo, G and Livitz, D and Li, S and Davids, MS and Biran, A and Fernandes, SM and Brown, JR and Lako, A and Ciantra, ZB and Lawlor, MA and Keskin, DB and Udeshi, ND and Wierda, WG and Livak, KJ and Letai, AG and Neuberg, D and Harper, JW and Carr, SA and Piccioni, F and Ott, CJ and Leshchiner, I and Johannessen, CM and Doench, J and Mootha, VK and Getz, G and Wu, CJ}, title = {Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies.}, journal = {Cancer cell}, volume = {36}, number = {4}, pages = {369-384.e13}, pmid = {31543463}, issn = {1878-3686}, support = {U10 CA180861/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; T32 HL007627/HL/NHLBI NIH HHS/United States ; U24 CA210986/CA/NCI NIH HHS/United States ; R35 GM122455/GM/NIGMS NIH HHS/United States ; R21 CA216772/CA/NCI NIH HHS/United States ; R01 CA155010/CA/NCI NIH HHS/United States ; UG1 CA233338/CA/NCI NIH HHS/United States ; U01 CA214125/CA/NCI NIH HHS/United States ; R00 CA190861/CA/NCI NIH HHS/United States ; R01 CA216273/CA/NCI NIH HHS/United States ; R37 NS083524/NS/NINDS NIH HHS/United States ; P01 CA206978/CA/NCI NIH HHS/United States ; R01 CA213442/CA/NCI NIH HHS/United States ; R01 GM095567/GM/NIGMS NIH HHS/United States ; P01 CA081534/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use ; Apoptosis/drug effects/genetics ; Bridged Bicyclo Compounds, Heterocyclic/*pharmacology/therapeutic use ; Cell Line, Tumor ; Clonal Evolution/drug effects ; Disease Progression ; Drug Resistance, Neoplasm/drug effects/genetics ; Energy Metabolism/drug effects/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy/pathology ; Male ; Mice ; Middle Aged ; Mitochondria/drug effects/*pathology ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Oxidative Phosphorylation/drug effects ; Proto-Oncogene Proteins c-bcl-2/*antagonists & inhibitors/metabolism ; Sulfonamides/*pharmacology/therapeutic use ; Treatment Outcome ; Xenograft Model Antitumor Assays ; }, abstract = {Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.}, } @article {pmid31536521, year = {2019}, author = {Yang, M and Gong, L and Sui, J and Li, X}, title = {The complete mitochondrial genome of Calyptogena marissinica (Heterodonta: Veneroida: Vesicomyidae): Insight into the deep-sea adaptive evolution of vesicomyids.}, journal = {PloS one}, volume = {14}, number = {9}, pages = {e0217952}, pmid = {31536521}, issn = {1932-6203}, mesh = {Adaptation, Biological ; Animals ; Base Sequence ; Bivalvia/*genetics ; Computational Biology/methods ; DNA, Mitochondrial ; Evolution, Molecular ; *Genome, Mitochondrial ; *Genomics/methods ; High-Throughput Nucleotide Sequencing ; Molecular Sequence Annotation ; Oceans and Seas ; Phylogeny ; Selection, Genetic ; Sequence Analysis, DNA ; }, abstract = {The deep-sea chemosynthetic environment is one of the most extreme environments on the Earth, with low oxygen, high hydrostatic pressure and high levels of toxic substances. Species of the family Vesicomyidae are among the dominant chemosymbiotic bivalves found in this harsh habitat. Mitochondria play a vital role in oxygen usage and energy metabolism; thus, they may be under selection during the adaptive evolution of deep-sea vesicomyids. In this study, the mitochondrial genome (mitogenome) of the vesicomyid bivalve Calyptogena marissinica was sequenced with Illumina sequencing. The mitogenome of C. marissinica is 17,374 bp in length and contains 13 protein-coding genes, 2 ribosomal RNA genes (rrnS and rrnL) and 22 transfer RNA genes. All of these genes are encoded on the heavy strand. Some special elements, such as tandem repeat sequences, "G(A)nT" motifs and AT-rich sequences, were observed in the control region of the C. marissinica mitogenome, which is involved in the regulation of replication and transcription of the mitogenome and may be helpful in adjusting the mitochondrial energy metabolism of organisms to adapt to the deep-sea chemosynthetic environment. The gene arrangement of protein-coding genes was identical to that of other sequenced vesicomyids. Phylogenetic analyses clustered C. marissinica with previously reported vesicomyid bivalves with high support values. Positive selection analysis revealed evidence of adaptive change in the mitogenome of Vesicomyidae. Ten potentially important adaptive residues were identified, which were located in cox1, cox3, cob, nad2, nad4 and nad5. Overall, this study sheds light on the mitogenomic adaptation of vesicomyid bivalves that inhabit the deep-sea chemosynthetic environment.}, } @article {pmid31452134, year = {2019}, author = {Soggiu, A and Roncada, P and Bonizzi, L and Piras, C}, title = {Role of Mitochondria in Host-Pathogen Interaction.}, journal = {Advances in experimental medicine and biology}, volume = {1158}, number = {}, pages = {45-57}, doi = {10.1007/978-981-13-8367-0_3}, pmid = {31452134}, issn = {0065-2598}, mesh = {Apoptosis ; *Host-Pathogen Interactions ; Immunity, Innate ; *Mitochondria/metabolism ; Signal Transduction ; }, abstract = {The centrality of the mitochondrion in the evolution and control of the cellare now supported by many experimental studies. Not only with regard to the energy metabolism but also and especially with regard to the other functions indispensable for the cell such as apoptosis and the control of innate immunity through different complex cell signaling pathways. All this makes them one of the main targets during infections supported by pathogenic microorganisms. The interaction and control of these organelles by pathogens results, from the latest experimental evidence, of fundamental importance in the fate of the host cell and in the progression of infectious diseases.}, } @article {pmid31431166, year = {2019}, author = {Gould, SB and Garg, SG and Handrich, M and Nelson-Sathi, S and Gruenheit, N and Tielens, AGM and Martin, WF}, title = {Adaptation to life on land at high O2 via transition from ferredoxin-to NADH-dependent redox balance.}, journal = {Proceedings. Biological sciences}, volume = {286}, number = {1909}, pages = {20191491}, pmid = {31431166}, issn = {1471-2954}, mesh = {Adaptation, Physiological/*physiology ; Anaerobiosis ; Animals ; Chlamydomonas reinhardtii/*physiology ; Electron Transport ; Energy Metabolism ; Ferredoxins/*metabolism ; Hydrogenase ; Iron-Sulfur Proteins ; NAD/*metabolism ; Oxygen/metabolism ; }, abstract = {Pyruvate : ferredoxin oxidoreductase (PFO) and iron only hydrogenase ([Fe]-HYD) are common enzymes among eukaryotic microbes that inhabit anaerobic niches. Their function is to maintain redox balance by donating electrons from food oxidation via ferredoxin (Fd) to protons, generating H2 as a waste product. Operating in series, they constitute a soluble electron transport chain of one-electron transfers between FeS clusters. They fulfil the same function-redox balance-served by two electron-transfers in the NADH- and O2-dependent respiratory chains of mitochondria. Although they possess O2-sensitive FeS clusters, PFO, Fd and [Fe]-HYD are also present among numerous algae that produce O2. The evolutionary persistence of these enzymes among eukaryotic aerobes is traditionally explained as adaptation to facultative anaerobic growth. Here, we show that algae express enzymes of anaerobic energy metabolism at ambient O2 levels (21% v/v), Chlamydomonas reinhardtii expresses them with diurnal regulation. High O2 environments arose on Earth only approximately 450 million years ago. Gene presence/absence and gene expression data indicate that during the transition to high O2 environments and terrestrialization, diverse algal lineages retained enzymes of Fd-dependent one-electron-based redox balance, while the land plant and land animal lineages underwent irreversible specialization to redox balance involving the O2-insensitive two-electron carrier NADH.}, } @article {pmid31380018, year = {2019}, author = {Ngatia, JN and Lan, TM and Dinh, TD and Zhang, L and Ahmed, AK and Xu, YC}, title = {Signals of positive selection in mitochondrial protein-coding genes of woolly mammoth: Adaptation to extreme environments?.}, journal = {Ecology and evolution}, volume = {9}, number = {12}, pages = {6821-6832}, pmid = {31380018}, issn = {2045-7758}, abstract = {The mammoths originated in warm and equatorial Africa and later colonized cold and high-latitude environments. Studies on nuclear genes suggest that woolly mammoth had evolved genetic variations involved in processes relevant to cold tolerance, including lipid metabolism and thermogenesis, and adaptation to extremely varied light and darkness cycles. The mitochondria is a major regulator of cellular energy metabolism, thus the mitogenome of mammoths may also exhibit adaptive evolution. However, little is yet known in this regard. In this study, we analyzed mitochondrial protein-coding genes (MPCGs) sequences of 75 broadly distributed woolly mammoths (Mammuthus primigenius) to test for signatures of positive selection. Results showed that a total of eleven amino acid sites in six genes, namely ND1, ND4, ND5, ND6, CYTB, and ATP6, displayed strong evidence of positive selection. Two sites were located in close proximity to proton-translocation channels in mitochondrial complex I. Biochemical and homology protein structure modeling analyses demonstrated that five amino acid substitutions in ND1, ND5, and ND6 might have influenced the performance of protein-protein interaction among subunits of complex I, and three substitutions in CYTB and ATP6 might have influenced the performance of metabolic regulatory chain. These findings suggest metabolic adaptations in the mitogenome of woolly mammoths in relation to extreme environments and provide a basis for further tests on the significance of the variations on other systems.}, } @article {pmid31299243, year = {2020}, author = {Montava-Garriga, L and Ganley, IG}, title = {Outstanding Questions in Mitophagy: What We Do and Do Not Know.}, journal = {Journal of molecular biology}, volume = {432}, number = {1}, pages = {206-230}, doi = {10.1016/j.jmb.2019.06.032}, pmid = {31299243}, issn = {1089-8638}, support = {MC_UU_00018/2/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Autophagy/genetics ; *Biological Evolution ; Homeostasis/genetics ; Humans ; Mitochondria/*genetics ; Mitophagy/*genetics ; Signal Transduction/genetics ; }, abstract = {The elimination of mitochondria via autophagy, termed mitophagy, is an evolutionarily conserved mechanism for mitochondrial quality control and homeostasis. Mitophagy, therefore, has an important contribution to cell function and integrity, which extends to the whole organism for development and survival. Research in mitophagy has boomed in recent years, and it is becoming clear that mitophagy is a complex and multi-factorial cellular response that depends on tissue, energetic, stress and signaling contexts. However, we know very little of its physiological regulation and the direct contribution of mitophagy to pathologies like neurodegenerative diseases. In this review, we aim to discuss the outstanding questions (and questions outstanding) in the field and reflect on our current understanding of mitophagy, the current challenges and the future directions to take.}, } @article {pmid31234590, year = {2019}, author = {Jiang, Z and Watanabe, CKA and Miyagi, A and Kawai-Yamada, M and Terashima, I and Noguchi, K}, title = {Mitochondrial AOX Supports Redox Balance of Photosynthetic Electron Transport, Primary Metabolite Balance, and Growth in Arabidopsis thaliana under High Light.}, journal = {International journal of molecular sciences}, volume = {20}, number = {12}, pages = {}, pmid = {31234590}, issn = {1422-0067}, mesh = {Arabidopsis/*physiology/*radiation effects ; Biomarkers ; *Electron Transport ; Energy Metabolism ; Gene Expression Regulation ; *Light ; Mitochondria/*metabolism/*radiation effects ; Mitochondrial Proteins/*metabolism ; *Oxidation-Reduction ; Oxidoreductases/*metabolism ; Photosynthesis/*radiation effects ; Plant Proteins/*metabolism ; }, abstract = {When leaves receive excess light energy, excess reductants accumulate in chloroplasts. It is suggested that some of the reductants are oxidized by the mitochondrial respiratory chain. Alternative oxidase (AOX), a non-energy conserving terminal oxidase, was upregulated in the photosynthetic mutant of Arabidopsis thaliana, pgr5, which accumulated reductants in chloroplast stroma. AOX is suggested to have an important role in dissipating reductants under high light (HL) conditions, but its physiological importance and underlying mechanisms are not yet known. Here, we compared wild-type (WT), pgr5, and a double mutant of AOX1a-knockout plant (aox1a) and pgr5 (aox1a/pgr5) grown under high- and low-light conditions, and conducted physiological analyses. The net assimilation rate (NAR) was lower in aox1a/pgr5 than that in the other genotypes at the early growth stage, while the leaf area ratio was higher in aox1a/pgr5. We assessed detailed mechanisms in relation to NAR. In aox1a/pgr5, photosystem II parameters decreased under HL, whereas respiratory O2 uptake rates increased. Some intermediates in the tricarboxylic acid (TCA) cycle and Calvin cycle decreased in aox1a/pgr5, whereas γ-aminobutyric acid (GABA) and N-rich amino acids increased in aox1a/pgr5. Under HL, AOX may have an important role in dissipating excess reductants to prevent the reduction of photosynthetic electron transport and imbalance in primary metabolite levels.}, } @article {pmid31196150, year = {2018}, author = {Gerlitz, M and Knopp, M and Kapust, N and Xavier, JC and Martin, WF}, title = {Elusive data underlying debate at the prokaryote-eukaryote divide.}, journal = {Biology direct}, volume = {13}, number = {1}, pages = {21}, pmid = {31196150}, issn = {1745-6150}, mesh = {*Biological Evolution ; Energy Metabolism ; Eukaryotic Cells/*physiology ; Mitochondria/metabolism ; Prokaryotic Cells/*physiology ; }, abstract = {BACKGROUND: The origin of eukaryotic cells was an important transition in evolution. The factors underlying the origin and evolutionary success of the eukaryote lineage are still discussed. One camp argues that mitochondria were essential for eukaryote origin because of the unique configuration of internalized bioenergetic membranes that they conferred to the common ancestor of all known eukaryotic lineages. A recent paper by Lynch and Marinov concluded that mitochondria were energetically irrelevant to eukaryote origin, a conclusion based on analyses of previously published numbers of various molecules and ribosomes per cell and cell volumes as a presumed proxy for the role of mitochondria in evolution. Their numbers were purportedly extracted from the literature.

RESULTS: We have examined the numbers upon which the recent study was based. We report that for a sample of 80 numbers that were purportedly extracted from the literature and that underlie key inferences of the recent study, more than 50% of the values do not exist in the cited papers to which the numbers are attributed. The published result cannot be independently reproduced. Other numbers that the recent study reports differ inexplicably from those in the literature to which they are ascribed. We list the discrepancies between the recently published numbers and the purported literature sources of those numbers in a head to head manner so that the discrepancies are readily evident, although the source of error underlying the discrepancies remains obscure.

CONCLUSION: The data purportedly supporting the view that mitochondria had no impact upon eukaryotic evolution data exhibits notable irregularities. The paper in question evokes the impression that the published numbers are of up to seven significant digit accuracy, when in fact more than half the numbers are nowhere to be found in the literature to which they are attributed. Though the reasons for the discrepancies are unknown, it is important to air these issues, lest the prominent paper in question become a point source of a snowballing error through the literature or become interpreted as a form of evidence that mitochondria were irrelevant to eukaryote evolution.

REVIEWERS: This article was reviewed by Eric Bapteste, Jianzhi Zhang and Martin Lercher.}, } @article {pmid31173136, year = {2019}, author = {Montooth, KL and Dhawanjewar, AS and Meiklejohn, CD}, title = {Temperature-Sensitive Reproduction and the Physiological and Evolutionary Potential for Mother's Curse.}, journal = {Integrative and comparative biology}, volume = {59}, number = {4}, pages = {890-899}, pmid = {31173136}, issn = {1557-7023}, mesh = {Animals ; *Biological Evolution ; Cell Nucleus/*genetics ; DNA, Mitochondrial/genetics ; Drosophila melanogaster/genetics/*physiology ; Female ; Male ; Maternal Inheritance/*genetics ; Mitochondria/*genetics ; Mutation/*genetics ; Reproduction/genetics ; Selection, Genetic ; *Temperature ; }, abstract = {Strict maternal transmission of mitochondrial DNA (mtDNA) is hypothesized to permit the accumulation of mitochondrial variants that are deleterious to males but not females, a phenomenon called mother's curse. However, direct evidence that mtDNA mutations exhibit such sexually antagonistic fitness effects is sparse. Male-specific mutational effects can occur when the physiological requirements of the mitochondria differ between the sexes. Such male-specific effects could potentially occur if sex-specific cell types or tissues have energy requirements that are differentially impacted by mutations affecting energy metabolism. Here we summarize findings from a model mitochondrial-nuclear incompatibility in the fruit fly Drosophila that demonstrates sex-biased effects, but with deleterious effects that are generally larger in females. We present new results showing that the mitochondrial-nuclear incompatibility does negatively affect male fertility, but only when males are developed at high temperatures. The temperature-dependent male sterility can be partially rescued by diet, suggesting an energetic basis. Finally, we discuss fruitful paths forward in understanding the physiological scope for sex-specific effects of mitochondrial mutations in the context of the recent discovery that many aspects of metabolism are sexually dimorphic and downstream of sex-determination pathways in Drosophila. A key parameter of these models that remains to be quantified is the fraction of mitochondrial mutations with truly male-limited fitness effects across extrinsic and intrinsic environments. Given the energy demands of reproduction in females, only a small fraction of the mitochondrial mutational spectrum may have the potential to contribute to mother's curse in natural populations.}, } @article {pmid31076245, year = {2019}, author = {Brunk, CF and Martin, WF}, title = {Archaeal Histone Contributions to the Origin of Eukaryotes.}, journal = {Trends in microbiology}, volume = {27}, number = {8}, pages = {703-714}, doi = {10.1016/j.tim.2019.04.002}, pmid = {31076245}, issn = {1878-4380}, mesh = {Archaea/*physiology ; *Biological Evolution ; DNA ; Eukaryotic Cells/*physiology ; Histones/*physiology ; Mitochondria/physiology ; Symbiosis ; }, abstract = {The eukaryotic lineage arose from bacterial and archaeal cells that underwent a symbiotic merger. At the origin of the eukaryote lineage, the bacterial partner contributed genes, metabolic energy, and the building blocks of the endomembrane system. What did the archaeal partner donate that made the eukaryotic experiment a success? The archaeal partner provided the potential for complex information processing. Archaeal histones were crucial in that regard by providing the basic functional unit with which eukaryotes organize DNA into nucleosomes, exert epigenetic control of gene expression, transcribe genes with CCAAT-box promoters, and a manifest cell cycle with condensed chromosomes. While mitochondrial energy lifted energetic constraints on eukaryotic protein production, histone-based chromatin organization paved the path to eukaryotic genome complexity, a critical hurdle en route to the evolution of complex cells.}, } @article {pmid31040181, year = {2019}, author = {Reis, LMD and Adamoski, D and Ornitz Oliveira Souza, R and Rodrigues Ascenção, CF and Sousa de Oliveira, KR and Corrêa-da-Silva, F and Malta de Sá Patroni, F and Meira Dias, M and Consonni, SR and Mendes de Moraes-Vieira, PM and Silber, AM and Dias, SMG}, title = {Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells.}, journal = {The Journal of biological chemistry}, volume = {294}, number = {24}, pages = {9342-9357}, pmid = {31040181}, issn = {1083-351X}, mesh = {Benzeneacetamides/*pharmacology ; Carnitine O-Palmitoyltransferase/*antagonists & inhibitors ; Cell Movement/*drug effects ; Cell Proliferation/*drug effects ; Drug Resistance, Neoplasm/*drug effects ; Female ; Glutaminase/*antagonists & inhibitors ; Glutamine/*metabolism ; Humans ; Oxidation-Reduction ; Thiadiazoles/*pharmacology ; Triple Negative Breast Neoplasms/*drug therapy/enzymology/pathology ; Tumor Cells, Cultured ; }, abstract = {Triple-negative breast cancers (TNBCs) lack progesterone and estrogen receptors and do not have amplified human epidermal growth factor receptor 2, the main therapeutic targets for managing breast cancer. TNBCs have an altered metabolism, including an increased Warburg effect and glutamine dependence, making the glutaminase inhibitor CB-839 therapeutically promising for this tumor type. Accordingly, CB-839 is currently in phase I/II clinical trials. However, not all TNBCs respond to CB-839 treatment, and the tumor resistance mechanism is not yet fully understood. Here we classified cell lines as CB-839-sensitive or -resistant according to their growth responses to CB-839. Compared with sensitive cells, resistant cells were less glutaminolytic and, upon CB-839 treatment, exhibited a smaller decrease in ATP content and less mitochondrial fragmentation, an indicator of poor mitochondrial health. Transcriptional analyses revealed that the expression levels of genes linked to lipid metabolism were altered between sensitive and resistant cells and between breast cancer tissues (available from The Cancer Genome Atlas project) with low versus high glutaminase (GLS) gene expression. Of note, CB-839-resistant TNBC cells had increased carnitine palmitoyltransferase 2 (CPT2) protein and CPT1 activity levels. In agreement, CB-839-resistant TNBC cells mobilized more fatty acids into mitochondria for oxidation, which responded to AMP-activated protein kinase and acetyl-CoA carboxylase signaling. Moreover, chemical inhibition of both glutaminase and CPT1 decreased cell proliferation and migration of CB-839-resistant cells compared with single inhibition of each enzyme. We propose that dual targeting of glutaminase and CPT1 activities may have therapeutic relevance for managing CB-839-resistant tumors.}, } @article {pmid30935869, year = {2019}, author = {Zimorski, V and Mentel, M and Tielens, AGM and Martin, WF}, title = {Energy metabolism in anaerobic eukaryotes and Earth's late oxygenation.}, journal = {Free radical biology & medicine}, volume = {140}, number = {}, pages = {279-294}, pmid = {30935869}, issn = {1873-4596}, mesh = {Anaerobiosis/genetics ; Atmosphere ; *Biological Evolution ; Energy Metabolism/genetics ; Eukaryota/*metabolism ; Mitochondria/genetics/metabolism ; Oxygen/*metabolism ; }, abstract = {Eukaryotes arose about 1.6 billion years ago, at a time when oxygen levels were still very low on Earth, both in the atmosphere and in the ocean. According to newer geochemical data, oxygen rose to approximately its present atmospheric levels very late in evolution, perhaps as late as the origin of land plants (only about 450 million years ago). It is therefore natural that many lineages of eukaryotes harbor, and use, enzymes for oxygen-independent energy metabolism. This paper provides a concise overview of anaerobic energy metabolism in eukaryotes with a focus on anaerobic energy metabolism in mitochondria. We also address the widespread assumption that oxygen improves the overall energetic state of a cell. While it is true that ATP yield from glucose or amino acids is increased in the presence of oxygen, it is also true that the synthesis of biomass costs thirteen times more energy per cell in the presence of oxygen than in anoxic conditions. This is because in the reaction of cellular biomass with O2, the equilibrium lies very far on the side of CO2. The absence of oxygen offers energetic benefits of the same magnitude as the presence of oxygen. Anaerobic and low oxygen environments are ancient. During evolution, some eukaryotes have specialized to life in permanently oxic environments (life on land), other eukaryotes have remained specialized to low oxygen habitats. We suggest that the Km of mitochondrial cytochrome c oxidase of 0.1-10 μM for O2, which corresponds to about 0.04%-4% (avg. 0.4%) of present atmospheric O2 levels, reflects environmental O2 concentrations that existed at the time that the eukaryotes arose.}, } @article {pmid30927526, year = {2019}, author = {Vays, VB and Vangeli, IM and Eldarov, CM and Efeykin, BD and Bakeeva, LE}, title = {Mitochondria in Obliquely Striated Muscles of the Horsehair Worm Gordionus alpestris (Nematomorpha, Gordioidea) with Structural Organization Typical of Cells with Energy-Intensive Processes.}, journal = {Biochemistry. Biokhimiia}, volume = {84}, number = {1}, pages = {56-61}, doi = {10.1134/S0006297919010073}, pmid = {30927526}, issn = {1608-3040}, mesh = {Animals ; Energy Metabolism ; Helminths/*anatomy & histology/cytology ; Mitochondria/*ultrastructure ; Mitochondria, Muscle ; Mitochondrial Membranes ; Muscle, Striated/*ultrastructure ; }, abstract = {The ultrastructure of mitochondria in the flattened circomyarian fibers of the horsehair worm Gordionus alpestris (Nemathelminthes) was examined. In contrast to the previously published data, we showed these mitochondria to be giant elongated organelles that densely fill the central cytoplasmic space of the ribbon-like muscle fibers. No fundamental differences were found in the ultrastructure of the muscle tissue mitochondria in actively moving free-living and parasitic G. alpestris worms. The functional significance of the observed ultrastructural organization of mitochondria is discussed in connection with the necessity for an extended mitochondrial membrane system for a uniform supply of active muscle tissue with energy.}, } @article {pmid30771209, year = {2019}, author = {Shin, MK and Cheong, JH}, title = {Mitochondria-centric bioenergetic characteristics in cancer stem-like cells.}, journal = {Archives of pharmacal research}, volume = {42}, number = {2}, pages = {113-127}, pmid = {30771209}, issn = {1976-3786}, mesh = {Animals ; Antineoplastic Agents/pharmacology ; Energy Metabolism/drug effects/*physiology ; Humans ; Mitochondria/drug effects/*metabolism ; Neoplastic Stem Cells/drug effects/*metabolism ; Oxidative Stress/drug effects/physiology ; Tumor Microenvironment/drug effects/*physiology ; }, abstract = {Metabolic and genotoxic stresses that arise during tumor progression and anti-cancer treatment, respectively, can impose a selective pressure to promote cancer evolution in the tumor microenvironment. This process ultimately selects for the most "fit" clones, which generally have a cancer stem cell like phenotype with features of drug resistance, epithelial-mesenchymal transition, invasiveness, and high metastatic potential. From a bioenergetics perspective, these cancer stem-like cells (CSCs) exhibit mitochondria-centric energy metabolism and are capable of opportunistically utilizing available nutrients such as fatty acids to generate ATP and other metabolic substances, providing a selective advantage for their survival in an impermissible environment and metabolic context. Thus, diverse therapeutic strategies are needed to efficiently tackle these CSCs and eliminate their advantage. Here, we review the metabolic and bioenergetic characteristics and vulnerabilities specific to CSCs, which can provide an unprecedented opportunity to curb CSC-driven cancer mortality rates. We particularly focus on the potential of a CSC bioenergetics-targeted strategy as a versatile therapeutic component of treatment modalities applicable to most cancer types. A cancer bioenergetics-targeted strategy can expand the inventory of combinatorial regimens in the current anti-cancer armamentarium.}, } @article {pmid30636322, year = {2019}, author = {Broddrick, JT and Du, N and Smith, SR and Tsuji, Y and Jallet, D and Ware, MA and Peers, G and Matsuda, Y and Dupont, CL and Mitchell, BG and Palsson, BO and Allen, AE}, title = {Cross-compartment metabolic coupling enables flexible photoprotective mechanisms in the diatom Phaeodactylum tricornutum.}, journal = {The New phytologist}, volume = {222}, number = {3}, pages = {1364-1379}, pmid = {30636322}, issn = {1469-8137}, support = {GMBF3828//Gordon and Betty Moore Foundation/International ; JP15K16156//Japan Society for the Promotion of Science/International ; JP16H06557//Japan Society for the Promotion of Science/International ; JP17K15326//Japan Society for the Promotion of Science/International ; JP24310015//Japan Society for the Promotion of Science/International ; SP16005//Japan Society for the Promotion of Science/International ; //Edna Bailey Sussman Foundation/International ; NSF-MCB-1024913//National Science Foundation/International ; No. 1614398//National Science Foundation/International ; DE-EE0003373//US Department of Energy/International ; DE-SC0008593//US Department of Energy/International ; DE-SC0008595//US Department of Energy/International ; //Individual Special Research Fund of Kwansei Gakuin University/International ; //Promotion and Mutual Aid Corporation for Private Schools of Japan (PMAC)/International ; }, mesh = {Acclimatization/radiation effects ; Alcohol Oxidoreductases/metabolism ; Biomass ; Cell Respiration/radiation effects ; Circadian Rhythm/radiation effects ; Computer Simulation ; Diatoms/*metabolism/*radiation effects ; Electron Transport/radiation effects ; *Light ; Metabolic Networks and Pathways/radiation effects ; Mitochondria/metabolism/radiation effects ; Models, Biological ; Photosynthesis/radiation effects ; Pyruvic Acid/metabolism ; }, abstract = {Photoacclimation consists of short- and long-term strategies used by photosynthetic organisms to adapt to dynamic light environments. Observable photophysiology changes resulting from these strategies have been used in coarse-grained models to predict light-dependent growth and photosynthetic rates. However, the contribution of the broader metabolic network, relevant to species-specific strategies and fitness, is not accounted for in these simple models. We incorporated photophysiology experimental data with genome-scale modeling to characterize organism-level, light-dependent metabolic changes in the model diatom Phaeodactylum tricornutum. Oxygen evolution and photon absorption rates were combined with condition-specific biomass compositions to predict metabolic pathway usage for cells acclimated to four different light intensities. Photorespiration, an ornithine-glutamine shunt, and branched-chain amino acid metabolism were hypothesized as the primary intercompartment reductant shuttles for mediating excess light energy dissipation. Additionally, simulations suggested that carbon shunted through photorespiration is recycled back to the chloroplast as pyruvate, a mechanism distinct from known strategies in photosynthetic organisms. Our results suggest a flexible metabolic network in P. tricornutum that tunes intercompartment metabolism to optimize energy transport between the organelles, consuming excess energy as needed. Characterization of these intercompartment reductant shuttles broadens our understanding of energy partitioning strategies in this clade of ecologically important primary producers.}, } @article {pmid30621777, year = {2018}, author = {Lynch, M and Marinov, GK}, title = {Response to Martin and colleagues: mitochondria do not boost the bioenergetic capacity of eukaryotic cells.}, journal = {Biology direct}, volume = {13}, number = {1}, pages = {26}, pmid = {30621777}, issn = {1745-6150}, support = {R35 GM122566/GM/NIGMS NIH HHS/United States ; }, mesh = {*Energy Metabolism ; *Eukaryotic Cells ; Mitochondria ; Prokaryotic Cells ; }, abstract = {A recent paper by (Gerlitz et al., Biol Direct 13:21, 2018) questions the validity of the data underlying prior analyses on the bioenergetics capacities of cells, and continues to promote the idea that the mitochondrion endowed eukaryotic cells with energetic superiority over prokaryotes. The former point has been addressed previously, with no resultant changes in the conclusions, and the latter point remains inconsistent with multiple lines of empirical data.}, } @article {pmid30537423, year = {2019}, author = {Tsakiri, EN and Gumeni, S and Iliaki, KK and Benaki, D and Vougas, K and Sykiotis, GP and Gorgoulis, VG and Mikros, E and Scorrano, L and Trougakos, IP}, title = {Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation.}, journal = {Aging cell}, volume = {18}, number = {1}, pages = {e12845}, pmid = {30537423}, issn = {1474-9726}, support = {BIOIMAGING-GR (MIS 5002755)//General Secretariat for Research and Technology, Greece/International ; TASCMAR (EU-H2020/634674)//European Union, H2020/International ; }, mesh = {*Adaptation, Physiological ; Aging/*physiology ; Animals ; Cytoprotection ; Drosophila Proteins/metabolism ; Drosophila melanogaster/*metabolism/*physiology ; Energy Metabolism ; Insulin/metabolism ; Metabolic Networks and Pathways ; Mitochondria/metabolism ; Mitochondrial Dynamics ; NF-E2-Related Factor 2/*metabolism ; Phenotype ; Signal Transduction ; Somatomedins/metabolism ; *Stress, Physiological ; }, abstract = {Metazoans viability depends on their ability to regulate metabolic processes and also to respond to harmful challenges by mounting anti-stress responses; these adaptations were fundamental forces during evolution. Central to anti-stress responses are a number of short-lived transcription factors that by functioning as stress sensors mobilize genomic responses aiming to eliminate stressors. We show here that increased expression of nuclear factor erythroid 2-related factor (Nrf2) in Drosophila activated cytoprotective modules and enhanced stress tolerance. However, while mild Nrf2 activation extended lifespan, high Nrf2 expression levels resulted in developmental lethality or, after inducible activation in adult flies, in altered mitochondrial bioenergetics, the appearance of Diabetes Type 1 hallmarks and aging acceleration. Genetic or dietary suppression of Insulin/IGF-like signaling (IIS) titrated Nrf2 activity to lower levels, largely normalized metabolic pathways signaling, and extended flies' lifespan. Thus, prolonged stress signaling by otherwise cytoprotective short-lived stress sensors perturbs IIS resulting in re-allocation of resources from growth and longevity to somatic preservation and stress tolerance. These findings provide a reasonable explanation of why most (if not all) cytoprotective stress sensors are short-lived proteins, and it also explains the build-in negative feedback loops (shown here for Nrf2); the low basal levels of these proteins, and why their suppressors were favored by evolution.}, } @article {pmid30481564, year = {2019}, author = {Xie, B and Wang, S and Jiang, N and Li, JJ}, title = {Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance.}, journal = {Cancer letters}, volume = {443}, number = {}, pages = {56-66}, pmid = {30481564}, issn = {1872-7980}, support = {R01 CA213830/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; CDC2 Protein Kinase/*metabolism ; Cell Cycle ; Cell Nucleus/metabolism ; Cyclin B1/*metabolism ; *Drug Resistance, Neoplasm ; Energy Metabolism ; Humans ; Mitochondria/metabolism ; Neoplasms/*metabolism ; }, abstract = {A mammalian cell houses two genomes located separately in the nucleus and mitochondria. During evolution, communications and adaptations between these two genomes occur extensively to achieve and sustain homeostasis for cellular functions and regeneration. Mitochondria provide the major cellular energy and contribute to gene regulation in the nucleus, whereas more than 98% of mitochondrial proteins are encoded by the nuclear genome. Such two-way signaling traffic presents an orchestrated dynamic between energy metabolism and consumption in cells. Recent reports have elucidated the way how mitochondrial bioenergetics synchronizes with the energy consumption for cell cycle progression mediated by cyclin B1/CDK1 as the communicator. This review is to recapitulate cyclin B1/CDK1 mediated mitochondrial activities in cell cycle progression and stress response as well as its potential link to reprogram energy metabolism in tumor adaptive resistance. Cyclin B1/CDK1-mediated mitochondrial bioenergetics is applied as an example to show how mitochondria could timely sense the cellular fuel demand and then coordinate ATP output. Such nucleus-mitochondria oscillation may play key roles in the flexible bioenergetics required for tumor cell survival and compromising the efficacy of anti-cancer therapy. Further deciphering the cyclin B1/CDK1-controlled mitochondrial metabolism may invent effect targets to treat resistant cancers.}, } @article {pmid30467693, year = {2019}, author = {Aw, WC and Garvin, MR and Ballard, JWO}, title = {Exogenous Factors May Differentially Influence the Selective Costs of mtDNA Mutations.}, journal = {Advances in anatomy, embryology, and cell biology}, volume = {231}, number = {}, pages = {51-74}, doi = {10.1007/102_2018_2}, pmid = {30467693}, issn = {0301-5556}, mesh = {Cell Nucleus/*metabolism ; DNA, Mitochondrial/*genetics ; Diet ; Electron Transport Complex I/*metabolism ; Energy Metabolism/*genetics/physiology ; Evolution, Molecular ; Genetic Fitness ; Humans ; Mitochondria/genetics/*metabolism ; Mutation ; Nutrients/*metabolism ; Signal Transduction/genetics ; Stress, Physiological ; Temperature ; }, abstract = {In this review, we provide evidence to suggest that the cost of specific mtDNA mutations can be influenced by exogenous factors. We focus on macronutrient-mitochondrial DNA interactions as factors that may differentially influence the consequences of a change as mitochondria must be flexible in its utilization of dietary proteins, carbohydrates, and fats. To understand this fundamental dynamic, we briefly discuss the energy processing pathways in mitochondria. Next, we explore the mitochondrial functions that are initiated during energy deficiency or when cells encounter cellular stress. We consider the anterograde response (nuclear control of mitochondrial function) and the retrograde response (nuclear changes in response to mitochondrial signaling) and how this mito-nuclear crosstalk may be influenced by exogenous factors such as temperature and diet. Finally, we employ Complex I of the mitochondrial electron transport system as a case study and discuss the potential role of the dietary macronutrient ratio as a strong selective force that may shape the frequencies of mitotypes in populations and species. We conclude that this underexplored field likely has implications in the fundamental disciplines of evolutionary biology and quantitative genetics and the more biomedical fields of nutrigenomics and pharmacogenomics.}, } @article {pmid30466901, year = {2019}, author = {Hampl, V and Čepička, I and Eliáš, M}, title = {Was the Mitochondrion Necessary to Start Eukaryogenesis?.}, journal = {Trends in microbiology}, volume = {27}, number = {2}, pages = {96-104}, doi = {10.1016/j.tim.2018.10.005}, pmid = {30466901}, issn = {1878-4380}, mesh = {Adenosine Triphosphate ; Archaea/physiology ; *Biological Evolution ; Eukaryota/genetics/*physiology ; Eukaryotic Cells/*physiology ; Genome ; Mitochondria/genetics/*physiology ; Phagocytosis ; Prokaryotic Cells/physiology ; Symbiosis ; }, abstract = {Arguments based on cell energetics favour the view that a mitochondrion capable of oxidative phosphorylation was a prerequisite for the evolution of other features of the eukaryotic cell, including increased volume, genome size and, eventually, phagotrophy. Contrary to this we argue that: (i) extant amitochondriate eukaryotes possess voluminous phagotrophic cells with large genomes; (ii) picoeukaryotes demonstrate that phagotrophy is feasible at prokaryotic cell sizes; and (iii) the assumption that evolution of complex features requires extra ATP, often mentioned in this context, is unfounded and should not be used in such considerations. We claim that the diversity of cell organisations and functions observed today in eukaryotes gives no reason to postulate that a mitochondrion must have preceded phagocytosis in eukaryogenesis.}, } @article {pmid30385634, year = {2018}, author = {Loell, K and Nanda, V}, title = {Marginal protein stability drives subcellular proteome isoelectric point.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {115}, number = {46}, pages = {11778-11783}, pmid = {30385634}, issn = {1091-6490}, support = {80NSSC18K0093//Intramural NASA/United States ; DP2 OD006478/OD/NIH HHS/United States ; }, mesh = {Computer Simulation ; Databases, Protein ; Evolution, Molecular ; Humans ; Hydrogen-Ion Concentration ; Isoelectric Point ; Lysosomes/metabolism ; Protein Folding ; Protein Stability ; Proteome/*chemistry/metabolism ; Proteomics/*methods ; Subcellular Fractions/chemistry/metabolism ; }, abstract = {There exists a positive correlation between the pH of subcellular compartments and the median isoelectric point (pI) for the associated proteomes. Proteins in the human lysosome-a highly acidic compartment in the cell-have a median pI of ∼6.5, whereas proteins in the more basic mitochondria have a median pI of ∼8.0. Proposed mechanisms reflect potential adaptations to pH. For example, enzyme active site general acid/base residue pKs are likely evolved to match environmental pH. However, such effects would be limited to a few residues on specific proteins, and might not affect the proteome at large. A protein model that considers residue burial upon folding recapitulates the correlation between proteome pI and environmental pH. This correlation can be fully described by a neutral evolution process; no functional selection is included in the model. Proteins in acidic environments incur a lower energetic penalty for burying acidic residues than basic residues, resulting in a net accumulation of acidic residues in the protein core. The inverse is true under alkaline conditions. The pI distributions of subcellular proteomes are likely not a direct result of functional adaptations to pH, but a molecular spandrel stemming from marginal stability.}, } @article {pmid30239783, year = {2018}, author = {Hood, WR and Austad, SN and Bize, P and Jimenez, AG and Montooth, KL and Schulte, PM and Scott, GR and Sokolova, I and Treberg, JR and Salin, K}, title = {The Mitochondrial Contribution to Animal Performance, Adaptation, and Life-History Variation.}, journal = {Integrative and comparative biology}, volume = {58}, number = {3}, pages = {480-485}, pmid = {30239783}, issn = {1557-7023}, support = {P30 DK056336/DK/NIDDK NIH HHS/United States ; P30 DK079626/DK/NIDDK NIH HHS/United States ; }, mesh = {*Acclimatization ; Animals ; *Energy Metabolism ; *Life History Traits ; Mitochondria/*physiology ; }, abstract = {Animals display tremendous variation in their rates of growth, reproductive output, and longevity. While the physiological and molecular mechanisms that underlie this variation remain poorly understood, the performance of the mitochondrion has emerged as a key player. Mitochondria not only impact the performance of eukaryotes via their capacity to produce ATP, but they also play a role in producing heat and reactive oxygen species and function as a major signaling hub for the cell. The papers included in this special issue emerged from a symposium titled "Inside the Black Box: The Mitochondrial Basis of Life-history Variation and Animal Performance." Based on studies of diverse animal taxa, three distinct themes emerged from these papers. (1) When linking mitochondrial function to components of fitness, it is crucial that mitochondrial assays are performed in conditions as close as the intracellular conditions experienced by the mitochondria in vivo. (2) Functional plasticity allows mitochondria to retain their performance, as well as that of their host, over a range of exogenous conditions, and selection on mitochondrial and nuclear-derived proteins can optimize the match between the environment and the bioenergetic capacity of the mitochondrion. Finally, (3) studies of wild and wild-derived animals suggest that mitochondria play a central role in animal performance and life history strategy. Taken as a whole, we hope that these papers will foster discussion and inspire new hypotheses and innovations that will further our understanding of the mitochondrial processes that underlie variation in life history traits and animal performance.}, } @article {pmid30230466, year = {2018}, author = {Cordier-Bussat, M and Thibert, C and Sujobert, P and Genestier, L and Fontaine, É and Billaud, M}, title = {[Even the Warburg effect can be oxidized: metabolic cooperation and tumor development].}, journal = {Medecine sciences : M/S}, volume = {34}, number = {8-9}, pages = {701-708}, doi = {10.1051/medsci/20183408017}, pmid = {30230466}, issn = {1958-5381}, mesh = {Cell Transformation, Neoplastic/metabolism/pathology ; Energy Metabolism/*physiology ; Glycolysis/*physiology ; Humans ; Mitochondria/metabolism ; Neoplasms/*metabolism/*pathology ; Oxidation-Reduction ; Tumor Microenvironment/*physiology ; }, abstract = {During tumor development, malignant cells rewire their metabolism to meet the biosynthetic needs required to increase their biomass and to overcome their microenvironment constraints. The sustained activation of aerobic glycolysis, also called Warburg effect, is one of these adaptative mechanisms. The progresses in this area of research have revealed the flexibility of cancer cells that alternate between glycolytic and oxidative metabolism to cope with their conditions of development while sharing their energetic resources. In this survey, we review these recent breakthroughs and discuss a model that likens tumor to an evolutive metabolic ecosystem. We further emphasize the ensuing therapeutic applications that target metabolic weaknesses of neoplastic cells.}, } @article {pmid30144423, year = {2018}, author = {Pustylnikov, S and Costabile, F and Beghi, S and Facciabene, A}, title = {Targeting mitochondria in cancer: current concepts and immunotherapy approaches.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {202}, number = {}, pages = {35-51}, pmid = {30144423}, issn = {1878-1810}, support = {R01 CA206012/CA/NCI NIH HHS/United States ; R01 CA219871/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; DNA, Mitochondrial/genetics ; Humans ; *Immunotherapy ; Mitochondria/*metabolism ; Mitochondrial Dynamics ; Neoplasms/*immunology/*therapy ; T-Lymphocytes/metabolism ; }, abstract = {An essential advantage during eukaryotic cell evolution was the acquisition of a network of mitochondria as a source of energy for cell metabolism and contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation including mitochondrial biogenesis, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. In cancer, the metabolism of cells is reprogrammed for energy generation from oxidative phosphorylation to aerobic glycolysis and impacts cancer mitochondrial function. Furthermore cancer cells can also modulate energy metabolism within the cancer microenvironment including immune cells and induce "metabolic anergy" of antitumor immune response. Classical approaches targeting the mitochondria of cancer cells usually aim at inducing changing energy metabolism or directly affecting functions of mitochondrial antiapoptotic proteins but most of such approaches miss the required specificity of action and carry important side effects. Several types of cancers harbor somatic mitochondrial DNA mutations and specific immune response to mutated mitochondrial proteins has been observed. An attractive alternative way to target the mitochondria in cancer cells is the induction of an adaptive immune response against mutated mitochondrial proteins. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial DNA mutations or Tumor Associated Mitochondria Antigens using the immune system.}, } @article {pmid30061407, year = {2018}, author = {Nagano, H and Hashimoto, N and Nakayama, A and Suzuki, S and Miyabayashi, Y and Yamato, A and Higuchi, S and Fujimoto, M and Sakuma, I and Beppu, M and Yokoyama, M and Suzuki, Y and Sugano, S and Ikeda, K and Tatsuno, I and Manabe, I and Yokote, K and Inoue, S and Tanaka, T}, title = {p53-inducible DPYSL4 associates with mitochondrial supercomplexes and regulates energy metabolism in adipocytes and cancer cells.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {115}, number = {33}, pages = {8370-8375}, pmid = {30061407}, issn = {1091-6490}, mesh = {Adenosine Triphosphate/biosynthesis ; Adipocytes/*metabolism ; Animals ; Cell Line, Tumor ; *Energy Metabolism ; Humans ; Male ; Mice ; Mice, SCID ; Mitochondria/*metabolism ; Neoplasms/*metabolism ; Nerve Tissue Proteins/*physiology ; Obesity/metabolism ; Oxygen Consumption ; Tumor Suppressor Protein p53/*physiology ; Tumor Suppressor Proteins/physiology ; }, abstract = {The tumor suppressor p53 regulates multiple cellular functions, including energy metabolism. Metabolic deregulation is implicated in the pathogenesis of some cancers and in metabolic disorders and may result from the inactivation of p53 functions. Using RNA sequencing and ChIP sequencing of cancer cells and preadipocytes, we demonstrate that p53 modulates several metabolic processes via the transactivation of energy metabolism genes including dihydropyrimidinase-like 4 (DPYSL4). DPYSL4 is a member of the collapsin response mediator protein family, which is involved in cancer invasion and progression. Intriguingly, DPYSL4 overexpression in cancer cells and preadipocytes up-regulated ATP production and oxygen consumption, while DPYSL4 knockdown using siRNA or CRISPR/Cas9 down-regulated energy production. Furthermore, DPYSL4 was associated with mitochondrial supercomplexes, and deletion of its dihydropyrimidinase-like domain abolished its association and its ability to stimulate ATP production and suppress the cancer cell invasion. Mouse-xenograft and lung-metastasis models indicated that DPYSL4 expression compromised tumor growth and metastasis in vivo. Consistently, database analyses demonstrated that low DPYSL4 expression was significantly associated with poor survival of breast and ovarian cancers in accordance with its reduced expression in certain types of cancer tissues. Moreover, immunohistochemical analysis using the adipose tissue of obese patients revealed that DPYSL4 expression was positively correlated with INFg and body mass index in accordance with p53 activation. Together, these results suggest that DPYSL4 plays a key role in the tumor-suppressor function of p53 by regulating oxidative phosphorylation and the cellular energy supply via its association with mitochondrial supercomplexes, possibly linking to the pathophysiology of both cancer and obesity.}, } @article {pmid30060189, year = {2018}, author = {Río Bártulos, C and Rogers, MB and Williams, TA and Gentekaki, E and Brinkmann, H and Cerff, R and Liaud, MF and Hehl, AB and Yarlett, NR and Gruber, A and Kroth, PG and van der Giezen, M}, title = {Mitochondrial Glycolysis in a Major Lineage of Eukaryotes.}, journal = {Genome biology and evolution}, volume = {10}, number = {9}, pages = {2310-2325}, pmid = {30060189}, issn = {1759-6653}, support = {//Wellcome Trust/United Kingdom ; 078566/A/05/Z//Wellcome Trust/United Kingdom ; }, mesh = {Biological Evolution ; Blastocystis/cytology/enzymology/genetics/*metabolism ; Diatoms/cytology/enzymology/genetics/*metabolism ; Energy Metabolism ; Genome, Mitochondrial ; *Glycolysis ; Mitochondria/genetics/*metabolism ; Symbiosis ; Transformation, Genetic ; }, abstract = {The establishment of the mitochondrion is seen as a transformational step in the origin of eukaryotes. With the mitochondrion came bioenergetic freedom to explore novel evolutionary space leading to the eukaryotic radiation known today. The tight integration of the bacterial endosymbiont with its archaeal host was accompanied by a massive endosymbiotic gene transfer resulting in a small mitochondrial genome which is just a ghost of the original incoming bacterial genome. This endosymbiotic gene transfer resulted in the loss of many genes, both from the bacterial symbiont as well the archaeal host. Loss of genes encoding redundant functions resulted in a replacement of the bulk of the host's metabolism for those originating from the endosymbiont. Glycolysis is one such metabolic pathway in which the original archaeal enzymes have been replaced by bacterial enzymes from the endosymbiont. Glycolysis is a major catabolic pathway that provides cellular energy from the breakdown of glucose. The glycolytic pathway of eukaryotes appears to be bacterial in origin, and in well-studied model eukaryotes it takes place in the cytosol. In contrast, here we demonstrate that the latter stages of glycolysis take place in the mitochondria of stramenopiles, a diverse and ecologically important lineage of eukaryotes. Although our work is based on a limited sample of stramenopiles, it leaves open the possibility that the mitochondrial targeting of glycolytic enzymes in stramenopiles might represent the ancestral state for eukaryotes.}, } @article {pmid30005062, year = {2018}, author = {Salunke, R and Mourier, T and Banerjee, M and Pain, A and Shanmugam, D}, title = {Highly diverged novel subunit composition of apicomplexan F-type ATP synthase identified from Toxoplasma gondii.}, journal = {PLoS biology}, volume = {16}, number = {7}, pages = {e2006128}, pmid = {30005062}, issn = {1545-7885}, mesh = {Amino Acid Sequence ; Animals ; Conserved Sequence ; Gene Expression Regulation ; Genetic Variation ; Hemagglutinins/metabolism ; Mitochondria/metabolism ; Mitochondrial Proton-Translocating ATPases/*metabolism ; Parasites/metabolism ; Phylogeny ; Plasmodium falciparum/metabolism ; Protein Multimerization ; Protein Subunits/*metabolism ; Proteome/metabolism ; Proteomics ; Protozoan Proteins/chemistry/isolation & purification/metabolism ; Recombinant Fusion Proteins/metabolism ; Toxoplasma/*enzymology ; }, abstract = {The mitochondrial F-type ATP synthase, a multisubunit nanomotor, is critical for maintaining cellular ATP levels. In T. gondii and other apicomplexan parasites, many subunit components necessary for proper assembly and functioning of this enzyme appear to be missing. Here, we report the identification of 20 novel subunits of T. gondii F-type ATP synthase from mass spectrometry analysis of partially purified monomeric (approximately 600 kDa) and dimeric (>1 MDa) forms of the enzyme. Despite extreme sequence diversification, key FO subunits a, b, and d can be identified from conserved structural features. Orthologs for these proteins are restricted to apicomplexan, chromerid, and dinoflagellate species. Interestingly, their absence in ciliates indicates a major diversion, with respect to subunit composition of this enzyme, within the alveolate clade. Discovery of these highly diversified novel components of the apicomplexan F-type ATP synthase complex could facilitate the development of novel antiparasitic agents. Structural and functional characterization of this unusual enzyme complex will advance our fundamental understanding of energy metabolism in apicomplexan species.}, } @article {pmid29992378, year = {2018}, author = {Kasperski, A and Kasperska, R}, title = {Bioenergetics of life, disease and death phenomena.}, journal = {Theory in biosciences = Theorie in den Biowissenschaften}, volume = {137}, number = {2}, pages = {155-168}, pmid = {29992378}, issn = {1611-7530}, mesh = {Adenosine Triphosphate/chemistry ; Animals ; *Cell Biology ; DNA/analysis ; *Energy Metabolism ; Genome, Human ; Glucose/chemistry ; Humans ; Mitochondria/metabolism ; Models, Biological ; Mutation ; Neoplasms/*genetics/*pathology ; Oxygen/chemistry ; Reactive Oxygen Species/chemistry ; }, abstract = {In this article, some new aspects of unified cell bioenergetics are presented. From the perspective of unified cell bioenergetics certain subsequent stages of cancer development, from initiation stage, through transformation to metastasis, are analyzed. Here we show that after transformation, cancer cells are permanently exposed to reactive oxygen species, that causes continual random DNA mutations and as a result genome and chromosomal destabilizations. The modern cancer attractor hypothesis has been extended in explaining cancer development. Discussion is conducted in light of current cancerogenesis research, including bioenergetic cancer initiation, the somatic mutation theory and the tissue organization field theory. In the article reasons complicating the discovery of patterns of cancer genome changes and cancer evolution are presented. In addition certain cancer therapeutic aspects are given attention to.}, } @article {pmid29987715, year = {2018}, author = {Rolland, N and Bouchnak, I and Moyet, L and Salvi, D and Kuntz, M}, title = {The Main Functions of Plastids.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {1829}, number = {}, pages = {73-85}, doi = {10.1007/978-1-4939-8654-5_5}, pmid = {29987715}, issn = {1940-6029}, mesh = {Biological Evolution ; Energy Metabolism ; Plastids/*physiology/ultrastructure ; }, abstract = {Plastids are semiautonomous organelles like mitochondria, and derive from a cyanobacterial ancestor that was engulfed by a host cell. During evolution, they have recruited proteins originating from the nuclear genome, and only parts of their ancestral metabolic properties were conserved and optimized to limit functional redundancy with other cell compartments. Furthermore, large disparities in metabolic functions exist among various types of plastids, and the characterization of their various metabolic properties is far from being accomplished. In this review, we provide an overview of the main functions, known to be achieved by plastids or shared by plastids and other compartments of the cell. In short, plastids appear at the heart of all main plant functions.}, } @article {pmid29950419, year = {2018}, author = {Bilz, NC and Jahn, K and Lorenz, M and Lüdtke, A and Hübschen, JM and Geyer, H and Mankertz, A and Hübner, D and Liebert, UG and Claus, C}, title = {Rubella Viruses Shift Cellular Bioenergetics to a More Oxidative and Glycolytic Phenotype with a Strain-Specific Requirement for Glutamine.}, journal = {Journal of virology}, volume = {92}, number = {17}, pages = {}, pmid = {29950419}, issn = {1098-5514}, mesh = {A549 Cells ; Endothelial Cells/metabolism/virology ; *Energy Metabolism ; Glucose/metabolism/pharmacology ; Glutamine/*metabolism/pharmacology ; Glycolysis/*drug effects ; Homeostasis ; Humans ; Kynurenine/metabolism ; Metabolic Networks and Pathways/drug effects ; Mitochondria/metabolism ; Nucleotides/biosynthesis ; Oxidation-Reduction ; Oxidative Stress ; Oxygen Consumption/drug effects/*physiology ; Phenotype ; Pyruvic Acid/metabolism/pharmacology ; Rubella virus/*metabolism ; Virus Replication/drug effects ; }, abstract = {The flexible regulation of cellular metabolic pathways enables cellular adaptation to changes in energy demand under conditions of stress such as posed by a virus infection. To analyze such an impact on cellular metabolism, rubella virus (RV) was used in this study. RV replication under selected substrate supplementation with glucose, pyruvate, and glutamine as essential nutrients for mammalian cells revealed its requirement for glutamine. The assessment of the mitochondrial respiratory (based on the oxygen consumption rate) and glycolytic (based on the extracellular acidification rate) rate and capacity by respective stress tests through Seahorse technology enabled determination of the bioenergetic phenotype of RV-infected cells. Irrespective of the cellular metabolic background, RV infection induced a shift of the bioenergetic state of epithelial cells (Vero and A549) and human umbilical vein endothelial cells to a higher oxidative and glycolytic level. Interestingly there was a RV strain-specific, but genotype-independent demand for glutamine to induce a significant increase in metabolic activity. While glutaminolysis appeared to be rather negligible for RV replication, glutamine could serve as donor of its amide nitrogen in biosynthesis pathways for important metabolites. This study suggests that the capacity of RVs to induce metabolic alterations could evolve differently during natural infection. Thus, changes in cellular bioenergetics represent an important component of virus-host interactions and could complement our understanding of the viral preference for a distinct host cell population.IMPORTANCE RV pathologies, especially during embryonal development, could be connected with its impact on mitochondrial metabolism. With bioenergetic phenotyping we pursued a rather novel approach in virology. For the first time it was shown that a virus infection could shift the bioenergetics of its infected host cell to a higher energetic state. Notably, the capacity to induce such alterations varied among different RV isolates. Thus, our data add viral adaptation of cellular metabolic activity to its specific needs as a novel aspect to virus-host evolution. In addition, this study emphasizes the implementation of different viral strains in the study of virus-host interactions and the use of bioenergetic phenotyping of infected cells as a biomarker for virus-induced pathological alterations.}, } @article {pmid29945242, year = {2018}, author = {Buchanan, JL and Meiklejohn, CD and Montooth, KL}, title = {Mitochondrial Dysfunction and Infection Generate Immunity-Fecundity Tradeoffs in Drosophila.}, journal = {Integrative and comparative biology}, volume = {58}, number = {3}, pages = {591-603}, pmid = {29945242}, issn = {1557-7023}, support = {R01 GM067862/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Drosophila melanogaster/genetics/*physiology ; Drosophila simulans/genetics/*physiology ; Female ; Fertility ; *Genotype ; Hybridization, Genetic ; Immunity, Innate ; *Life History Traits ; Male ; Mitochondria/*physiology ; Nutritional Status ; Oxidative Phosphorylation ; Stress, Physiological ; }, abstract = {Physiological responses to short-term environmental stressors, such as infection, can have long-term consequences for fitness, particularly if the responses are inappropriate or nutrient resources are limited. Genetic variation affecting energy acquisition, storage, and usage can limit cellular energy availability and may influence resource-allocation tradeoffs even when environmental nutrients are plentiful. Here, we utilized Drosophila mitochondrial-nuclear genotypes to test whether disrupted mitochondrial function interferes with nutrient-sensing pathways, and whether this disruption has consequences for tradeoffs between immunity and fecundity. We found that an energetically-compromised genotype was relatively resistant to rapamycin-a drug that targets nutrient-sensing pathways and mimics resource limitation. Dietary resource limitation decreased survival of energetically-compromised flies. Furthermore, survival of infection with a natural pathogen was decreased in this genotype, and females of this genotype experienced immunity-fecundity tradeoffs that were not evident in genotypic controls with normal energy metabolism. Together, these results suggest that this genotype may have little excess energetic capacity and fewer cellular nutrients, even when environmental nutrients are not limiting. Genetic variation in energy metabolism may therefore act to limit the resources available for allocation to life-history traits in ways that generate tradeoffs even when environmental resources are not limiting.}, } @article {pmid29892953, year = {2018}, author = {Liu, W and Hu, C and Xie, W and Chen, P and Zhang, Y and Yao, R and Li, K and Chang, Q}, title = {The mitochondrial genome of red-necked phalarope Phalaropus lobatus (Charadriiformes: Scolopacidae) and phylogeny analysis among Scolopacidae.}, journal = {Genes & genomics}, volume = {40}, number = {5}, pages = {455-463}, pmid = {29892953}, issn = {2092-9293}, mesh = {Animals ; Base Composition/genetics ; Base Sequence/genetics ; Birds/genetics ; Charadriiformes/*genetics ; DNA, Mitochondrial/genetics ; Genome, Mitochondrial/*genetics ; Mitochondria/genetics ; Nucleic Acid Conformation ; Phylogeny ; RNA, Ribosomal/genetics ; RNA, Transfer/genetics ; Sequence Analysis, DNA ; }, abstract = {The red-necked phalarope is a wonderful species with specific morphological characters and lifestyles. Mitochondrial genomes, encoding necessary proteins involved in the system of energy metabolism, are important for the evolution and adaption of species. In this study, we determined the complete mitogenome sequence of Phalaropus lobatus (Charadriiformes: Scolopacidae). The circular genome is 16714 bp in size, containing 13 PCGs, two ribosomal RNAs and 22 tRNAs and a high AT-rich control region. The AT skew and GC skew of major strand is positive and negative respectively. Most of PCGs are biased towards A-rich except ND1. A codon usage analysis shows that 3 start codons (ATG, GTG and ATA), 4 stop codons (TAA, TAG, AGG, AGA) and two incomplete terminate codons (T-). Twenty two transfer RNAs have the typical cloverleaf structure, and a total of ten base pairs are mismatched throughout the nine tRNA genes. The phylogenetic tree based on 13 PCGs and 2 rRNA genes indicates that monophyly of the family and genus Phalaropus is close to genus Xenus plus Tringa. The analysis of selective pressure shows 13 protein-coding genes are evolving under the purifying selection and P. lobatus is different from other Scolopacidae species on the selective pressure of gene ND4. This study helps us know the inherent mechanism of mitochondrial structure and natural selection.}, } @article {pmid29873740, year = {2018}, author = {Scott, GR and Guo, KH and Dawson, NJ}, title = {The Mitochondrial Basis for Adaptive Variation in Aerobic Performance in High-Altitude Deer Mice.}, journal = {Integrative and comparative biology}, volume = {58}, number = {3}, pages = {506-518}, doi = {10.1093/icb/icy056}, pmid = {29873740}, issn = {1557-7023}, mesh = {*Acclimatization ; *Altitude ; Animals ; Mitochondria/*physiology ; Peromyscus/*physiology ; }, abstract = {Mitochondria play a central role in aerobic performance. Studies aimed at elucidating how evolved variation in mitochondrial physiology contributes to adaptive variation in aerobic performance can therefore provide a unique and powerful lens to understanding the evolution of complex physiological traits. Here, we review our ongoing work on the importance of changes in mitochondrial quantity and quality to adaptive variation in aerobic performance in high-altitude deer mice. Whole-organism aerobic capacity in hypoxia (VO2max) increases in response to hypoxia acclimation in this species, but high-altitude populations have evolved consistently greater VO2max than populations from low altitude. The evolved increase in VO2max in highlanders is associated with an evolved increase in the respiratory capacity of the gastrocnemius muscle. This appears to result from highlanders having more mitochondria in this tissue, attributed to a higher proportional abundance of oxidative fiber-types and a greater mitochondrial volume density within oxidative fibers. The latter is primarily caused by an over-abundance of subsarcolemmal mitochondria in high-altitude mice, which is likely advantageous for mitochondrial O2 supply because more mitochondria are situated adjacent to the cell membrane and close to capillaries. Evolved changes in gastrocnemius phenotype appear to be underpinned by population differences in the expression of genes involved in energy metabolism, muscle development, and vascular development. Hypoxia acclimation has relatively little effect on respiratory capacity of the gastrocnemius, but it increases respiratory capacity of the diaphragm. However, the mechanisms responsible for this increase differ between populations: lowlanders appear to adjust mitochondrial quantity and quality (i.e., increases in citrate synthase [CS] activity, and mitochondrial respiration relative to CS activity) and they exhibit higher rates of mitochondrial release of reactive oxygen species, whereas highlanders only increase mitochondrial quantity in response to hypoxia acclimation. In contrast to the variation in skeletal muscles, the respiratory capacity of cardiac muscle does not appear to be affected by hypoxia acclimation and varies little between populations. Therefore, evolved changes in mitochondrial quantity and quality make important tissue-specific contributions to adaptive variation in aerobic performance in high-altitude deer mice.}, } @article {pmid29848286, year = {2018}, author = {Darbani, B and Kell, DB and Borodina, I}, title = {Energetic evolution of cellular Transportomes.}, journal = {BMC genomics}, volume = {19}, number = {1}, pages = {418}, pmid = {29848286}, issn = {1471-2164}, support = {BB/P009042/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/M006891/1, BB/M017702/1 and BB/P009042/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {*Energy Metabolism ; *Evolution, Molecular ; *Genomics ; Membrane Transport Proteins/*metabolism ; }, abstract = {BACKGROUND: Transporter proteins mediate the translocation of substances across the membranes of living cells. Many transport processes are energetically expensive and the cells use 20 to 60% of their energy to power the transportomes. We hypothesized that there may be an evolutionary selection pressure for lower energy transporters.

RESULTS: We performed a genome-wide analysis of the compositional reshaping of the transportomes across the kingdoms of bacteria, archaea, and eukarya. We found that the share of ABC transporters is much higher in bacteria and archaea (ca. 27% of the transportome) than in primitive eukaryotes (13%), algae and plants (10%) and in fungi and animals (5-6%). This decrease is compensated by an increased occurrence of secondary transporters and ion channels. The share of ion channels is particularly high in animals (ca. 30% of the transportome) and algae and plants with (ca. 13%), when compared to bacteria and archaea with only 6-7%. Therefore, our results show a move to a preference for the low-energy-demanding transporters (ion channels and carriers) over the more energy-costly transporter classes (ATP-dependent families, and ABCs in particular) as part of the transition from prokaryotes to eukaryotes. The transportome analysis also indicated seven bacterial species, including Neorickettsia risticii and Neorickettsia sennetsu, as likely origins of the mitochondrion in eukaryotes, based on the phylogenetically restricted presence therein of clear homologues of modern mitochondrial solute carriers.

CONCLUSIONS: The results indicate that the transportomes of eukaryotes evolved strongly towards a higher energetic efficiency, as ATP-dependent transporters diminished and secondary transporters and ion channels proliferated. These changes have likely been important in the development of tissues performing energetically costly cellular functions.}, } @article {pmid29730527, year = {2018}, author = {van der Hoek, MD and Madsen, O and Keijer, J and van der Leij, FR}, title = {Evolutionary analysis of the carnitine- and choline acyltransferases suggests distinct evolution of CPT2 versus CPT1 and related variants.}, journal = {Biochimica et biophysica acta. Molecular and cell biology of lipids}, volume = {1863}, number = {8}, pages = {909-918}, doi = {10.1016/j.bbalip.2018.05.001}, pmid = {29730527}, issn = {1388-1981}, mesh = {Animals ; Caenorhabditis elegans/enzymology/genetics ; Carnitine/metabolism ; Carnitine O-Palmitoyltransferase/*genetics/metabolism ; Choline/metabolism ; Drosophila/enzymology/genetics ; *Evolution, Molecular ; Exons/genetics ; Introns/genetics ; Isoenzymes/genetics/metabolism ; Mitochondria/*enzymology ; *Phylogeny ; Yeasts/enzymology/genetics ; }, abstract = {Carnitine/choline acyltransferases play diverse roles in energy metabolism and neuronal signalling. Our knowledge of their evolutionary relationships, important for functional understanding, is incomplete. Therefore, we aimed to determine the evolutionary relationships of these eukaryotic transferases. We performed extensive phylogenetic and intron position analyses. We found that mammalian intramitochondrial CPT2 is most closely related to cytosolic yeast carnitine transferases (Sc-YAT1 and 2), whereas the other members of the family are related to intraorganellar yeast Sc-CAT2. Therefore, the cytosolically active CPT1 more closely resembles intramitochondrial ancestors than CPT2. The choline acetyltransferase is closely related to carnitine acetyltransferase and shows lower evolutionary rates than long chain acyltransferases. In the CPT1 family several duplications occurred during animal radiation, leading to the isoforms CPT1A, CPT1B and CPT1C. In addition, we found five CPT1-like genes in Caenorhabditis elegans that strongly group to the CPT1 family. The long branch leading to mammalian brain isoform CPT1C suggests that either strong positive or relaxed evolution has taken place on this node. The presented evolutionary delineation of carnitine/choline acyltransferases adds to current knowledge on their functions and provides tangible leads for further experimental research.}, } @article {pmid29495437, year = {2018}, author = {Mansilla, N and Racca, S and Gras, DE and Gonzalez, DH and Welchen, E}, title = {The Complexity of Mitochondrial Complex IV: An Update of Cytochrome c Oxidase Biogenesis in Plants.}, journal = {International journal of molecular sciences}, volume = {19}, number = {3}, pages = {}, pmid = {29495437}, issn = {1422-0067}, mesh = {Animals ; Catalytic Domain ; Electron Transport Complex IV/chemistry/genetics/*metabolism ; *Energy Metabolism ; Enzyme Activation ; Gene Expression Regulation, Plant ; Humans ; Mammals/genetics/metabolism ; Mitochondria/genetics/*metabolism ; Mutation ; Plant Development ; Plant Physiological Phenomena ; Plants/genetics/*metabolism ; Protein Subunits ; Yeasts/genetics/metabolism ; }, abstract = {Mitochondrial respiration is an energy producing process that involves the coordinated action of several protein complexes embedded in the inner membrane to finally produce ATP. Complex IV or Cytochrome c Oxidase (COX) is the last electron acceptor of the respiratory chain, involved in the reduction of O2 to H2O. COX is a multimeric complex formed by multiple structural subunits encoded in two different genomes, prosthetic groups (heme a and heme a3), and metallic centers (CuA and CuB). Tens of accessory proteins are required for mitochondrial RNA processing, synthesis and delivery of prosthetic groups and metallic centers, and for the final assembly of subunits to build a functional complex. In this review, we perform a comparative analysis of COX composition and biogenesis factors in yeast, mammals and plants. We also describe possible external and internal factors controlling the expression of structural proteins and assembly factors at the transcriptional and post-translational levels, and the effect of deficiencies in different steps of COX biogenesis to infer the role of COX in different aspects of plant development. We conclude that COX assembly in plants has conserved and specific features, probably due to the incorporation of a different set of subunits during evolution.}, } @article {pmid29383422, year = {2018}, author = {Yu, H and Wang, D and Zou, L and Zhang, Z and Xu, H and Zhu, F and Ren, X and Xu, B and Yuan, J and Liu, J and Spencer, PS and Yang, X}, title = {Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: implication for Alzheimer's disease.}, journal = {Archives of toxicology}, volume = {92}, number = {4}, pages = {1363-1382}, doi = {10.1007/s00204-018-2163-6}, pmid = {29383422}, issn = {1432-0738}, mesh = {Alzheimer Disease/*chemically induced/*metabolism ; Animals ; Brain/*drug effects/metabolism/ultrastructure ; Copper/*toxicity ; Hippocampus/drug effects/metabolism/ultrastructure ; Memory Disorders ; Mice ; Mice, Transgenic ; Mitochondria/*metabolism ; Mitochondrial Proteins/*metabolism ; Proteomics ; Spatial Memory ; }, abstract = {Excessive copper intake can lead to neurotoxicity, but there is a lack of comprehensive understanding on the potential impact of copper exposure especially at a low-dose on brain. We used 3xTg-AD mice to explore the potential neurotoxicity of chronic, low-dose copper treatment (0.13 ppm copper chloride in drinking water) on behavior and the brain hippocampal mitochondrial and nuclear proteome. Low-dose copper increased the spatial memory impairment of these animals, increased accumulation of intracellular amyloid 1-42 (Aβ1-42), decreased ATP content, increased the positive staining of 8-hydroxyguanosine (8-OHdG), a marker of DNA oxidative damage, and caused apoptosis and a decrease in synaptic proteins. Mitochondrial proteomic analysis by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) revealed modulation of 24 hippocampal mitochondrial proteins (14 increased and 10 decreased) in copper-treated vs. untreated 3xTg-AD mice. Nuclear proteomic analysis revealed 43 modulated hippocampal nuclear proteins (25 increased and 18 decreased) in copper-treated 3xTg-AD vs. untreated mice. Classification of modulated mitochondrial and nuclear proteins included functional categories such as energy metabolism, synaptic-related proteins, DNA damage and apoptosis-related proteins, and oxidative stress-related proteins. Among these differentially expressed mitochondrial and nuclear proteins, nine proteins were abnormally expressed in both hippocampus mitochondria and nuclei, including electron transport chain-related proteins NADH dehydrogenase 1 alpha subcomplex subunit 10 (NDUAA), cytochrome b-c1 complex subunit Rieske (UCRI), cytochrome c oxidase subunit 5B (COX5B), and ATP synthase subunit d (ATP5H), glycolytic-related pyruvate kinase PKM (KPYM) and pyruvate dehydrogenase E1 component subunit alpha (ODPA). Furthermore, we found coenzyme Q10 (CoQ10), an endogenous mitochondrial protective factor/antioxidant, modulated the expression of 12 differentially expressed hippocampal proteins (4 increased and 8 decreased), which could be classified in functional categories such as glycolysis and synaptic-related proteins, oxidative stress-related proteins, implying that CoQ10 improved synaptic function, suppress oxidative stress, and regulate glycolysis. For the proteomics study, we validated the expression of several proteins related to synapses, DNA and apoptosis. The data confirmed that synapsin-2, a synaptic-related protein, was significantly decreased in both mitochondria and nuclei of copper-exposed 3xTg-AD mice. In mitochondria, dynamin-1 (DYN1), an apoptosis-related proteins, was significantly decreased. In the cellular nuclei, paraspeckle protein 1 (PSPC1) and purin-rich element-binding protein alpha (Purα), two DNA damage-related proteins, were significantly decreased and increased, respectively. We conclude that low-dose copper exposure exacerbates the spatial memory impairment of 3xTg-AD mice and perturbs multiple biological/pathogenic processes by dysregulating the mitochondrial and nuclear proteome. Exposure to copper might therefore contribute to the evolution of AD.}, } @article {pmid29370159, year = {2018}, author = {Lane, N}, title = {Hot mitochondria?.}, journal = {PLoS biology}, volume = {16}, number = {1}, pages = {e2005113}, pmid = {29370159}, issn = {1545-7885}, mesh = {Animals ; Energy Metabolism ; Fluorescent Dyes ; Hot Temperature ; Humans ; Membrane Proteins ; Mitochondria/*physiology ; Temperature ; Thermogenesis/*physiology ; Xanthenes ; }, abstract = {Mitochondria generate most of the heat in endotherms. Given some impedance of heat transfer across protein-rich bioenergetic membranes, mitochondria must operate at a higher temperature than body temperature in mammals and birds. But exactly how much hotter has been controversial, with physical calculations suggesting that maximal heat gradients across cells could not be greater than 10(-5) K. Using the thermosensitive mitochondrial-targeted fluorescent dye Mito Thermo Yellow (MTY), Chrétien and colleagues suggest that mitochondria are optimised to nearly 50 °C, 10 °C hotter than body temperature. This extreme value questions what temperature really means in confined far-from-equilibrium systems but encourages a reconsideration of thermal biology.}, } @article {pmid29182013, year = {2017}, author = {Dickerson, T and Jauregui, CE and Teng, Y}, title = {Friend or foe? Mitochondria as a pharmacological target in cancer treatment.}, journal = {Future medicinal chemistry}, volume = {9}, number = {18}, pages = {2197-2210}, doi = {10.4155/fmc-2017-0110}, pmid = {29182013}, issn = {1756-8927}, mesh = {ATPases Associated with Diverse Cellular Activities/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Antineoplastic Agents/pharmacology/therapeutic use ; DNA, Mitochondrial/drug effects/metabolism ; Energy Metabolism/drug effects ; Humans ; Membrane Proteins/metabolism ; Mitochondria/genetics/*metabolism ; Mitochondrial Proteins/metabolism ; Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Mitochondria have acquired numerous functions over the course of evolution, such as those involved in controlling energy production, cellular metabolism, cell survival, apoptosis and autophagy within host cells. Tumor cells can develop defects in mitochondrial function, presenting a potential strategy for designing selective anticancer therapies. Therefore, cancer has been the main focus of recent research to uncover possible mitochondrial targets for therapeutic benefit. This comprehensive review covers not only the recent discoveries of the roles of mitochondria in cancer development, progression and therapeutic implications but also the findings regarding emerging mitochondrial therapeutic targets and mitochondria-targeted agents. Current challenges and future directions for developments and applications of mitochondrial-targeted therapeutics are also discussed.}, } @article {pmid29155008, year = {2018}, author = {McDonald, AE and Pichaud, N and Darveau, CA}, title = {"Alternative" fuels contributing to mitochondrial electron transport: Importance of non-classical pathways in the diversity of animal metabolism.}, journal = {Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology}, volume = {224}, number = {}, pages = {185-194}, doi = {10.1016/j.cbpb.2017.11.006}, pmid = {29155008}, issn = {1879-1107}, mesh = {Animals ; Citric Acid Cycle/*physiology ; Electron Transport/physiology ; Glycolysis/*physiology ; Humans ; Mitochondria/*physiology ; *Oxidative Phosphorylation ; }, abstract = {The study of glycolysis, the TCA cycle, and oxidative phosphorylation in animals has yielded a wealth of information about bioenergetics. Less is known about how animals use fuels other than glucose and less characterized enzymes that are also used to provide electrons to the electron transport system. It has become clear that bioenergetic flexibility is employed by a wide variety of animals in order to successfully grow, maintain cells, and reproduce, and has contributed to the exploitation of new environments and ecological niches through evolution. In most cases, the discovery of these "alternative" fuels and non-classical pathways is relatively recent, but is starting to call into question long believed paradigms about the diversity of animal bioenergetics. We present several specific examples of these "alternatives" and the animals that use them and present some implications for animal mitochondrial physiology research.}, } @article {pmid29145028, year = {2018}, author = {Sun, S and Hui, M and Wang, M and Sha, Z}, title = {The complete mitochondrial genome of the alvinocaridid shrimp Shinkaicaris leurokolos (Decapoda, Caridea): Insight into the mitochondrial genetic basis of deep-sea hydrothermal vent adaptation in the shrimp.}, journal = {Comparative biochemistry and physiology. Part D, Genomics & proteomics}, volume = {25}, number = {}, pages = {42-52}, doi = {10.1016/j.cbd.2017.11.002}, pmid = {29145028}, issn = {1878-0407}, mesh = {Adaptation, Physiological/*genetics ; Animals ; Arthropod Proteins/*genetics ; Base Sequence ; Conserved Sequence ; Decapoda/*genetics/physiology ; *Genome, Mitochondrial ; *Hydrothermal Vents ; Open Reading Frames ; Phylogeny ; RNA, Ribosomal/genetics ; RNA, Transfer/genetics ; Sequence Homology, Nucleic Acid ; }, abstract = {Deep-sea hydrothermal vent is one of the most extreme environments on Earth with low oxygen and high levels of toxins. Decapod species from the family Alvinocarididae have colonized and successfully adapted to this extremely harsh environment. Mitochondria plays a vital role in oxygen usage and energy metabolism, thus it may be under selection in the adaptive evolution of the hydrothermal vent shrimps. In this study, the mitochondrial genome (mitogenome) of alvinocaridid shrimp Shinkaicaris leurokolos (Kikuchi & Hashimoto, 2000) was determined through Illumina sequencing. The mitogenome of S. leurokolos was 15,903bp in length, containing 13 protein-coding genes, 2 rRNAs, and 22 tRNAs. The gene order and orientation were identical to those of sequenced alvinocaridids. It has the longest concatenated sequences of protein-coding genes, tRNAs and shortest pooled rRNAs among the alvinocaridids. The control regions (CRs) of alvinocaridid were significantly longer (p<0.01) than those of the other caridaen. The alignment of the alvinocaridid CRs revealed two conserved sequence blocks (CSBs), and each of the CSBs included a noncanonical open reading frame (ORF), which may be involved in adjusting mitochondrial energy metabolism to adapt to the hydrothermal environment. Phylogenetic analysis supported that the deep-sea hydrothermal vent shrimps may have originated from those living in shallow area. Positive selection analysis reveals the evidence of adaptive change in the mitogenome of Alvinocarididae. Thirty potentially important adaptive residues were identified, which were located in atp6, cox1, cox3, cytb and nad1-5. This study explores the mitochondrial genetic basis of hydrothermal vent adaptation in alvinocaridid for the first time, and provides valuable clues regarding the adaptation.}, } @article {pmid29104545, year = {2017}, author = {Dobson, GP and Arsyad, A and Letson, HL}, title = {The Adenosine Hypothesis Revisited: Modulation of Coupling between Myocardial Perfusion and Arterial Compliance.}, journal = {Frontiers in physiology}, volume = {8}, number = {}, pages = {824}, pmid = {29104545}, issn = {1664-042X}, abstract = {For over four decades the thoracic aortic ring model has become one of the most widely used methods to study vascular reactivity and electromechanical coupling. A question that is rarely asked, however, is what function does a drug-mediated relaxation (or contraction) in this model serve in the intact system? The physiological significance of adenosine relaxation in rings isolated from large elastic conduit arteries from a wide range of species remains largely unknown. We propose that adenosine relaxation increases aortic compliance in acute stress states and facilitates ventricular-arterial (VA) coupling, and thereby links compliance and coronary artery perfusion to myocardial energy metabolism. In 1963 Berne argued that adenosine acts as a local negative feedback regulator between oxygen supply and demand in the heart during hypoxic/ischemic stress. The adenosine VA coupling hypothesis extends and enhances Berne's "adenosine hypothesis" from a local regulatory scheme in the heart to include conduit arterial function. In multicellular organisms, evolution may have selected adenosine, nitric oxide, and other vascular mediators, to modulate VA coupling for optimal transfer of oxygen (and nutrients) from the lung, heart, large conduit arteries, arterioles and capillaries to respiring mitochondria. Finally, a discussion of the potential clinical significance of adenosine modulation of VA coupling is extended to vascular aging and disease, including hypertension, diabetes, obesity, coronary artery disease and heart failure.}, } @article {pmid28993269, year = {2017}, author = {Bombaça, ACS and Dias, FA and Ennes-Vidal, V and Garcia-Gomes, ADS and Sorgine, MHF and d'Avila-Levy, CM and Menna-Barreto, RFS}, title = {Hydrogen peroxide resistance in Strigomonas culicis: Effects on mitochondrial functionality and Aedes aegypti interaction.}, journal = {Free radical biology & medicine}, volume = {113}, number = {}, pages = {255-266}, doi = {10.1016/j.freeradbiomed.2017.10.006}, pmid = {28993269}, issn = {1873-4596}, mesh = {Adenosine Triphosphate/biosynthesis ; Aedes/*parasitology ; Animals ; Antioxidants/metabolism ; Betaproteobacteria/metabolism ; Biological Evolution ; Drug Resistance ; Electron Transport Chain Complex Proteins/*genetics/metabolism ; Energy Metabolism/*genetics ; Gastrointestinal Tract/parasitology ; Gene Expression Regulation ; *Host-Parasite Interactions ; Hydrogen Peroxide/*pharmacology ; Mitochondria/drug effects/genetics/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Protozoan Proteins/*genetics/metabolism ; Signal Transduction ; Symbiosis/physiology ; Trypanosomatina/drug effects/genetics/*metabolism/microbiology ; }, abstract = {Reactive oxygen species (ROS) are toxic molecules involved in several biological processes such as cellular signaling, proliferation, differentiation and cell death. Adaptations to oxidative environments are crucial for the success of the colonization of insects by protozoa. Strigomonas culicis is a monoxenic trypanosomatid found in the midgut of mosquitoes and presenting a life cycle restricted to the epimastigote form. Among S. culicis peculiarities, there is an endosymbiotic bacterium in the cytoplasm, which completes essential biosynthetic routes of the host cell and may represent an intermediary evolutive step in organelle origin, thus constituting an interesting model for evolutive researches. In this work, we induced ROS resistance in wild type S. culicis epimastigotes by the incubation with increasing concentrations of hydrogen peroxide (H2O2), and compared the oxidative and energetic metabolisms among wild type, wild type-H2O2 resistant and aposymbiotic strains. Resistant protozoa were less sensitive to the oxidative challenge and more dependent on oxidative phosphorylation, which was demonstrated by higher oxygen consumption and mitochondrial membrane potential, increased activity of complexes II-III and IV, increased complex II gene expression and higher ATP production. Furthermore, the wild type-H2O2 resistant strain produced reduced ROS levels and showed lower lipid peroxidation, as well as an increase in gene expression of antioxidant enzymes and thiol-dependent peroxidase activity. On the other hand, the aposymbiotic strain showed impaired mitochondrial function, higher H2O2 production and deficient antioxidant response. The induction of H2O2 resistance also led to a remarkable increase in Aedes aegypti midgut binding in vitro and colonization in vivo, indicating that both the pro-oxidant environment in the mosquito gut and the oxidative stress susceptibility regulate S. culicis population in invertebrates.}, } @article {pmid28966595, year = {2017}, author = {Wiens, L and Banh, S and Sotiri, E and Jastroch, M and Block, BA and Brand, MD and Treberg, JR}, title = {Comparison of Mitochondrial Reactive Oxygen Species Production of Ectothermic and Endothermic Fish Muscle.}, journal = {Frontiers in physiology}, volume = {8}, number = {}, pages = {704}, pmid = {28966595}, issn = {1664-042X}, support = {R01 AG033542/AG/NIA NIH HHS/United States ; }, abstract = {Recently we demonstrated that the capacity of isolated muscle mitochondria to produce reactive oxygen species, measured as H2O2 efflux, is temperature-sensitive in isolated muscle mitochondria of ectothermic fish and the rat, a representative endothermic mammal. However, at physiological temperatures (15° and 37°C for the fish and rat, respectively), the fraction of total mitochondrial electron flux that generated H2O2, the fractional electron leak (FEL), was far lower in the rat than in fish. Those results suggested that the elevated body temperatures associated with endothermy may lead to a compensatory decrease in mitochondrial ROS production relative to respiratory capacity. To test this hypothesis we compare slow twitch (red) muscle mitochondria from the endothermic Pacific bluefin tuna (Thunnus orientalis) with mitochondria from three ectothermic fishes [rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio), and the lake sturgeon (Acipenser fulvescens)] and the rat. At a common assay temperature (25°C) rates of mitochondrial respiration and H2O2 efflux were similar in tuna and the other fishes. The thermal sensitivity of fish mitochondria was similar irrespective of ectothermy or endothermy. Comparing tuna to the rat at a common temperature, respiration rates were similar, or lower depending on mitochondrial substrates. FEL was not different across fish species at a common assay temperature (25°C) but was markedly higher in fishes than in rat. Overall, endothermy and warming of Pacific Bluefin tuna red muscle may increase the potential for ROS production by muscle mitochondria but the evolution of endothermy in this species is not necessarily associated with a compensatory reduction of ROS production relative to the respiratory capacity of mitochondria.}, } @article {pmid28943271, year = {2017}, author = {Chaturvedi, D and Mahalakshmi, R}, title = {Transmembrane β-barrels: Evolution, folding and energetics.}, journal = {Biochimica et biophysica acta. Biomembranes}, volume = {1859}, number = {12}, pages = {2467-2482}, pmid = {28943271}, issn = {0005-2736}, support = {/WT_/Wellcome Trust/United Kingdom ; IA/I/14/1/501305/WTDBT_/DBT-Wellcome Trust India Alliance/India ; }, mesh = {Amino Acid Sequence ; Bacteria/genetics/*metabolism ; Bacterial Outer Membrane Proteins/*chemistry/genetics/metabolism ; *Biological Evolution ; Eukaryota/genetics/metabolism ; Gene Expression ; Mitochondria/chemistry/*metabolism ; Mitochondrial Proteins/*chemistry/genetics/metabolism ; Molecular Chaperones/*chemistry/genetics/metabolism ; Protein Binding ; Protein Conformation, beta-Strand ; Protein Folding ; Protein Interaction Domains and Motifs ; Sequence Alignment ; Sequence Homology, Amino Acid ; Thermodynamics ; }, abstract = {The biogenesis of transmembrane β-barrels (outer membrane proteins, or OMPs) is an elaborate multistep orchestration of the nascent polypeptide with translocases, barrel assembly machinery, and helper chaperone proteins. Several theories exist that describe the mechanism of chaperone-assisted OMP assembly in vivo and unassisted (spontaneous) folding in vitro. Structurally, OMPs of bacterial origin possess even-numbered strands, while mitochondrial β-barrels are even- and odd-stranded. Several underlying similarities between prokaryotic and eukaryotic β-barrels and their folding machinery are known; yet, the link in their evolutionary origin is unclear. While OMPs exhibit diversity in sequence and function, they share similar biophysical attributes and structure. Similarly, it is important to understand the intricate OMP assembly mechanism, particularly in eukaryotic β-barrels that have evolved to perform more complex functions. Here, we deliberate known facets of β-barrel evolution, folding, and stability, and attempt to highlight outstanding questions in β-barrel biogenesis and proteostasis.}, } @article {pmid28916841, year = {2017}, author = {Dunn, CD}, title = {Some Liked It Hot: A Hypothesis Regarding Establishment of the Proto-Mitochondrial Endosymbiont During Eukaryogenesis.}, journal = {Journal of molecular evolution}, volume = {85}, number = {3-4}, pages = {99-106}, pmid = {28916841}, issn = {1432-1432}, support = {637649/ERC_/European Research Council/International ; }, mesh = {Archaea/*genetics/metabolism ; Bacteria/genetics ; *Biological Evolution ; Energy Metabolism ; Eukaryota/*genetics/metabolism ; *Hot Temperature ; Mitochondria/genetics/*metabolism/physiology ; *Symbiosis ; }, abstract = {Eukaryotic cells are characterized by a considerable increase in subcellular compartmentalization when compared to prokaryotes. Most evidence suggests that the earliest eukaryotes consisted of mitochondria derived from an α-proteobacterial ancestor enclosed within an archaeal host cell. However, what benefits the archaeal host and the proto-mitochondrial endosymbiont might have obtained at the beginning of this endosymbiotic relationship remains unclear. In this work, I argue that heat generated by the proto-mitochondrion initially permitted an archaeon living at high temperatures to colonize a cooler environment, thereby removing apparent limitations on cellular complexity. Furthermore, heat generation by the endosymbiont would have provided phenotypic flexibility not available through fixed alleles selected for fitness at specific temperatures. Finally, a role for heat production by the proto-mitochondrion bridges a conceptual gap between initial endosymbiont entry to the archaeal host and a later role for mitochondrial ATP production in permitting increased cellular complexity.}, } @article {pmid28878314, year = {2017}, author = {Sun, S and Li, Q and Kong, L and Yu, H}, title = {Limited locomotive ability relaxed selective constraints on molluscs mitochondrial genomes.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {10628}, pmid = {28878314}, issn = {2045-2322}, mesh = {Animals ; Evolution, Molecular ; *Genome, Mitochondrial ; Genomics/methods ; *Locomotion ; Mitochondria/*genetics/*metabolism ; Mollusca/*physiology ; Open Reading Frames ; Phylogeny ; Selection, Genetic ; }, abstract = {Mollusca are the second largest phylum in the animal kingdom with different types of locomotion. Some molluscs are poor-migrating, while others are free-moving or fast-swimming. Most of the energy required for locomotion is provided by mitochondria via oxidative phosphorylation. Here, we conduct a comparative genomic analysis of 256 molluscs complete mitochondrial genomes and evaluate the role of energetic functional constraints on the protein-coding genes, providing a new insight into mitochondrial DNA (mtDNA) evolution. The weakly locomotive molluscs, compared to strongly locomotive molluscs, show significantly higher Ka/Ks ratio, which suggest they accumulated more nonsynonymous mutations in mtDNA and have experienced more relaxed evolutionary constraints. Eleven protein-coding genes (CoxI, CoxII, ATP6, Cytb, ND1-6, ND4L) show significant difference for Ka/Ks ratios between the strongly and weakly locomotive groups. The relaxation of selective constraints on Atp8 arise in the common ancestor of bivalves, and the further relaxation occurred in marine bivalves lineage. Our study thus demonstrates that selective constraints relevant to locomotive ability play an essential role in evolution of molluscs mtDNA.}, } @article {pmid28854599, year = {2017}, author = {Rauch, C and Christa, G and de Vries, J and Woehle, C and Gould, SB}, title = {Mitochondrial Genome Assemblies of Elysia timida and Elysia cornigera and the Response of Mitochondrion-Associated Metabolism during Starvation.}, journal = {Genome biology and evolution}, volume = {9}, number = {7}, pages = {1873-1879}, pmid = {28854599}, issn = {1759-6653}, mesh = {Animals ; Chloroplasts/metabolism ; DNA, Mitochondrial/genetics ; Gastropoda/classification/*genetics/*metabolism ; *Genome, Mitochondrial ; Mitochondria/genetics/metabolism ; Photosynthesis ; Plastids/metabolism ; }, abstract = {Some sacoglossan sea slugs sequester functional plastids (kleptoplasts) from their food, which continue to fix CO2 in a light dependent manner inside the animals. In plants and algae, plastid and mitochondrial metabolism are linked in ways that reach beyond the provision of energy-rich carbon compounds through photosynthesis, but how slug mitochondria respond to starvation or alterations in plastid biochemistry has not been explored. We assembled the mitochondrial genomes of the plastid-sequestering sea slugs Elysia timida and Elysia cornigera from RNA-Seq data that was complemented with standard sequencing of mitochondrial DNA through primer walking. Our data confirm the sister species relationship of the two Sacoglossa and from the analysis of changes in mitochondrial-associated metabolism during starvation we speculate that kleptoplasts might aid in the rerouting or recycling of reducing power independent of, yet maybe improved by, photosynthesis.}, } @article {pmid28837072, year = {2017}, author = {Hikmat, O and Eichele, T and Tzoulis, C and Bindoff, LA}, title = {Understanding the Epilepsy in POLG Related Disease.}, journal = {International journal of molecular sciences}, volume = {18}, number = {9}, pages = {}, pmid = {28837072}, issn = {1422-0067}, mesh = {Animals ; Cerebral Cortex/pathology ; DNA Polymerase gamma/*genetics/*metabolism ; Disease Susceptibility ; Electroencephalography ; Epilepsy/diagnosis/*etiology/*metabolism/therapy ; Humans ; Magnetic Resonance Imaging/methods ; Neurons/metabolism ; }, abstract = {Epilepsy is common in polymerase gamma (POLG) related disease and is associated with high morbidity and mortality. Epileptiform discharges typically affect the occipital regions initially and focal seizures, commonly evolving to bilateral convulsive seizures which are the most common seizure types in both adults and children. Our work has shown that mtDNA depletion-i.e., the quantitative loss of mtDNA-in neurones is the earliest and most important factor of the subsequent development of cellular dysfunction. Loss of mtDNA leads to loss of mitochondrial respiratory chain (MRC) components that, in turn, progressively disables energy metabolism. This critically balanced neuronal energy metabolism leads to both a chronic and continuous attrition (i.e., neurodegeneration) and it leaves the neurone unable to cope with increased demand that can trigger a potentially catastrophic cycle that results in acute focal necrosis. We believe that it is the onset of epilepsy that triggers the cascade of damage. These events can be identified in the stepwise evolution that characterizes the clinical, Electroencephalography (EEG), neuro-imaging, and neuropathology findings. Early recognition with prompt and aggressive seizure management is vital and may play a role in modifying the epileptogenic process and improving survival.}, } @article {pmid28806979, year = {2017}, author = {Zachar, I and Szathmáry, E}, title = {Breath-giving cooperation: critical review of origin of mitochondria hypotheses : Major unanswered questions point to the importance of early ecology.}, journal = {Biology direct}, volume = {12}, number = {1}, pages = {19}, pmid = {28806979}, issn = {1745-6150}, mesh = {*Biological Evolution ; Energy Metabolism ; Genome, Mitochondrial ; *Mitochondria ; *Models, Biological ; Phagocytosis ; Phylogeny ; }, abstract = {UNLABELLED: The origin of mitochondria is a unique and hard evolutionary problem, embedded within the origin of eukaryotes. The puzzle is challenging due to the egalitarian nature of the transition where lower-level units took over energy metabolism. Contending theories widely disagree on ancestral partners, initial conditions and unfolding of events. There are many open questions but there is no comparative examination of hypotheses. We have specified twelve questions about the observable facts and hidden processes leading to the establishment of the endosymbiont that a valid hypothesis must address. We have objectively compared contending hypotheses under these questions to find the most plausible course of events and to draw insight on missing pieces of the puzzle. Since endosymbiosis borders evolution and ecology, and since a realistic theory has to comply with both domains' constraints, the conclusion is that the most important aspect to clarify is the initial ecological relationship of partners. Metabolic benefits are largely irrelevant at this initial phase, where ecological costs could be more disruptive. There is no single theory capable of answering all questions indicating a severe lack of ecological considerations. A new theory, compliant with recent phylogenomic results, should adhere to these criteria.

REVIEWERS: This article was reviewed by Michael W. Gray, William F. Martin and Purificación López-García.}, } @article {pmid28704930, year = {2017}, author = {Lai, YC and Baker, JS and Donti, T and Graham, BH and Craigen, WJ and Anderson, AE}, title = {Mitochondrial Dysfunction Mediated by Poly(ADP-Ribose) Polymerase-1 Activation Contributes to Hippocampal Neuronal Damage Following Status Epilepticus.}, journal = {International journal of molecular sciences}, volume = {18}, number = {7}, pages = {}, pmid = {28704930}, issn = {1422-0067}, support = {K08 NS063117/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Blotting, Western ; Electroencephalography ; Hippocampus/*metabolism/*pathology ; Mitochondria/*metabolism/*pathology ; Neurons/*metabolism/*pathology ; Poly (ADP-Ribose) Polymerase-1/*metabolism ; Rats ; Rats, Sprague-Dawley ; Status Epilepticus/*metabolism/*pathology ; }, abstract = {Mitochondrial dysfunction plays a central role in the neuropathology associated with status epilepticus (SE) and is implicated in the development of epilepsy. While excitotoxic mechanisms are well-known mediators affecting mitochondrial health following SE, whether hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) also contributes to SE-induced mitochondrial dysfunction remains to be examined. Here we first evaluated the temporal evolution of poly-ADP-ribosylated protein levels in hippocampus following kainic acid-induced SE as a marker for PARP-1 activity, and found that PARP-1 was hyperactive at 24 h following SE. We evaluated oxidative metabolism and found decreased NAD[+] levels by enzymatic cycling, and impaired NAD[+]-dependent mitochondrial respiration as measured by polarography at 24 h following SE. Stereological estimation showed significant cell loss in the hippocampal CA1 and CA3 subregions 72 h following SE. PARP-1 inhibition using N-(6-Oxo-5,6-dihydro-phenanthridin-2-yl)- N,N-dimethylacetamide (PJ-34) in vivo administration was associated with preserved NAD[+] levels and NAD[+]-dependent mitochondrial respiration, and improved CA1 neuronal survival. These findings suggest that PARP-1 hyperactivation contributes to SE-associated mitochondrial dysfunction and CA1 hippocampal damage. The deleterious effects of PARP-1 hyperactivation on mitochondrial respiration are in part mediated through intracellular NAD[+] depletion. Therefore, modulating PARP-1 activity may represent a potential therapeutic target to preserve intracellular energetics and mitochondrial function following SE.}, } @article {pmid28699890, year = {2017}, author = {Brandt, T and Mourier, A and Tain, LS and Partridge, L and Larsson, NG and Kühlbrandt, W}, title = {Changes of mitochondrial ultrastructure and function during ageing in mice and Drosophila.}, journal = {eLife}, volume = {6}, number = {}, pages = {}, pmid = {28699890}, issn = {2050-084X}, mesh = {Aging/*physiology ; Animals ; Cryoelectron Microscopy ; DNA, Mitochondrial/genetics ; Drosophila melanogaster/*physiology ; Energy Metabolism ; Imaging, Three-Dimensional ; Mice ; Mitochondria/metabolism/*ultrastructure ; Organ Specificity ; Tomography ; }, abstract = {Ageing is a progressive decline of intrinsic physiological functions. We examined the impact of ageing on the ultrastructure and function of mitochondria in mouse and fruit flies (Drosophila melanogaster) by electron cryo-tomography and respirometry. We discovered distinct age-related changes in both model organisms. Mitochondrial function and ultrastructure are maintained in mouse heart, whereas subpopulations of mitochondria from mouse liver show age-related changes in membrane morphology. Subpopulations of mitochondria from young and old mouse kidney resemble those described for apoptosis. In aged flies, respiratory activity is compromised and the production of peroxide radicals is increased. In about 50% of mitochondria from old flies, the inner membrane organization breaks down. This establishes a clear link between inner membrane architecture and functional decline. Mitochondria were affected by ageing to very different extents, depending on the organism and possibly on the degree to which tissues within the same organism are protected against mitochondrial damage.}, } @article {pmid28690821, year = {2017}, author = {Zhang, B and Zhang, YH and Wang, X and Zhang, HX and Lin, Q}, title = {The mitochondrial genome of a sea anemone Bolocera sp. exhibits novel genetic structures potentially involved in adaptation to the deep-sea environment.}, journal = {Ecology and evolution}, volume = {7}, number = {13}, pages = {4951-4962}, pmid = {28690821}, issn = {2045-7758}, abstract = {The deep sea is one of the most extensive ecosystems on earth. Organisms living there survive in an extremely harsh environment, and their mitochondrial energy metabolism might be a result of evolution. As one of the most important organelles, mitochondria generate energy through energy metabolism and play an important role in almost all biological activities. In this study, the mitogenome of a deep-sea sea anemone (Bolocera sp.) was sequenced and characterized. Like other metazoans, it contained 13 energy pathway protein-coding genes and two ribosomal RNAs. However, it also exhibited some unique features: just two transfer RNA genes, two group I introns, two transposon-like noncanonical open reading frames (ORFs), and a control region-like (CR-like) element. All of the mitochondrial genes were coded by the same strand (the H-strand). The genetic order and orientation were identical to those of most sequenced actiniarians. Phylogenetic analyses showed that this species was closely related to Bolocera tuediae. Positive selection analysis showed that three residues (31 L and 42 N in ATP6, 570 S in ND5) of Bolocera sp. were positively selected sites. By comparing these features with those of shallow sea anemone species, we deduced that these novel gene features may influence the activity of mitochondrial genes. This study may provide some clues regarding the adaptation of Bolocera sp. to the deep-sea environment.}, } @article {pmid28646582, year = {2017}, author = {Heiske, M and Letellier, T and Klipp, E}, title = {Comprehensive mathematical model of oxidative phosphorylation valid for physiological and pathological conditions.}, journal = {The FEBS journal}, volume = {284}, number = {17}, pages = {2802-2828}, doi = {10.1111/febs.14151}, pmid = {28646582}, issn = {1742-4658}, mesh = {Adenosine Triphosphate/biosynthesis ; Algorithms ; Animals ; Biocatalysis ; Cattle ; Kinetics ; Metabolic Flux Analysis ; Mitochondria, Heart/metabolism ; *Models, Biological ; *Oxidative Phosphorylation ; }, abstract = {We developed a mathematical model of oxidative phosphorylation (OXPHOS) that allows for a precise description of mitochondrial function with respect to the respiratory flux and the ATP production. The model reproduced flux-force relationships under various experimental conditions (state 3 and 4, uncoupling, and shortage of respiratory substrate) as well as time courses, exhibiting correct P/O ratios. The model was able to reproduce experimental threshold curves for perturbations of the respiratory chain complexes, the F1 F0 -ATP synthase, the ADP/ATP carrier, the phosphate/OH carrier, and the proton leak. Thus, the model is well suited to study complex interactions within the OXPHOS system, especially with respect to physiological adaptations or pathological modifications, influencing substrate and product affinities or maximal catalytic rates. Moreover, it could be a useful tool to study the role of OXPHOS and its capacity to compensate or enhance physiopathologies of the mitochondrial and cellular energy metabolism.}, } @article {pmid28646188, year = {2017}, author = {Wang, J and Xiang, H and Liu, L and Kong, M and Yin, T and Zhao, X}, title = {Mitochondrial haplotypes influence metabolic traits across bovine inter- and intra-species cybrids.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {4179}, pmid = {28646188}, issn = {2045-2322}, mesh = {Acids/metabolism ; Animals ; Cattle/*genetics ; DNA, Mitochondrial/genetics ; Female ; Gene Dosage ; Gene Expression Regulation ; Genome, Mitochondrial ; Haplotypes/*genetics ; Hybrid Cells/metabolism ; *Hybridization, Genetic ; Lipids/biosynthesis ; Mitochondria/*genetics/*metabolism ; Organelle Biogenesis ; Oxygen Consumption ; Phylogeny ; *Quantitative Trait, Heritable ; Sequence Analysis, DNA ; Species Specificity ; }, abstract = {In bovine species, mitochondrial DNA polymorphisms and their correlation to productive or reproductive performances have been widely reported across breeds and individuals. However, experimental evidence of this correlation has never been provided. In order to identify differences among bovine mtDNA haplotypes, transmitochondrial cybrids were generated, with the nucleus from MAC-T cell line, derived from a Holstein dairy cow (Bos taurus) and mitochondria from either primary cell line derived from a domestic Chinese native beef Luxi cattle breed or central Asian domestic yak (Bos grunniens). Yak primary cells illustrated a stronger metabolic capacity than that of Luxi. However, all yak cybrid parameters illustrated a drop in relative yak mtDNA compared to Luxi mtDNA, in line with a mitonuclear imbalance in yak interspecies cybrid. Luxi has 250 divergent variations relative to the mitogenome of Holsteins. In cybrids there were generally higher rates of oxygen consumption (OCR) and extracellular acidification (ECAR), and lower mRNA expression levels of nuclear-encoded mitochondrial genes, potentially reflecting active energy metabolism and cellular stress resistance. The results demonstrate that functional differences exist between bovine cybrid cells. While cybrid viability was similar between Holstein and Luxi breeds, the mitonuclear mismatch caused a marked metabolic dysfunction in cattle:yak cybrid species.}, } @article {pmid28615286, year = {2017}, author = {Martin, WF and Tielens, AGM and Mentel, M and Garg, SG and Gould, SB}, title = {The Physiology of Phagocytosis in the Context of Mitochondrial Origin.}, journal = {Microbiology and molecular biology reviews : MMBR}, volume = {81}, number = {3}, pages = {}, pmid = {28615286}, issn = {1098-5557}, mesh = {Adenosine Triphosphate/metabolism ; Archaea/genetics ; Biological Evolution ; Endocytosis/physiology ; Energy Metabolism ; Eukaryotic Cells/*physiology ; Metagenomics ; Mitochondria/*physiology ; Phagocytosis/*physiology ; Phylogeny ; Prokaryotic Cells/*physiology ; Symbiosis ; }, abstract = {How mitochondria came to reside within the cytosol of their host has been debated for 50 years. Though current data indicate that the last eukaryote common ancestor possessed mitochondria and was a complex cell, whether mitochondria or complexity came first in eukaryotic evolution is still discussed. In autogenous models (complexity first), the origin of phagocytosis poses the limiting step at eukaryote origin, with mitochondria coming late as an undigested growth substrate. In symbiosis-based models (mitochondria first), the host was an archaeon, and the origin of mitochondria was the limiting step at eukaryote origin, with mitochondria providing bacterial genes, ATP synthesis on internalized bioenergetic membranes, and mitochondrion-derived vesicles as the seed of the eukaryote endomembrane system. Metagenomic studies are uncovering new host-related archaeal lineages that are reported as complex or phagocytosing, although images of such cells are lacking. Here we review the physiology and components of phagocytosis in eukaryotes, critically inspecting the concept of a phagotrophic host. From ATP supply and demand, a mitochondrion-lacking phagotrophic archaeal fermenter would have to ingest about 34 times its body weight in prokaryotic prey to obtain enough ATP to support one cell division. It would lack chemiosmotic ATP synthesis at the plasma membrane, because phagocytosis and chemiosmosis in the same membrane are incompatible. It would have lived from amino acid fermentations, because prokaryotes are mainly protein. Its ATP yield would have been impaired relative to typical archaeal amino acid fermentations, which involve chemiosmosis. In contrast, phagocytosis would have had great physiological benefit for a mitochondrion-bearing cell.}, } @article {pmid28551806, year = {2017}, author = {Sharma, K}, title = {Mitochondrial Dysfunction in the Diabetic Kidney.}, journal = {Advances in experimental medicine and biology}, volume = {982}, number = {}, pages = {553-562}, doi = {10.1007/978-3-319-55330-6_28}, pmid = {28551806}, issn = {0065-2598}, mesh = {Animals ; Blood Glucose/metabolism ; Diabetic Nephropathies/*metabolism/pathology/physiopathology/prevention & control ; *Energy Metabolism/drug effects ; Humans ; Kidney/drug effects/*metabolism/pathology/physiopathology ; Mitochondria/drug effects/*metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {The role of mitochondria in diabetic complications has been viewed as a source of excess superoxide production leading to cell dysfunction. However, with the lack of benefit of non-specific anti-oxidant approaches this view needs to be re-evaluated. With recent studies using real-time imaging of superoxide, metabolomics, flux studies, transcriptomics and proteomics a new appreciation for the role of mitochondria in the evolution of diabetic kidney disease has emerged. Ongoing studies to further unravel the time course and mechanisms that reduce mitochondrial function will be relevant to novel therapies that could have a major impact on diabetic kidney disease and other diabetic complications.}, } @article {pmid28533386, year = {2017}, author = {Horscroft, JA and Kotwica, AO and Laner, V and West, JA and Hennis, PJ and Levett, DZH and Howard, DJ and Fernandez, BO and Burgess, SL and Ament, Z and Gilbert-Kawai, ET and Vercueil, A and Landis, BD and Mitchell, K and Mythen, MG and Branco, C and Johnson, RS and Feelisch, M and Montgomery, HE and Griffin, JL and Grocott, MPW and Gnaiger, E and Martin, DS and Murray, AJ}, title = {Metabolic basis to Sherpa altitude adaptation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {114}, number = {24}, pages = {6382-6387}, pmid = {28533386}, issn = {1091-6490}, support = {BB/F016581/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; FS/09/050/BHF_/British Heart Foundation/United Kingdom ; MR/P01836X/1/MRC_/Medical Research Council/United Kingdom ; MR/P011705/1/MRC_/Medical Research Council/United Kingdom ; MC_UP_A090_1006/MRC_/Medical Research Council/United Kingdom ; MC_PC_13030/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*Adaptation, Physiological/genetics ; Adult ; *Altitude ; Atmospheric Pressure ; Citric Acid Cycle ; Energy Metabolism ; *Ethnicity/genetics ; Fatty Acids/metabolism ; Female ; Gene Frequency ; Glucose/metabolism ; Glycolysis ; Humans ; Hypoxia/genetics/*metabolism/physiopathology ; Male ; Mitochondria, Muscle/metabolism ; Muscle, Skeletal/metabolism ; Nepal ; Nitric Oxide/blood ; Oxidative Phosphorylation ; Oxidative Stress ; Oxygen Consumption ; PPAR alpha/genetics/metabolism ; Polymorphism, Single Nucleotide ; Tibet/ethnology ; }, abstract = {The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature.}, } @article {pmid28501637, year = {2017}, author = {Lane, N}, title = {Serial endosymbiosis or singular event at the origin of eukaryotes?.}, journal = {Journal of theoretical biology}, volume = {434}, number = {}, pages = {58-67}, doi = {10.1016/j.jtbi.2017.04.031}, pmid = {28501637}, issn = {1095-8541}, mesh = {*Biological Evolution ; Energy Metabolism ; Eukaryota/*cytology ; Genomics ; Membranes/metabolism ; Organelles ; Organogenesis/*genetics ; Symbiosis/*genetics ; }, abstract = {'On the Origin of Mitosing Cells' heralded a new way of seeing cellular evolution, with symbiosis at its heart. Lynn Margulis (then Sagan) marshalled an impressive array of evidence for endosymbiosis, from cell biology to atmospheric chemistry and Earth history. Despite her emphasis on symbiosis, she saw plenty of evidence for gradualism in eukaryotic evolution, with multiple origins of mitosis and sex, repeated acquisitions of plastids, and putative evolutionary intermediates throughout the microbial world. Later on, Margulis maintained her view of multiple endosymbioses giving rise to other organelles such as hydrogenosomes, in keeping with the polyphyletic assumptions of the serial endosymbiosis theory. She stood at the threshold of the phylogenetic era, and anticipated its potential. Yet while predicting that the nucleotide sequences of genes would enable a detailed reconstruction of eukaryotic evolution, Margulis did not, and could not, imagine the radically different story that would eventually emerge from comparative genomics. The last eukaryotic common ancestor now seems to have been essentially a modern eukaryotic cell that had already evolved mitosis, meiotic sex, organelles and endomembrane systems. The long search for missing evolutionary intermediates has failed to turn up a single example, and those discussed by Margulis turn out to have evolved reductively from more complex ancestors. Strikingly, Margulis argued that all eukaryotes had mitochondria in her 1967 paper (a conclusion that she later disavowed). But she developed her ideas in the context of atmospheric oxygen and aerobic respiration, neither of which is consistent with more recent geological and phylogenetic findings. Instead, a modern synthesis of genomics and bioenergetics points to the endosymbiotic restructuring of eukaryotic genomes in relation to bioenergetic membranes as the singular event that permitted the evolution of morphological complexity.}, } @article {pmid28473298, year = {2017}, author = {Yin, Q and Zhang, Y and Dong, D and Lei, M and Zhang, S and Liao, CC and Pan, YH}, title = {Maintenance of neural activities in torpid Rhinolophus ferrumequinum bats revealed by 2D gel-based proteome analysis.}, journal = {Biochimica et biophysica acta. Proteins and proteomics}, volume = {1865}, number = {8}, pages = {1004-1019}, doi = {10.1016/j.bbapap.2017.04.006}, pmid = {28473298}, issn = {1570-9639}, mesh = {Adaptation, Physiological/physiology ; Animals ; Brain/metabolism/physiology ; Chiroptera/*metabolism/*physiology ; Energy Metabolism/physiology ; Hibernation/physiology ; Mitochondria/metabolism/physiology ; Proteome/*metabolism ; Proteomics/methods ; Seasons ; }, abstract = {Bats are the only mammals capable of self-powered flying. Many bat species hibernate in winter. A reversible control of cerebral activities is critical for bats to accommodate a repeated torpor-arousal cycle during hibernation. Little is known about the molecular mechanisms that regulate neuronal activities in torpid bats. In this study, Rhinolophus ferrumequinum bat brain proteins were fractionated, and their abundance in active and torpid states was compared. Results of 2D gel-based proteomics showed that 38% of identified proteins with a significant change in abundance are involved in synaptic vesicle recycling and cytoskeletal integrity. Changes in the abundance of proteins related to RNA splicing, proteostasis, redox homeostasis, mitochondrial function, and energy metabolism were also detected. In addition, the levels of GNAO1 (guanine nucleotide-binding protein Gαo subunit), an important modulator of neuronal transmembrane signaling, were significantly increased in the insoluble protein fraction of torpid bats; this may be due to GNAO1 palmitoylation making it insoluble. Our data provide molecular evidence for the maintenance of neuronal activities in torpid bats and suggest that a reversible palmitoylation of the G protein plays a role in the regulation of neuronal activities during bat hibernation.}, } @article {pmid28463550, year = {2017}, author = {Nakazawa, M and Hayashi, R and Takenaka, S and Inui, H and Ishikawa, T and Ueda, M and Sakamoto, T and Nakano, Y and Miyatake, K}, title = {Physiological functions of pyruvate:NADP[+] oxidoreductase and 2-oxoglutarate decarboxylase in Euglena gracilis under aerobic and anaerobic conditions.}, journal = {Bioscience, biotechnology, and biochemistry}, volume = {81}, number = {7}, pages = {1386-1393}, doi = {10.1080/09168451.2017.1318696}, pmid = {28463550}, issn = {1347-6947}, mesh = {Aerobiosis/genetics ; Amino Acid Sequence ; Anaerobiosis/genetics ; Carboxy-Lyases/genetics/*metabolism ; Cloning, Molecular ; Culture Media/chemistry ; Decarboxylation ; Energy Metabolism/*genetics ; Escherichia coli/genetics/metabolism ; Euglena gracilis/*enzymology/genetics ; Fermentation ; Gene Expression ; Gene Expression Regulation ; Glucose/metabolism ; Ketone Oxidoreductases/genetics/*metabolism ; Kinetics ; Mitochondria/genetics/*metabolism ; Oxidation-Reduction ; Protozoan Proteins/genetics/*metabolism ; Recombinant Proteins/genetics/metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Substrate Specificity ; }, abstract = {In Euglena gracilis, pyruvate:NADP[+] oxidoreductase, in addition to the pyruvate dehydrogenase complex, functions for the oxidative decarboxylation of pyruvate in the mitochondria. Furthermore, the 2-oxoglutarate dehydrogenase complex is absent, and instead 2-oxoglutarate decarboxylase is found in the mitochondria. To elucidate the central carbon and energy metabolisms in Euglena under aerobic and anaerobic conditions, physiological significances of these enzymes involved in 2-oxoacid metabolism were examined by gene silencing experiments. The pyruvate dehydrogenase complex was indispensable for aerobic cell growth in a glucose medium, although its activity was less than 1% of that of pyruvate:NADP[+] oxidoreductase. In contrast, pyruvate:NADP[+] oxidoreductase was only involved in the anaerobic energy metabolism (wax ester fermentation). Aerobic cell growth was almost completely suppressed when the 2-oxoglutarate decarboxylase gene was silenced, suggesting that the tricarboxylic acid cycle is modified in Euglena and 2-oxoglutarate decarboxylase takes the place of the 2-oxoglutarate dehydrogenase complex in the aerobic respiratory metabolism.}, } @article {pmid28444733, year = {2017}, author = {Du, SNN and Khajali, F and Dawson, NJ and Scott, GR}, title = {Hybridization increases mitochondrial production of reactive oxygen species in sunfish.}, journal = {Evolution; international journal of organic evolution}, volume = {71}, number = {6}, pages = {1643-1652}, doi = {10.1111/evo.13254}, pmid = {28444733}, issn = {1558-5646}, mesh = {Animals ; *Hybridization, Genetic ; Mitochondria/*metabolism ; Oxidative Phosphorylation ; Oxidative Stress ; Perciformes/genetics/*physiology ; *Reactive Oxygen Species ; }, abstract = {Mitochondrial dysfunction and oxidative stress have been suggested to be possible mechanisms underlying hybrid breakdown, as a result of mito-nuclear incompatibilities in respiratory complexes of the electron transport system. However, it remains unclear whether hybridization increases the production of reactive oxygen species (ROS) by mitochondria. We used high-resolution respirometry and fluorometry on isolated liver mitochondria to examine mitochondrial physiology and ROS emission in naturally occurring hybrids of pumpkinseed (Lepomis gibbosus) and bluegill (L. macrochirus). ROS emission was greater in hybrids than in both parent species when respiration was supported by complex I (but not complex II) substrates, and was associated with increases in lipid peroxidation. However, respiratory capacities for oxidative phosphorylation, phosphorylation efficiency, and O2 kinetics in hybrids were intermediate between those in parental species. Flux control ratios of capacities for electron transport (measured in uncoupled mitochondria) relative to oxidative phosphorylation suggested that the limiting influence of the phosphorylation system is reduced in hybrids. This likely helped offset impairments in electron transport capacity and complex III activity, but contributed to augmenting ROS production. Therefore, hybridization can increase mitochondrial ROS production, in support of previous suggestions that mitochondrial dysfunction can induce oxidative stress and thus contribute to hybrid breakdown.}, } @article {pmid28429315, year = {2017}, author = {Zimorski, V and Rauch, C and van Hellemond, JJ and Tielens, AGM and Martin, WF}, title = {The Mitochondrion of Euglena gracilis.}, journal = {Advances in experimental medicine and biology}, volume = {979}, number = {}, pages = {19-37}, doi = {10.1007/978-3-319-54910-1_2}, pmid = {28429315}, issn = {0065-2598}, mesh = {Anaerobiosis/physiology ; Euglena gracilis/*metabolism ; Fatty Acids/biosynthesis ; Glycolysis/physiology ; Malonyl Coenzyme A/metabolism ; Mitochondria/*physiology ; Oxidation-Reduction ; Pyruvic Acid/metabolism ; }, abstract = {In the presence of oxygen, Euglena gracilis mitochondria function much like mammalian mitochondria. Under anaerobiosis, E. gracilis mitochondria perform a malonyl-CoA independent synthesis of fatty acids leading to accumulation of wax esters, which serve as the sink for electrons stemming from glycolytic ATP synthesis and pyruvate oxidation. Some components (enzymes and cofactors) of Euglena's anaerobic energy metabolism are found among the anaerobic mitochondria of invertebrates, others are found among hydrogenosomes, the H2-producing anaerobic mitochondria of protists.}, } @article {pmid28420087, year = {2017}, author = {Devarshi, PP and McNabney, SM and Henagan, TM}, title = {Skeletal Muscle Nucleo-Mitochondrial Crosstalk in Obesity and Type 2 Diabetes.}, journal = {International journal of molecular sciences}, volume = {18}, number = {4}, pages = {}, pmid = {28420087}, issn = {1422-0067}, mesh = {Animals ; Cell Nucleus/*metabolism ; Diabetes Mellitus, Type 2/etiology/*metabolism ; Diet, High-Fat ; Energy Metabolism ; Evolution, Molecular ; Glucose/metabolism ; Humans ; Insulin/metabolism ; Insulin Resistance ; Mitochondria, Muscle/genetics/*metabolism ; Muscle, Skeletal/*metabolism ; Obesity/etiology/*metabolism ; Oxidation-Reduction ; *Signal Transduction ; }, abstract = {Skeletal muscle mitochondrial dysfunction, evidenced by incomplete beta oxidation and accumulation of fatty acid intermediates in the form of long and medium chain acylcarnitines, may contribute to ectopic lipid deposition and insulin resistance during high fat diet (HFD)-induced obesity. The present review discusses the roles of anterograde and retrograde communication in nucleo-mitochondrial crosstalk that determines skeletal muscle mitochondrial adaptations, specifically alterations in mitochondrial number and function in relation to obesity and insulin resistance. Special emphasis is placed on the effects of high fat diet (HFD) feeding on expression of nuclear-encoded mitochondrial genes (NEMGs) nuclear receptor factor 1 (NRF-1) and 2 (NRF-2) and peroxisome proliferator receptor gamma coactivator 1 alpha (PGC-1α) in the onset and progression of insulin resistance during obesity and how HFD-induced alterations in NEMG expression affect skeletal muscle mitochondrial adaptations in relation to beta oxidation of fatty acids. Finally, the potential ability of acylcarnitines or fatty acid intermediates resulting from mitochondrial beta oxidation to act as retrograde signals in nucleo-mitochondrial crosstalk is reviewed and discussed.}, } @article {pmid28366720, year = {2017}, author = {Schönfeld, P and Reiser, G}, title = {Brain energy metabolism spurns fatty acids as fuel due to their inherent mitotoxicity and potential capacity to unleash neurodegeneration.}, journal = {Neurochemistry international}, volume = {109}, number = {}, pages = {68-77}, doi = {10.1016/j.neuint.2017.03.018}, pmid = {28366720}, issn = {1872-9754}, mesh = {Animals ; Brain/*metabolism ; Energy Metabolism/*physiology ; Fatty Acids/*metabolism ; Humans ; Mitochondria/*metabolism ; Neurodegenerative Diseases/*metabolism ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {The brain uses long-chain fatty acids (LCFAs) to a negligible extent as fuel for the mitochondrial energy generation, in contrast to other tissues that also demand high energy. Besides this generally accepted view, some studies using cultured neural cells or whole brain indicate a moderately active mitochondrial β-oxidation. Here, we corroborate the conclusion that brain mitochondria are unable to oxidize fatty acids. In contrast, the combustion of liver-derived ketone bodies by neural cells is long-known. Furthermore, new insights indicate the use of odd-numbered medium-chain fatty acids as valuable source for maintaining the level of intermediates of the citric acid cycle in brain mitochondria. Non-esterified LCFAs or their activated forms exert a large variety of harmful side-effects on mitochondria, such as enhancing the mitochondrial ROS generation in distinct steps of the β-oxidation and therefore potentially increasing oxidative stress. Hence, the question arises: Why do in brain energy metabolism mitochondria selectively spurn LCFAs as energy source? The most likely answer are the relatively higher content of peroxidation-sensitive polyunsaturated fatty acids and the low antioxidative defense in brain tissue. There are two remarkable peroxisomal defects, one relating to α-oxidation of phytanic acid and the other to uptake of very long-chain fatty acids (VLCFAs) which lead to pathologically high tissue levels of such fatty acids. Both, the accumulation of phytanic acid and that of VLCFAs give an enlightening insight into harmful activities of fatty acids on neural cells, which possibly explain why evolution has prevented brain mitochondria from the equipment with significant β-oxidation enzymatic capacity.}, } @article {pmid28358800, year = {2017}, author = {Roberts, RG}, title = {Mitochondria-A billion years of cohabitation.}, journal = {PLoS biology}, volume = {15}, number = {3}, pages = {e2002338}, pmid = {28358800}, issn = {1545-7885}, mesh = {Animals ; Apoptosis ; Archaea/*cytology/*physiology ; *Bacterial Physiological Phenomena ; *Biological Evolution ; Cytophagocytosis ; Endoplasmic Reticulum/physiology ; Energy Metabolism ; Humans ; Mitochondria/genetics/*physiology ; Models, Biological ; *Symbiosis ; }, } @article {pmid28357316, year = {2016}, author = {Karnkowska, A and Hampl, V}, title = {The curious case of vanishing mitochondria.}, journal = {Microbial cell (Graz, Austria)}, volume = {3}, number = {10}, pages = {491-494}, pmid = {28357316}, issn = {2311-2638}, abstract = {Due to their involvement in the energy metabolism, mitochondria are essential for most eukaryotic cells. Microbial eukaryotes living in low oxygen environments possess reduced forms of mitochondria, namely mitochondrion-related organelles (MROs). These do not produce ATP by oxidative phosphorylation on their membranes and some do not produce ATP at all. Still, they are indispensable because of other essential functions such as iron-sulphur (Fe-S) cluster assembly. Recently, the first microbial eukaryote with neither mitochondrion nor MRO was characterized - Monocercomonoides sp. Genome and transcriptome sequencing of Monocercomonoides revealed that it lacks all hallmark mitochondrial proteins. Crucially, the essential mitochondrial pathway for the Fe-S cluster assembly (ISC) was replaced by a bacterial sulphur mobilization (SUF) system. The discovery of such bona fide amitochondriate eukaryote broadens our knowledge about the diversity and plasticity of eukaryotic cells and provides a substantial contribution to our understanding of eukaryotic cell evolution.}, } @article {pmid28300533, year = {2017}, author = {Lynch, M and Marinov, GK}, title = {Membranes, energetics, and evolution across the prokaryote-eukaryote divide.}, journal = {eLife}, volume = {6}, number = {}, pages = {}, pmid = {28300533}, issn = {2050-084X}, support = {R01 GM036827/GM/NIGMS NIH HHS/United States ; R35 GM122566/GM/NIGMS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; *Biological Evolution ; *Energy Metabolism ; Eukaryotic Cells/*physiology ; Mitochondria/metabolism ; Prokaryotic Cells/*physiology ; }, abstract = {The evolution of the eukaryotic cell marked a profound moment in Earth's history, with most of the visible biota coming to rely on intracellular membrane-bound organelles. It has been suggested that this evolutionary transition was critically dependent on the movement of ATP synthesis from the cell surface to mitochondrial membranes and the resultant boost to the energetic capacity of eukaryotic cells. However, contrary to this hypothesis, numerous lines of evidence suggest that eukaryotes are no more bioenergetically efficient than prokaryotes. Thus, although the origin of the mitochondrion was a key event in evolutionary history, there is no reason to think membrane bioenergetics played a direct, causal role in the transition from prokaryotes to eukaryotes and the subsequent explosive diversification of cellular and organismal complexity.}, } @article {pmid28232454, year = {2017}, author = {Krishnan, A and Abdullah, TS and Mounajjed, T and Hartono, S and McConico, A and White, T and LeBrasseur, N and Lanza, I and Nair, S and Gores, G and Charlton, M}, title = {A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {312}, number = {6}, pages = {G666-G680}, pmid = {28232454}, issn = {1522-1547}, support = {F30 DK102232/DK/NIDDK NIH HHS/United States ; R01 DK041876/DK/NIDDK NIH HHS/United States ; }, mesh = {Adiposity ; Animals ; Biomarkers/blood ; Blood Glucose/metabolism ; Diet, High-Fat ; Disease Models, Animal ; Disease Progression ; Energy Metabolism ; Humans ; Inflammation Mediators/blood ; Insulin/blood ; Insulin Resistance ; Lipids/blood ; Liver/*metabolism/physiology/physiopathology ; Liver Cirrhosis/genetics/*metabolism/pathology/physiopathology ; Male ; Mice, Inbred C57BL ; Mitochondria, Liver/metabolism/pathology ; Non-alcoholic Fatty Liver Disease/genetics/*metabolism/pathology/physiopathology ; Organ Size ; Species Specificity ; Time Factors ; Weight Gain ; }, abstract = {The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) is incompletely understood. Hence, we investigated the chronology of whole body, tissue, and cellular events that occur during the evolution of diet-induced NASH. Male C57Bl/6 mice were assigned to a fast-food (FF; high calorie, high cholesterol, high fructose) or standard-chow (SC) diet over a period of 36 wk. Liver histology, body composition, mitochondrial respiration, metabolic rate, gene expression, and hepatic lipid content were analyzed. Insulin resistance [homeostasis model assessment-insulin resistance (HOMA-IR)] increased 10-fold after 4 wk. Fibrosing NASH was fully established by 16 wk. Total hepatic lipids increased by 4 wk and remained two- to threefold increased throughout. Hepatic triglycerides declined from sixfold increase at 8 wk to threefold increase by 36 wk. In contrast, hepatic cholesterol levels steadily increased from baseline at 8 wk to twofold by 36 wk. The hepatic immune cell population altered over time with macrophages persisting beyond 16 wk. Mitochondrial oxygen flux rates of FF mice diet were uniformly lower with all the tested substrates (13-276 pmol·s[-1]·ml[-1] per unit citrate synthase) than SC mice (17-394 pmol·s[-1]·ml[-1] per unit citrate synthase) and was accompanied by decreased mitochondrial:nuclear gene copy number ratios after 4 wk. Metabolic rate was lower in FF mice. Mitochondrial glutathione was significantly decreased at 24 wk in FF mice. Expression of dismutases and catalase was also decreased in FF mice. The evolution of NASH in the FF diet-induced model is multiphasic, particularly in terms of hepatic lipid composition. Insulin resistance precedes hepatic inflammation and fibrosis. Mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent. Collectively, these observations provide a unique overview of the sequence of changes that coevolve with the histological evolution of NASH.NEW & NOTEWORTHY This study demonstrates in a first of kind longitudinal analysis, the evolution of nonalcoholic steatohepatitis (NASH) on a fast-food diet-induced model. Key findings include 1) hepatic lipid composition changes in a multiphasic fashion as NASH evolves; 2) insulin resistance precedes hepatic inflammation and fibrosis, answering a longstanding chicken-and-egg question regarding the relationship of insulin resistance to liver histology in NASH; and 3) mitochondrial dysfunction and depletion occur after the histological features of NASH are apparent.}, } @article {pmid28128409, year = {2017}, author = {Ling, SS and Zhu, Y and Lan, D and Li, DS and Pang, HZ and Wang, Y and Li, DY and Wei, RP and Zhang, HM and Wang, CD and Hu, YD}, title = {Analysis of the cytochrome c oxidase subunit II (COX2) gene in giant panda, Ailuropoda melanoleuca.}, journal = {Genetics and molecular research : GMR}, volume = {16}, number = {1}, pages = {}, doi = {10.4238/gmr16019158}, pmid = {28128409}, issn = {1676-5680}, mesh = {Animals ; Electron Transport Complex IV/*genetics ; Energy Metabolism/genetics ; Mitochondria/genetics/metabolism ; Ursidae/*genetics/metabolism ; }, abstract = {The giant panda, Ailuropoda melanoleuca (Ursidae), has a unique bamboo-based diet; however, this low-energy intake has been sufficient to maintain the metabolic processes of this species since the fourth ice age. As mitochondria are the main sites for energy metabolism in animals, the protein-coding genes involved in mitochondrial respiratory chains, particularly cytochrome c oxidase subunit II (COX2), which is the rate-limiting enzyme in electron transfer, could play an important role in giant panda metabolism. Therefore, the present study aimed to isolate, sequence, and analyze the COX2 DNA from individuals kept at the Giant Panda Protection and Research Center, China, and compare these sequences with those of the other Ursidae family members. Multiple sequence alignment showed that the COX2 gene had three point mutations that defined three haplotypes, with 60% of the sequences corresponding to haplotype I. The neutrality tests revealed that the COX2 gene was conserved throughout evolution, and the maximum likelihood phylogenetic analysis, using homologous sequences from other Ursidae species, showed clustering of the COX2 sequences of giant pandas, suggesting that this gene evolved differently in them.}, } @article {pmid28088333, year = {2017}, author = {Baffy, G}, title = {Mitochondrial uncoupling in cancer cells: Liabilities and opportunities.}, journal = {Biochimica et biophysica acta. Bioenergetics}, volume = {1858}, number = {8}, pages = {655-664}, doi = {10.1016/j.bbabio.2017.01.005}, pmid = {28088333}, issn = {0005-2728}, mesh = {Animals ; Antineoplastic Agents/pharmacokinetics ; Cell Hypoxia ; Cell Line, Tumor ; Cellular Reprogramming ; Drug Resistance, Neoplasm/physiology ; Drug Synergism ; Energy Metabolism ; Humans ; Mitochondria/drug effects/*metabolism ; Mitochondrial Uncoupling Proteins/*physiology ; Models, Biological ; Neoplasm Proteins/physiology ; Neoplasms/drug therapy/*metabolism ; Oxidative Phosphorylation/drug effects ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Symbiosis ; Uncoupling Agents/pharmacology/therapeutic use ; }, abstract = {Acquisition of the endosymbiotic ancestor of mitochondria was a critical event in eukaryote evolution. Mitochondria offered an unparalleled source of metabolic energy through oxidative phosphorylation and allowed the development of multicellular life. However, as molecular oxygen had become the terminal electron acceptor in most eukaryotic cells, the electron transport chain proved to be the largest intracellular source of superoxide, contributing to macromolecular injury, aging, and cancer. Hence, the 'contract of endosymbiosis' represents a compromise between the possibilities and perils of multicellular life. Uncoupling proteins (UCPs), a group of the solute carrier family of transporters, may remove some of the physiologic constraints that link mitochondrial respiration and ATP synthesis by mediating inducible proton leak and limiting oxidative cell injury. This important property makes UCPs an ancient partner in the metabolic adaptation of cancer cells. Efforts are underway to explore the therapeutic opportunities stemming from the intriguing relationship of UCPs and cancer. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.}, } @article {pmid28054713, year = {2017}, author = {Speijer, D}, title = {Alternating terminal electron-acceptors at the basis of symbiogenesis: How oxygen ignited eukaryotic evolution.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {39}, number = {2}, pages = {}, doi = {10.1002/bies.201600174}, pmid = {28054713}, issn = {1521-1878}, mesh = {Archaea/genetics ; Bacteria/genetics ; *Biological Evolution ; *Electron Transport ; Energy Metabolism ; Eukaryota/genetics/*metabolism ; Mitochondria/genetics/metabolism ; Oxygen/*metabolism ; *Symbiosis ; }, abstract = {What kind of symbiosis between archaeon and bacterium gave rise to their eventual merger at the origin of the eukaryotes? I hypothesize that conditions favouring bacterial uptake were based on exchange of intermediate carbohydrate metabolites required by recurring changes in availability and use of the two different terminal electron chain acceptors, the bacterial one being oxygen. Oxygen won, and definitive loss of the archaeal membrane potential allowed permanent establishment of the bacterial partner as the proto-mitochondrion, further metabolic integration and highly efficient ATP production. This represents initial symbiogenesis, when crucial eukaryotic traits arose in response to the archaeon-bacterium merger. The attendant generation of internal reactive oxygen species (ROS) gave rise to a myriad of further eukaryotic adaptations, such as extreme mitochondrial genome reduction, nuclei, peroxisomes and meiotic sex. Eukaryotic origins could have started with shuffling intermediate metabolites as is still essential today.}, } @article {pmid27018240, year = {2016}, author = {Faktorová, D and Dobáková, E and Peña-Diaz, P and Lukeš, J}, title = {From simple to supercomplex: mitochondrial genomes of euglenozoan protists.}, journal = {F1000Research}, volume = {5}, number = {}, pages = {}, pmid = {27018240}, issn = {2046-1402}, abstract = {Mitochondria are double membrane organelles of endosymbiotic origin, best known for constituting the centre of energetics of a eukaryotic cell. They contain their own mitochondrial genome, which as a consequence of gradual reduction during evolution typically contains less than two dozens of genes. In this review, we highlight the extremely diverse architecture of mitochondrial genomes and mechanisms of gene expression between the three sister groups constituting the phylum Euglenozoa - Euglenida, Diplonemea and Kinetoplastea. The earliest diverging euglenids possess a simplified mitochondrial genome and a conventional gene expression, whereas both are highly complex in the two other groups. The expression of their mitochondrial-encoded proteins requires extensive post-transcriptional modifications guided by complex protein machineries and multiple small RNA molecules. Moreover, the least studied diplonemids, which have been recently discovered as a highly abundant component of the world ocean plankton, possess one of the most complicated mitochondrial genome organisations known to date.}, } @article {pmid27931183, year = {2016}, author = {Liu, S and Roellig, DM and Guo, Y and Li, N and Frace, MA and Tang, K and Zhang, L and Feng, Y and Xiao, L}, title = {Evolution of mitosome metabolism and invasion-related proteins in Cryptosporidium.}, journal = {BMC genomics}, volume = {17}, number = {1}, pages = {1006}, pmid = {27931183}, issn = {1471-2164}, mesh = {Citric Acid Cycle/genetics ; Contig Mapping ; Cryptosporidium/classification/*genetics ; Electron Transport Chain Complex Proteins/metabolism ; Energy Metabolism/genetics ; Evolution, Molecular ; Genome ; Metabolic Networks and Pathways/genetics ; Mitochondria/genetics/*metabolism ; Phylogeny ; Protozoan Proteins/metabolism ; }, abstract = {BACKGROUND: The switch from photosynthetic or predatory to parasitic life strategies by apicomplexans is accompanied with a reductive evolution of genomes and losses of metabolic capabilities. Cryptosporidium is an extreme example of reductive evolution among apicomplexans, with losses of both the mitosome genome and many metabolic pathways. Previous observations on reductive evolution were largely based on comparative studies of various groups of apicomplexans. In this study, we sequenced two divergent Cryptosporidium species and conducted a comparative genomic analysis to infer the reductive evolution of metabolic pathways and differential evolution of invasion-related proteins within the Cryptosporidium lineage.

RESULTS: In energy metabolism, Cryptosporidium species differ from each other mostly in mitosome metabolic pathways. Compared with C. parvum and C. hominis, C. andersoni possesses more aerobic metabolism and a conventional electron transport chain, whereas C. ubiquitum has further reductions in ubiquinone and polyisprenoid biosynthesis and has lost both the conventional and alternative electron transport systems. For invasion-associated proteins, similar to C. hominis, a reduction in the number of genes encoding secreted MEDLE and insulinase-like proteins in the subtelomeric regions of chromosomes 5 and 6 was also observed in C. ubiquitum and C. andersoni, whereas mucin-type glycoproteins are highly divergent between the gastric C. andersoni and intestinal Cryptosporidium species.

CONCLUSIONS: Results of the study suggest that rapidly evolving mitosome metabolism and secreted invasion-related proteins could be involved in tissue tropism and host specificity in Cryptosporidium spp. The finding of progressive reduction in mitosome metabolism among Cryptosporidium species improves our knowledge of organelle evolution within apicomplexans.}, } @article {pmid27918601, year = {2016}, author = {Malecki, M and Bähler, J}, title = {Identifying genes required for respiratory growth of fission yeast.}, journal = {Wellcome open research}, volume = {1}, number = {}, pages = {12}, pmid = {27918601}, issn = {2398-502X}, support = {/WT_/Wellcome Trust/United Kingdom ; 095598/WT_/Wellcome Trust/United Kingdom ; }, abstract = {We have used both auxotroph and prototroph versions of the latest deletion-mutant library to identify genes required for respiratory growth on solid glycerol medium in fission yeast. This data set complements and enhances our recent study on functional and regulatory aspects of energy metabolism by providing additional proteins that are involved in respiration. Most proteins identified in this mutant screen have not been implicated in respiration in budding yeast. We also provide a protocol to generate a prototrophic mutant library, and data on technical and biological reproducibility of colony-based high-throughput screens.}, } @article {pmid27908782, year = {2017}, author = {Raefsky, SM and Mattson, MP}, title = {Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance.}, journal = {Free radical biology & medicine}, volume = {102}, number = {}, pages = {203-216}, pmid = {27908782}, issn = {1873-4596}, support = {ZIA AG000312-16//Intramural NIH HHS/United States ; ZIA AG000317-16//Intramural NIH HHS/United States ; ZIA AG000315-16//Intramural NIH HHS/United States ; ZIA AG000314-16//Intramural NIH HHS/United States ; ZIA AG000317-15//Intramural NIH HHS/United States ; ZIA AG000314-15//Intramural NIH HHS/United States ; ZIA AG000315-15//Intramural NIH HHS/United States ; ZIA AG000312-15//Intramural NIH HHS/United States ; }, mesh = {DNA Repair/genetics ; Disease Resistance/genetics ; Energy Metabolism ; Humans ; Mitochondria/*metabolism/pathology ; Neurodegenerative Diseases/*genetics/pathology ; Neuronal Plasticity/genetics ; Neurons/*metabolism/pathology ; *Organelle Biogenesis ; Signal Transduction ; }, abstract = {An important concept in neurobiology is "neurons that fire together, wire together" which means that the formation and maintenance of synapses is promoted by activation of those synapses. Very similar to the effects of the stress of exercise on muscle cells, emerging findings suggest that neurons respond to activity by activating signaling pathways (e.g., Ca[2+], CREB, PGC-1α, NF-κB) that stimulate mitochondrial biogenesis and cellular stress resistance. These pathways are also activated by aerobic exercise and food deprivation, two bioenergetic challenges of fundamental importance in the evolution of the brains of all mammals, including humans. The metabolic 'switch' in fuel source from liver glycogen store-derived glucose to adipose cell-derived fatty acids and their ketone metabolites during fasting and sustained exercise, appears to be a pivotal trigger of both brain-intrinsic and peripheral organ-derived signals that enhance learning and memory and underlying synaptic plasticity and neurogenesis. Brain-intrinsic extracellular signals include the excitatory neurotransmitter glutamate and the neurotrophic factor BDNF, and peripheral signals may include the liver-derived ketone 3-hydroxybutyrate and the muscle cell-derived protein irisin. Emerging findings suggest that fasting, exercise and an intellectually challenging lifestyle can protect neurons against the dysfunction and degeneration that they would otherwise suffer in acute brain injuries (stroke and head trauma) and neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease. Among the prominent intracellular responses of neurons to these bioenergetic challenges are up-regulation of antioxidant defenses, autophagy/mitophagy and DNA repair. A better understanding of such fundamental hormesis-based adaptive neuronal response mechanisms is expected to result in the development and implementation of novel interventions to promote optimal brain function and healthy brain aging.}, } @article {pmid27905116, year = {2017}, author = {Sanchez-Puerta, MV and García, LE and Wohlfeiler, J and Ceriotti, LF}, title = {Unparalleled replacement of native mitochondrial genes by foreign homologs in a holoparasitic plant.}, journal = {The New phytologist}, volume = {214}, number = {1}, pages = {376-387}, doi = {10.1111/nph.14361}, pmid = {27905116}, issn = {1469-8137}, mesh = {Base Sequence ; Chromosome Mapping ; DNA, Mitochondrial/genetics ; Fatty Acids, Unsaturated/genetics ; Gene Transfer, Horizontal ; *Genes, Mitochondrial ; Genes, Plant ; Genetic Speciation ; Genome, Mitochondrial ; Open Reading Frames/genetics ; Phylogeny ; Plants/*genetics ; Selection, Genetic ; *Sequence Homology, Nucleic Acid ; }, abstract = {Horizontal gene transfer (HGT) among flowering plant mitochondria occurs frequently and, in most cases, leads to nonfunctional transgenes in the recipient genome. Parasitic plants are particularly prone to this phenomenon, but their mitochondrial genomes (mtDNA) have been largely unexplored. We undertook a large-scale mitochondrial genomic study of the holoparasitic plant Lophophytum mirabile (Balanophoraceae). Comprehensive phylogenetic analyses were performed to address the frequency, origin, and impact of HGT. The sequencing of the complete mtDNA of L. mirabile revealed the unprecedented acquisition of host-derived mitochondrial genes, representing 80% of the protein-coding gene content. All but two of these foreign genes replaced the native homologs and are probably functional in energy metabolism. The genome consists of 54 circular-mapping chromosomes, 25 of which carry no intact genes. The likely functional replacement of up to 26 genes in L. mirabile represents a stunning example of the potential effect of rampant HGT on plant mitochondria. The use of host-derived genes may have a positive effect on the host-parasite relationship, but could also be the result of nonadaptive forces.}, } @article {pmid27887640, year = {2016}, author = {Malecki, M and Bitton, DA and Rodríguez-López, M and Rallis, C and Calavia, NG and Smith, GC and Bähler, J}, title = {Functional and regulatory profiling of energy metabolism in fission yeast.}, journal = {Genome biology}, volume = {17}, number = {1}, pages = {240}, pmid = {27887640}, issn = {1474-760X}, support = {095598/Z/11/Z//Wellcome Trust/United Kingdom ; }, mesh = {Acetyl Coenzyme A/metabolism ; Adaptation, Biological ; Cell Nucleus/genetics/metabolism ; Energy Metabolism/*genetics ; Fermentation ; *Gene Expression Profiling ; *Gene Expression Regulation, Fungal ; Glucose/metabolism ; High-Throughput Nucleotide Sequencing ; Mitochondria/genetics/metabolism ; Mutation ; Schizosaccharomyces/*genetics/*metabolism ; Signal Transduction ; *Transcriptome ; }, abstract = {BACKGROUND: The control of energy metabolism is fundamental for cell growth and function and anomalies in it are implicated in complex diseases and ageing. Metabolism in yeast cells can be manipulated by supplying different carbon sources: yeast grown on glucose rapidly proliferates by fermentation, analogous to tumour cells growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration.

RESULTS: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth. Growth media and auxotrophic mutants strongly influenced respiratory metabolism. Most genes uncovered in the mutant screens have not been implicated in respiration in budding yeast. We applied gene-expression profiling approaches to compare steady-state fermentative and respiratory growth and to analyse the dynamic adaptation to respiratory growth. The transcript levels of most genes functioning in energy metabolism pathways are coherently tuned, reflecting anticipated differences in metabolic flows between fermenting and respiring cells. We show that acetyl-CoA synthase, rather than citrate lyase, is essential for acetyl-CoA synthesis in fission yeast. We also investigated the transcriptional response to mitochondrial damage by genetic or chemical perturbations, defining a retrograde response that involves the concerted regulation of distinct groups of nuclear genes that may avert harm from mitochondrial malfunction.

CONCLUSIONS: This study provides a rich framework of the genetic and regulatory basis of energy metabolism in fission yeast and beyond, and it pinpoints weaknesses of commonly used auxotroph mutants for investigating metabolism. As a model for cellular energy regulation, fission yeast provides an attractive and complementary system to budding yeast.}, } @article {pmid27861795, year = {2017}, author = {Đorđević, M and Stojković, B and Savković, U and Immonen, E and Tucić, N and Lazarević, J and Arnqvist, G}, title = {Sex-specific mitonuclear epistasis and the evolution of mitochondrial bioenergetics, ageing, and life history in seed beetles.}, journal = {Evolution; international journal of organic evolution}, volume = {71}, number = {2}, pages = {274-288}, doi = {10.1111/evo.13109}, pmid = {27861795}, issn = {1558-5646}, mesh = {*Aging ; Animals ; Coleoptera/genetics/*physiology ; Electron Transport Chain Complex Proteins/genetics/metabolism ; *Energy Metabolism ; *Epistasis, Genetic ; Female ; Insect Proteins/genetics/metabolism ; *Life History Traits ; Male ; Mitochondria/*genetics ; Selection, Genetic ; }, abstract = {The role of mitochondrial DNA for the evolution of life-history traits remains debated. We examined mitonuclear effects on the activity of the multisubunit complex of the electron transport chain (ETC) involved in oxidative phosphorylation (OXPHOS) across lines of the seed beetle Acanthoscelides obtectus selected for a short (E) or a long (L) life for more than >160 generations. We constructed and phenotyped mitonuclear introgression lines, which allowed us to assess the independent effects of the evolutionary history of the nuclear and the mitochondrial genome. The nuclear genome was responsible for the largest share of divergence seen in ageing. However, the mitochondrial genome also had sizeable effects, which were sex-specific and expressed primarily as epistatic interactions with the nuclear genome. The effects of mitonuclear disruption were largely consistent with mitonuclear coadaptation. Variation in ETC activity explained a large proportion of variance in ageing and life-history traits and this multivariate relationship differed somewhat between the sexes. In conclusion, mitonuclear epistasis has played an important role in the laboratory evolution of ETC complex activity, ageing, and life histories and these are closely associated. The mitonuclear architecture of evolved differences in life-history traits and mitochondrial bioenergetics was sex-specific.}, } @article {pmid27812979, year = {2016}, author = {Bullon, P and Marin-Aguilar, F and Roman-Malo, L}, title = {AMPK/Mitochondria in Metabolic Diseases.}, journal = {Experientia supplementum (2012)}, volume = {107}, number = {}, pages = {129-152}, doi = {10.1007/978-3-319-43589-3_6}, pmid = {27812979}, issn = {1664-431X}, mesh = {AMP-Activated Protein Kinases/*genetics/metabolism ; Autophagy/genetics ; Diabetes Mellitus/drug therapy/enzymology/*genetics/pathology ; Energy Metabolism/genetics ; Gene Expression Regulation ; Homeostasis/genetics ; Humans ; Hypoglycemic Agents/therapeutic use ; Inflammation ; Insulin Resistance/genetics ; Metabolic Syndrome/drug therapy/enzymology/*genetics/pathology ; Metformin/therapeutic use ; Mitochondria/*enzymology/pathology ; Obesity/drug therapy/enzymology/*genetics/pathology ; Protein Subunits/genetics/metabolism ; Signal Transduction ; Thiazolidinediones/therapeutic use ; }, abstract = {The obtaining of nutrients is the most important task in our lives. Energy is central to life's evolutions; this was one of the aspect that induced the selection of the more adaptable and more energetically profitable species. Nowadays things have changed in our modern society. A high proportion of people has access to plenty amount of food and the obesity appear as one of the pathological characteristics of our society. Energy is obtained essentially in the mitochondria with the transfer of protons across the inner membrane that produce ATP. The exactly regulation of the synthesis and degradation of ATP (ATP ↔ ADP + phosphate) is essential to all form of life. This task is performed by the 5' adenosine monophosphate-activated protein kinase (AMPK). mtDNA is highly exposed to oxidative damage and could play a central role in human health and disease. This high potential rate of abnormalities is controlled by one of the most complex mechanism: the autophagy. AMPK appears to be the key cellular energy sensor involved in multiple cellular mechanisms and is essential to have a good metabolic homeostasis to face all the aggression and start the inflammatory reaction. Therefore its disturbances have been related with multiple diseases. Recent findings support the role of AMPK in inflammation and immunity such as Metabolic Syndrome, Obesity and Diabetes. All these Metabolic Disorders are considered pandemics and they need an adequate control and prevention. One important way to achieve it is deepen in the pathogenic mechanisms. Mitochondria and AMPK are the key elements through which it happen, their knowledge and research allow us to a better management. The discovery and use of drugs that can modulate them is imperative to improve our way of manage the metabolic disorders.}, } @article {pmid27663234, year = {2017}, author = {Kadam, AA and Jubin, T and Mir, HA and Begum, R}, title = {Potential role of Apoptosis Inducing Factor in evolutionarily significant eukaryote, Dictyostelium discoideum survival.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1861}, number = {1 Pt A}, pages = {2942-2955}, doi = {10.1016/j.bbagen.2016.09.021}, pmid = {27663234}, issn = {0304-4165}, mesh = {Adenosine Triphosphate/metabolism ; Annexin A5/metabolism ; Apoptosis Inducing Factor/*metabolism ; *Biological Evolution ; Calcium/metabolism ; Cell Cycle/drug effects ; Cell Death/drug effects ; Cell Shape/drug effects ; Cytosol/drug effects/metabolism ; Dictyostelium/*cytology/growth & development/*metabolism/ultrastructure ; Down-Regulation/drug effects ; Flow Cytometry ; Fluorescein-5-isothiocyanate/metabolism ; Fluorometry ; Glucose/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Models, Biological ; NAD/metabolism ; Oxidative Stress/drug effects ; Propidium/metabolism ; Protein Transport/drug effects ; RNA, Antisense/metabolism ; Reactive Oxygen Species/metabolism ; Staining and Labeling ; }, abstract = {Apoptosis Inducing Factor (AIF), a phylogenetically conserved mitochondrial inter-membrane space flavoprotein has an important role in caspase independent cell death. Nevertheless, AIF is also essential for cell survival. It is required for mitochondrial organization and energy metabolism. Upon apoptotic stimulation, AIF induces DNA fragmentation after its mitochondrio-nuclear translocation. Although it executes critical cellular functions in a coordinated manner, the exact mechanism still remains obscure. The present study aims to understand AIF's role in cell survival, growth and development by its down-regulation in an interesting unicellular eukaryote, D. discoideum which exhibits multicellularity upon starvation. Constitutive AIF down-regulated (dR) cells exhibited slower growth and delayed developmental morphogenesis. Also, constitutive AIF dR cells manifested high intracellular ROS, oxidative DNA damage and calcium levels with lower ATP content. Interestingly, constitutive AIF dR cells showed amelioration in cell growth upon antioxidant treatment, strengthening its role as ROS regulator. Under oxidative stress, AIF dR cells showed early mitochondrial membrane depolarization followed by AIF translocation from mitochondria to nucleus and exhibited necrotic cell death as compared to paraptoptic cell death of control cells. Thus, the results of this study provide an exemplar where AIF is involved in growth and development by regulating ROS levels and maintaining mitochondrial function in D. discoideum, an evolutionarily significant model organism exhibiting caspase independent apoptosis.}, } @article {pmid27577682, year = {2016}, author = {Sookoian, S and Flichman, D and Scian, R and Rohr, C and Dopazo, H and Gianotti, TF and Martino, JS and Castaño, GO and Pirola, CJ}, title = {Mitochondrial genome architecture in non-alcoholic fatty liver disease.}, journal = {The Journal of pathology}, volume = {240}, number = {4}, pages = {437-449}, doi = {10.1002/path.4803}, pmid = {27577682}, issn = {1096-9896}, mesh = {Adult ; Case-Control Studies ; DNA, Mitochondrial/genetics ; Female ; Genetic Predisposition to Disease ; *Genome, Mitochondrial ; Germ-Line Mutation ; Haplotypes ; Humans ; Liver Cirrhosis/genetics ; Male ; Middle Aged ; Mitochondria, Liver/genetics ; Mutation ; Mutation, Missense/genetics ; Non-alcoholic Fatty Liver Disease/*genetics ; Oxidative Phosphorylation ; Polymorphism, Genetic ; Severity of Illness Index ; }, abstract = {Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype-oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest. We also assessed the potential protein-level impact of the observed mutations. To determine whether the observed changes are tissue-specific, we compared the liver and the corresponding peripheral blood entire mitochondrial genomes. The nuclear genes POLG and POLG2 (mitochondrial DNA polymerase-γ) were also sequenced. We observed that the liver mtDNA of patients with NAFLD harbours complex genomes with a significantly higher mutational (1.28-fold) rate and degree of heteroplasmy than in controls. The analysis of liver mitochondrial genomes of patients with different degrees of fibrosis revealed that the disease severity is associated with an overall 1.4-fold increase in mutation rate, including mutations in genes of the oxidative phosphorylation (OXPHOS) chain. Significant differences in gene and protein expression patterns were observed in association with the cumulative number of OXPHOS polymorphic sites. We observed a high degree of homology (∼98%) between the blood and liver mitochondrial genomes. A missense POLG p.Gln1236His variant was associated with liver mtDNA copy number. In conclusion, we have demonstrated that OXPHOS genes contain the highest number of hotspot positions associated with a more severe phenotype. The variability of the mitochondrial genomes probably originates from a common germline source; hence, it may explain a fraction of the 'missing heritability' of NAFLD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.}, } @article {pmid27528758, year = {2016}, author = {Nunn, AV and Guy, GW and Bell, JD}, title = {The quantum mitochondrion and optimal health.}, journal = {Biochemical Society transactions}, volume = {44}, number = {4}, pages = {1101-1110}, pmid = {27528758}, issn = {1470-8752}, support = {MC_U120061305/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adaptation, Physiological ; Adenosine Triphosphate/metabolism ; Aging ; Animals ; Biological Evolution ; *Energy Metabolism ; *Health Status ; Hormesis ; Humans ; Inflammation/metabolism ; *Longevity ; Mitochondria/*metabolism ; Models, Biological ; Reactive Oxygen Species/metabolism ; }, abstract = {A sufficiently complex set of molecules, if subject to perturbation, will self-organize and show emergent behaviour. If such a system can take on information it will become subject to natural selection. This could explain how self-replicating molecules evolved into life and how intelligence arose. A pivotal step in this evolutionary process was of course the emergence of the eukaryote and the advent of the mitochondrion, which both enhanced energy production per cell and increased the ability to process, store and utilize information. Recent research suggest that from its inception life embraced quantum effects such as 'tunnelling' and 'coherence' while competition and stressful conditions provided a constant driver for natural selection. We believe that the biphasic adaptive response to stress described by hormesis-a process that captures information to enable adaptability, is central to this whole process. Critically, hormesis could improve mitochondrial quantum efficiency, improving the ATP/ROS ratio, whereas inflammation, which is tightly associated with the aging process, might do the opposite. This all suggests that to achieve optimal health and healthy aging, one has to sufficiently stress the system to ensure peak mitochondrial function, which itself could reflect selection of optimum efficiency at the quantum level.}, } @article {pmid27463650, year = {2016}, author = {Pennisi, E}, title = {EVOLUTIONARY BIOLOGY. Do genomic conflicts drive evolution?.}, journal = {Science (New York, N.Y.)}, volume = {353}, number = {6297}, pages = {334-335}, doi = {10.1126/science.353.6297.334}, pmid = {27463650}, issn = {1095-9203}, mesh = {Animals ; *Biological Evolution ; Birds/genetics ; Cell Nucleus/*genetics ; Energy Metabolism/*genetics ; Female ; *Genetic Fitness ; *Genome, Mitochondrial ; Genomics ; Male ; *Mating Preference, Animal ; Mitochondria/genetics/metabolism ; Pigmentation ; Plants/genetics ; }, } @article {pmid27449544, year = {2016}, author = {Rey, B and Dégletagne, C and Bodennec, J and Monternier, PA and Mortz, M and Roussel, D and Romestaing, C and Rouanet, JL and Tornos, J and Duchamp, C}, title = {Hormetic response triggers multifaceted anti-oxidant strategies in immature king penguins (Aptenodytes patagonicus).}, journal = {Free radical biology & medicine}, volume = {97}, number = {}, pages = {577-587}, doi = {10.1016/j.freeradbiomed.2016.07.015}, pmid = {27449544}, issn = {1873-4596}, mesh = {Animals ; Antioxidants/*metabolism ; Basal Metabolism ; Energy Metabolism ; *Hormesis ; Hydrogen Peroxide/metabolism ; Mitochondria, Muscle/metabolism ; Oxidation-Reduction ; Spheniscidae/*physiology ; *Thermotolerance ; }, abstract = {Repeated deep dives are highly pro-oxidative events for air-breathing aquatic foragers such as penguins. At fledging, the transition from a strictly terrestrial to a marine lifestyle may therefore trigger a complex set of anti-oxidant responses to prevent chronic oxidative stress in immature penguins but these processes are still undefined. By combining in vivo and in vitro approaches with transcriptome analysis, we investigated the adaptive responses of sea-acclimatized (SA) immature king penguins (Aptenodytes patagonicus) compared with pre-fledging never-immersed (NI) birds. In vivo, experimental immersion into cold water stimulated a higher thermogenic response in SA penguins than in NI birds, but both groups exhibited hypothermia, a condition favouring oxidative stress. In vitro, the pectoralis muscles of SA birds displayed increased oxidative capacity and mitochondrial protein abundance but unchanged reactive oxygen species (ROS) generation per g tissue because ROS production per mitochondria was reduced. The genes encoding oxidant-generating proteins were down-regulated in SA birds while mRNA abundance and activity of the main antioxidant enzymes were up-regulated. Genes encoding proteins involved in repair mechanisms of oxidized DNA or proteins and in degradation processes were also up-regulated in SA birds. Sea life also increased the degree of fatty acid unsaturation in muscle mitochondrial membranes resulting in higher intrinsic susceptibility to ROS. Oxidative damages to protein or DNA were reduced in SA birds. Repeated experimental immersions of NI penguins in cold-water partially mimicked the effects of acclimatization to marine life, modified the expression of fewer genes related to oxidative stress but in a similar way as in SA birds and increased oxidative damages to DNA. It is concluded that the multifaceted plasticity observed after marine life may be crucial to maintain redox homeostasis in active tissues subjected to high pro-oxidative pressure in diving birds. Initial immersions in cold-water may initiate an hormetic response triggering essential changes in the adaptive antioxidant response to marine life.}, } @article {pmid27345956, year = {2016}, author = {Garg, SG and Martin, WF}, title = {Mitochondria, the Cell Cycle, and the Origin of Sex via a Syncytial Eukaryote Common Ancestor.}, journal = {Genome biology and evolution}, volume = {8}, number = {6}, pages = {1950-1970}, pmid = {27345956}, issn = {1759-6653}, mesh = {Adenosine Triphosphate/*genetics/metabolism ; Archaea/genetics/physiology ; Biological Evolution ; Cell Cycle/genetics ; Cytosol/physiology ; Eukaryotic Cells/physiology ; *Evolution, Molecular ; Meiosis/genetics ; Mitochondria/*genetics ; Mitosis/genetics ; Prokaryotic Cells/physiology ; Protein Interaction Maps/genetics ; *Recombination, Genetic ; }, abstract = {Theories for the origin of sex traditionally start with an asexual mitosing cell and add recombination, thereby deriving meiosis from mitosis. Though sex was clearly present in the eukaryote common ancestor, the order of events linking the origin of sex and the origin of mitosis is unknown. Here, we present an evolutionary inference for the origin of sex starting with a bacterial ancestor of mitochondria in the cytosol of its archaeal host. We posit that symbiotic association led to the origin of mitochondria and gene transfer to host's genome, generating a nucleus and a dedicated translational compartment, the eukaryotic cytosol, in which-by virtue of mitochondria-metabolic energy was not limiting. Spontaneous protein aggregation (monomer polymerization) and Adenosine Tri-phosphate (ATP)-dependent macromolecular movement in the cytosol thereby became selectable, giving rise to continuous microtubule-dependent chromosome separation (reduction division). We propose that eukaryotic chromosome division arose in a filamentous, syncytial, multinucleated ancestor, in which nuclei with insufficient chromosome numbers could complement each other through mRNA in the cytosol and generate new chromosome combinations through karyogamy. A syncytial (or coenocytic, a synonym) eukaryote ancestor, or Coeca, would account for the observation that the process of eukaryotic chromosome separation is more conserved than the process of eukaryotic cell division. The first progeny of such a syncytial ancestor were likely equivalent to meiospores, released into the environment by the host's vesicle secretion machinery. The natural ability of archaea (the host) to fuse and recombine brought forth reciprocal recombination among fusing (syngamy and karyogamy) progeny-sex-in an ancestrally meiotic cell cycle, from which the simpler haploid and diploid mitotic cell cycles arose. The origin of eukaryotes was the origin of vertical lineage inheritance, and sex was required to keep vertically evolving lineages viable by rescuing the incipient eukaryotic lineage from Muller's ratchet. The origin of mitochondria was, in this view, the decisive incident that precipitated symbiosis-specific cell biological problems, the solutions to which were the salient features that distinguish eukaryotes from prokaryotes: A nuclear membrane, energetically affordable ATP-dependent protein-protein interactions in the cytosol, and a cell cycle involving reduction division and reciprocal recombination (sex).}, } @article {pmid27339178, year = {2016}, author = {Martin, WF and Neukirchen, S and Zimorski, V and Gould, SB and Sousa, FL}, title = {Energy for two: New archaeal lineages and the origin of mitochondria.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {38}, number = {9}, pages = {850-856}, doi = {10.1002/bies.201600089}, pmid = {27339178}, issn = {1521-1878}, mesh = {Archaea/*genetics ; *Energy Metabolism ; Eukaryota/*genetics/metabolism ; *Metagenomics ; *Mitochondria ; *Phylogeny ; }, abstract = {Metagenomics bears upon all aspects of microbiology, including our understanding of mitochondrial and eukaryote origin. Recently, ribosomal protein phylogenies show the eukaryote host lineage - the archaeal lineage that acquired the mitochondrion - to branch within the archaea. Metagenomic studies are now uncovering new archaeal lineages that branch more closely to the host than any cultivated archaea do. But how do they grow? Carbon and energy metabolism as pieced together from metagenome assemblies of these new archaeal lineages, such as the Deep Sea Archaeal Group (including Lokiarchaeota) and Bathyarchaeota, do not match the physiology of any cultivated microbes. Understanding how these new lineages live in their environment is important, and might hold clues about how mitochondria arose and how the eukaryotic lineage got started. Here we look at these exciting new metagenomic studies, what they say about archaeal physiology in modern environments, how they impact views on host-mitochondrion physiological interactions at eukaryote origin.}, } @article {pmid27327899, year = {2016}, author = {Cardoso, S and Carvalho, C and Correia, SC and Seiça, RM and Moreira, PI}, title = {Alzheimer's Disease: From Mitochondrial Perturbations to Mitochondrial Medicine.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {26}, number = {5}, pages = {632-647}, pmid = {27327899}, issn = {1750-3639}, mesh = {Aging ; *Alzheimer Disease/complications/drug therapy/pathology ; Animals ; Antioxidants/*therapeutic use ; Autophagy/drug effects/physiology ; Energy Metabolism/drug effects ; *Healthy Lifestyle ; Humans ; Mitochondria/*drug effects ; Mitochondrial Diseases/metabolism/*therapy ; Oxidative Stress/drug effects ; }, abstract = {Age-related neurodegenerative diseases such as Alzheimer's disease (AD) are distressing conditions causing countless levels of suffering for which treatment is often insufficient or inexistent. Considered to be the most common cause of dementia and an incurable, progressive neurodegenerative disorder, the intricate pathogenic mechanisms of AD continue to be revealed and, consequently, an effective treatment needs to be developed. Among the diverse hypothesis that have been proposed to explain AD pathogenesis, the one concerning mitochondrial dysfunction has raised as one of the most discussed with an actual acceptance in the field. It posits that manipulating mitochondrial function and understanding the deficits that result in mitochondrial injury may help to control and/or limit the development of AD. To achieve such goal, the concept of mitochondrial medicine places itself as a promising gathering of strategies to directly manage the major insidious disturbances of mitochondrial homeostasis as well as attempts to directly or indirectly manage its consequences in the context of AD. The aim of this review is to summarize the evolution that occurred from the establishment of mitochondrial homeostasis perturbation as masterpieces in AD pathogenesis up until the development of mitochondrial medicine. Following a brief glimpse in the past and current hypothesis regarding the triad of aging, mitochondria and AD, this manuscript will address the major mechanisms currently believed to participate in above mentioned events. Both pharmacological and lifestyle interventions will also be reviewed as AD-related mitochondrial therapeutics.}, } @article {pmid27179589, year = {2016}, author = {Mesa-Torres, N and Calvo, AC and Oppici, E and Titelbaum, N and Montioli, R and Miranda-Vizuete, A and Cellini, B and Salido, E and Pey, AL}, title = {Caenorhabditis elegans AGXT-1 is a mitochondrial and temperature-adapted ortholog of peroxisomal human AGT1: New insights into between-species divergence in glyoxylate metabolism.}, journal = {Biochimica et biophysica acta}, volume = {1864}, number = {9}, pages = {1195-1205}, doi = {10.1016/j.bbapap.2016.05.004}, pmid = {27179589}, issn = {0006-3002}, mesh = {Adaptation, Biological ; Alanine/chemistry/metabolism ; Amino Acid Sequence ; Animals ; Biological Evolution ; Caenorhabditis elegans/genetics/*metabolism ; Caenorhabditis elegans Proteins/*chemistry/genetics/metabolism ; Cloning, Molecular ; Dimerization ; Energy Metabolism ; Enzyme Stability ; Escherichia coli/genetics/metabolism ; Gene Expression ; Glyoxylates/chemistry/*metabolism ; Humans ; Mitochondria/*metabolism ; Mutation ; Peroxisomes/*metabolism ; Protein Structure, Secondary ; Pyridoxal Phosphate/chemistry/metabolism ; Recombinant Proteins/chemistry/genetics/metabolism ; Sequence Alignment ; Species Specificity ; Structural Homology, Protein ; Temperature ; Transaminases/*chemistry/genetics/metabolism ; }, abstract = {In humans, glyoxylate is an intermediary product of metabolism, whose concentration is finely balanced. Mutations in peroxisomal alanine:glyoxylate aminotransferase (hAGT1) cause primary hyperoxaluria type 1 (PH1), which results in glyoxylate accumulation that is converted to toxic oxalate. In contrast, glyoxylate is used by the nematode Caenorhabditis elegans through a glyoxylate cycle to by-pass the decarboxylation steps of the tricarboxylic acid cycle and thus contributing to energy production and gluconeogenesis from stored lipids. To investigate the differences in glyoxylate metabolism between humans and C. elegans and to determine whether the nematode might be a suitable model for PH1, we have characterized here the predicted nematode ortholog of hAGT1 (AGXT-1) and compared its molecular properties with those of the human enzyme. Both enzymes form active PLP-dependent dimers with high specificity towards alanine and glyoxylate, and display similar three-dimensional structures. Interestingly, AGXT-1 shows 5-fold higher activity towards the alanine/glyoxylate pair than hAGT1. Thermal and chemical stability of AGXT-1 is lower than that of hAGT1, suggesting temperature-adaptation of the nematode enzyme linked to the lower optimal growth temperature of C. elegans. Remarkably, in vivo experiments demonstrate the mitochondrial localization of AGXT-1 in contrast to the peroxisomal compartmentalization of hAGT1. Our results support the view that the different glyoxylate metabolism in the nematode is associated with the divergent molecular properties and subcellular localization of the alanine:glyoxylate aminotransferase activity.}, } @article {pmid27135161, year = {2016}, author = {Allen, JF and Martin, WF}, title = {Why Have Organelles Retained Genomes?.}, journal = {Cell systems}, volume = {2}, number = {2}, pages = {70-72}, doi = {10.1016/j.cels.2016.02.007}, pmid = {27135161}, issn = {2405-4712}, mesh = {Cell Nucleus ; *Chloroplasts ; Electron Transport ; Genome ; Mitochondria/genetics ; *Organelles ; Plants/genetics ; Protein Transport ; }, abstract = {Genes in mitochondria and chloroplasts are co-located with their gene products to permit regulation of trans-membrane electron transport at the energetic boundary of the cell.}, } @article {pmid26917748, year = {2016}, author = {Hamers, L}, title = {EVOLUTION. Why do cells' power plants hang on to their own genomes?.}, journal = {Science (New York, N.Y.)}, volume = {351}, number = {6276}, pages = {903}, doi = {10.1126/science.351.6276.903}, pmid = {26917748}, issn = {1095-9203}, mesh = {Animals ; Chiroptera ; Energy Metabolism/*genetics ; *Evolution, Molecular ; *Genes, Mitochondrial ; *Genome, Mitochondrial ; Mitochondria/*genetics ; Mitochondria, Liver/ultrastructure ; Symbiosis/genetics ; }, } @article {pmid26912842, year = {2016}, author = {Ball, SG and Bhattacharya, D and Weber, AP}, title = {EVOLUTION. Pathogen to powerhouse.}, journal = {Science (New York, N.Y.)}, volume = {351}, number = {6274}, pages = {659-660}, doi = {10.1126/science.aad8864}, pmid = {26912842}, issn = {1095-9203}, mesh = {Alphaproteobacteria/*genetics/pathogenicity ; Animals ; Archaea/metabolism ; *Biological Evolution ; Endocytosis ; Energy Metabolism/genetics ; Eukaryota/genetics ; *Host-Pathogen Interactions ; Humans ; Mitochondria/*genetics ; Plastids/*genetics ; Rickettsia/genetics/pathogenicity ; Symbiosis/*genetics ; }, } @article {pmid26861137, year = {2016}, author = {Kelley, JL and Arias-Rodriguez, L and Patacsil Martin, D and Yee, MC and Bustamante, CD and Tobler, M}, title = {Mechanisms Underlying Adaptation to Life in Hydrogen Sulfide-Rich Environments.}, journal = {Molecular biology and evolution}, volume = {33}, number = {6}, pages = {1419-1434}, pmid = {26861137}, issn = {1537-1719}, mesh = {Acclimatization/genetics/physiology ; Adaptation, Physiological/genetics/*physiology ; Animals ; Biological Evolution ; Ecosystem ; Environment ; Evolution, Molecular ; Gene Flow ; Genetics, Population/methods ; Genome ; Hydrogen Sulfide/*metabolism ; Poecilia/genetics/metabolism/*physiology ; Selection, Genetic ; Sequence Alignment/methods ; Sequence Analysis, RNA/methods ; Transcriptome ; }, abstract = {Hydrogen sulfide (H2S) is a potent toxicant interfering with oxidative phosphorylation in mitochondria and creating extreme environmental conditions in aquatic ecosystems. The mechanistic basis of adaptation to perpetual exposure to H2S remains poorly understood. We investigated evolutionarily independent lineages of livebearing fishes that have colonized and adapted to springs rich in H2S and compared their genome-wide gene expression patterns with closely related lineages from adjacent, nonsulfidic streams. Significant differences in gene expression were uncovered between all sulfidic and nonsulfidic population pairs. Variation in the number of differentially expressed genes among population pairs corresponded to differences in divergence times and rates of gene flow, which is consistent with neutral drift driving a substantial portion of gene expression variation among populations. Accordingly, there was little evidence for convergent evolution shaping large-scale gene expression patterns among independent sulfide spring populations. Nonetheless, we identified a small number of genes that was consistently differentially expressed in the same direction in all sulfidic and nonsulfidic population pairs. Functional annotation of shared differentially expressed genes indicated upregulation of genes associated with enzymatic H2S detoxification and transport of oxidized sulfur species, oxidative phosphorylation, energy metabolism, and pathways involved in responses to oxidative stress. Overall, our results suggest that modification of processes associated with H2S detoxification and toxicity likely complement each other to mediate elevated H2S tolerance in sulfide spring fishes. Our analyses allow for the development of novel hypotheses about biochemical and physiological mechanisms of adaptation to extreme environments.}, } @article {pmid26811484, year = {2016}, author = {Lane, N and Martin, WF}, title = {Mitochondria, complexity, and evolutionary deficit spending.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {113}, number = {6}, pages = {E666}, pmid = {26811484}, issn = {1091-6490}, mesh = {Animals ; *Energy Metabolism ; Eukaryotic Cells/*cytology/*metabolism ; *Evolution, Molecular ; Genome/*genetics ; Humans ; *Models, Biological ; Prokaryotic Cells/*cytology/*metabolism ; }, } @article {pmid26771520, year = {2016}, author = {Ray, S and Kassan, A and Busija, AR and Rangamani, P and Patel, HH}, title = {The plasma membrane as a capacitor for energy and metabolism.}, journal = {American journal of physiology. Cell physiology}, volume = {310}, number = {3}, pages = {C181-92}, pmid = {26771520}, issn = {1522-1563}, support = {HL-091071/HL/NHLBI NIH HHS/United States ; HL-107200/HL/NHLBI NIH HHS/United States ; P01 HL066941/HL/NHLBI NIH HHS/United States ; T32 GM007752/GM/NIGMS NIH HHS/United States ; I01 BX001963/BX/BLRD VA/United States ; HL-066941/HL/NHLBI NIH HHS/United States ; R01 HL091071/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Biological Evolution ; Cell Membrane/*metabolism ; Elasticity ; *Electric Capacitance ; *Energy Metabolism ; Humans ; Membrane Fluidity ; Membrane Lipids/metabolism ; Membrane Microdomains/metabolism ; Membrane Proteins/metabolism ; Models, Biological ; Oxidation-Reduction ; Oxygen/metabolism ; Signal Transduction ; }, abstract = {When considering which components of the cell are the most critical to function and physiology, we naturally focus on the nucleus, the mitochondria that regulate energy and apoptotic signaling, or other organelles such as the endoplasmic reticulum, Golgi, ribosomes, etc. Few people will suggest that the membrane is the most critical element of a cell in terms of function and physiology. Those that consider the membrane critical will point to its obvious barrier function regulated by the lipid bilayer and numerous ion channels that regulate homeostatic gradients. What becomes evident upon closer inspection is that not all membranes are created equal and that there are lipid-rich microdomains that serve as platforms of signaling and a means of communication with the intracellular environment. In this review, we explore the evolution of membranes, focus on lipid-rich microdomains, and advance the novel concept that membranes serve as "capacitors for energy and metabolism." Within this framework, the membrane then is the primary and critical regulator of stress and disease adaptation of the cell.}, } @article {pmid26685167, year = {2016}, author = {Jaromin, E and Wyszkowska, J and Labecka, AM and Sadowska, ET and Koteja, P}, title = {Hindlimb muscle fibre size and glycogen stores in bank voles with increased aerobic exercise metabolism.}, journal = {The Journal of experimental biology}, volume = {219}, number = {Pt 4}, pages = {470-473}, doi = {10.1242/jeb.130476}, pmid = {26685167}, issn = {1477-9145}, mesh = {Animals ; Arvicolinae/genetics/*metabolism ; Energy Metabolism/*genetics ; Glycogen/*metabolism ; Hindlimb ; Muscle Fibers, Skeletal/*physiology ; Muscle, Skeletal/chemistry/*metabolism ; *Physical Conditioning, Animal ; Swimming ; }, abstract = {To test hypotheses concerning physiological factors limiting the rate of aerobic exercise metabolism, we used a unique experimental evolution model: lines of bank voles selected for high swim-induced aerobic metabolism (A) and unselected, control lines (C). We investigated putative adaptations that result in the increased performance of the hindlimb muscle (gastrocnemius joined with plantaris). The body mass-adjusted muscle mass was higher in A-lines (0.093 g) than in C-lines (0.083 g; P=0.01). However, selection did not affect mean muscle fibre cross-sectional area (P=0.34) or glycogen content assessed with a histochemical periodic acid-Schiff reaction (PAS; P=0.82). The results suggest that the increased aerobic performance is achieved by an increase of total muscle mass, without major qualitative changes in the muscle fibre architecture. However, such a conclusion should be treated with caution, because other modifications, such as increased density of capillaries or mitochondria, could occur.}, } @article {pmid26634536, year = {2015}, author = {Xu, X and Tan, YP and Cheng, G and Liu, XQ and Xia, CJ and Luo, FY and Wang, CT}, title = {Genomic survey and gene expression analysis of the VDAC gene family in rice.}, journal = {Genetics and molecular research : GMR}, volume = {14}, number = {4}, pages = {15683-15696}, doi = {10.4238/2015.December.1.20}, pmid = {26634536}, issn = {1676-5680}, mesh = {Chromosome Mapping ; Cluster Analysis ; Computational Biology/methods ; Gene Duplication ; Gene Expression Profiling ; *Gene Expression Regulation, Plant ; Gene Order ; Gene Regulatory Networks ; Genetic Loci ; Genome, Plant ; *Genomics ; *Multigene Family ; Oryza/classification/*genetics/metabolism ; Phylogeny ; Voltage-Dependent Anion Channels/*genetics/metabolism ; }, abstract = {The voltage-dependent anion channel (VDAC), also known as a mitochondrial porin, plays an important role in the regulation of metabolic and energetic functions of mitochondria, as well as in mitochondria-mediated apoptosis. Cytoplasmic male sterility (CMS) is of major economic importance for commercial hybrid production and a research model for the interaction be-tween nuclear and cytoplasmic genomes. Recent research has revealed that CMS is associated with programmed cell death. Here, we used the Honglian (HL)-CMS line of rice (Oryza sativa) as material to investigate the association of O. sativa VDAC (OsVDAC) expression to CMS. Eight VDACs were extracted from rice in this study. Bioinformatic analysis of the rice VDACs was conducted at the DNA, cDNA, and protein level. Expression patterns of OsVDACs were analyzed in different organs and during different stages of pollen development using sterile line YuetaiA (YTA), and its maintainer line YuetaiB (YTB). Differential expression of OsVDACs between YTA and YTB was observed, suggesting that VDACs may be involved in the formation of HL-CMS.}, } @article {pmid26583150, year = {2015}, author = {Roussel, E and Drolet, MC and Walsh-Wilkinson, E and Dhahri, W and Lachance, D and Gascon, S and Sarrhini, O and Rousseau, JA and Lecomte, R and Couet, J and Arsenault, M}, title = {Transcriptional Changes Associated with Long-Term Left Ventricle Volume Overload in Rats: Impact on Enzymes Related to Myocardial Energy Metabolism.}, journal = {BioMed research international}, volume = {2015}, number = {}, pages = {949624}, pmid = {26583150}, issn = {2314-6141}, support = {MOP-106479//Canadian Institutes of Health Research/Canada ; MOP-61818//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Aortic Valve Insufficiency/drug therapy/*genetics/physiopathology ; Cardiac Volume/genetics ; Disease Models, Animal ; Energy Metabolism/*genetics ; Fenofibrate/administration & dosage ; Heart Failure/drug therapy/*genetics/physiopathology ; Heart Ventricles/drug effects/metabolism/physiopathology ; Humans ; Hypertrophy, Left Ventricular/*genetics/metabolism/physiopathology ; Mitochondria, Heart/genetics ; Oxidation-Reduction ; PPAR alpha/genetics ; Rats ; Transcriptome ; Ventricular Function, Left/drug effects/genetics ; }, abstract = {Patients with left ventricle (LV) volume overload (VO) remain in a compensated state for many years although severe dilation is present. The myocardial capacity to fulfill its energetic demand may delay decompensation. We performed a gene expression profile, a model of chronic VO in rat LV with severe aortic valve regurgitation (AR) for 9 months, and focused on the study of genes associated with myocardial energetics. Methods. LV gene expression profile was performed in rats after 9 months of AR and compared to sham-operated controls. LV glucose and fatty acid (FA) uptake was also evaluated in vivo by positron emission tomography in 8-week AR rats treated or not with fenofibrate, an activator of FA oxidation (FAO). Results. Many LV genes associated with mitochondrial function and metabolism were downregulated in AR rats. FA β-oxidation capacity was significantly impaired as early as two weeks after AR. Treatment with fenofibrate, a PPARα agonist, normalized both FA and glucose uptake while reducing LV dilation caused by AR. Conclusion. Myocardial energy substrate preference is affected early in the evolution of LV-VO cardiomyopathy. Maintaining a relatively normal FA utilization in the myocardium could translate into less glucose uptake and possibly lesser LV remodeling.}, } @article {pmid26539745, year = {2016}, author = {He, S and Lu, J and Jiang, W and Yang, S and Yang, J and Shi, Q}, title = {The complete mitochondrial genome sequence of a cavefish Sinocyclocheilus anshuiensis (Cypriniformes: Cyprinidae).}, journal = {Mitochondrial DNA. Part A, DNA mapping, sequencing, and analysis}, volume = {27}, number = {6}, pages = {4256-4258}, doi = {10.3109/19401736.2015.1046127}, pmid = {26539745}, issn = {2470-1408}, mesh = {Animals ; China ; Cyprinidae/*genetics ; Cypriniformes/*genetics ; Genes, rRNA/genetics ; Genome, Mitochondrial/*genetics ; Mitochondria/genetics ; Open Reading Frames/genetics ; RNA, Transfer/genetics ; Sequence Analysis, DNA/methods ; Whole Genome Sequencing/methods ; }, abstract = {Sinocyclocheilus anshuiensis is a special cavefish that lives in the Southwestern China with many specific regressive features, such as rudimentary eyes and scales, and loss of pigmentation. In this study, we performed sequencing and assembly of its complete mitochondrial genome. We confirmed that total length of the mitochondrion is 16 618 bp with an AT ratio of 55.4%. The complete mitochondrial genome contains 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs and a 963 bp control region. Our current data provide important resources for the research of cavefish mitochondrial evolution and energy metabolism.}, } @article {pmid26497252, year = {2017}, author = {Long, Z and Zhang, X and Sun, Q and Liu, Y and Liao, N and Wu, H and Wang, X and Hai, C}, title = {Evolution of metabolic disorder in rats fed high sucrose or high fat diet: Focus on redox state and mitochondrial function.}, journal = {General and comparative endocrinology}, volume = {242}, number = {}, pages = {92-100}, doi = {10.1016/j.ygcen.2015.10.012}, pmid = {26497252}, issn = {1095-6840}, mesh = {Animals ; Diet, High-Fat/*adverse effects ; Dietary Sucrose/administration & dosage/*adverse effects ; Energy Metabolism ; Glucose/metabolism ; Glucose Intolerance/metabolism ; Insulin/metabolism ; Insulin Resistance ; Male ; Metabolic Diseases ; Mitochondria/*drug effects/physiology ; Oxidation-Reduction ; Oxidative Stress ; Rats ; }, abstract = {Glucotoxicity and lipotoxicity are major hallmarks of metabolic disorder. High consumption of fat or carbohydrate rich food is a major risk of metabolic disorder. However, the evolution of high fat or high carbohydrate diet-induced metabolic disorder is not clear. In the study, we tried to find distinguished and common ways involved in the pathogenesis of insulin resistance induced by high fat (HF) and high sucrose (HS) diet. We found that HS diet induced mild glucose intolerance (2month), followed by a "temporary non-symptom phase" (3month), and then induced significant metabolic abnormality (4month). HF diet induced an early "responsive enhancement phase" (2month), and then gradually caused severe metabolic dysfunction (3-4month). After a mild induction of mitochondrial ROS generation (2month), HS diet resulted in a "temporary non-symptom phase" (3month), and then induced a more significant mitochondrial ROS production (4month). The impairment of mitochondrial function induced by HS diet was progressive (2-4month). HF diet induced gradual mitochondrial ROS generation and hyperpolarization. HF diet induced an early "responsive enhancement" of mitochondrial function (2month), and then gradually resulted in severe decrease of mitochondrial function (3-4month). Despite the patterns of HS and HF diet-induced insulin resistance were differential, final mitochondrial ROS generation combined with mitochondrial dysfunction may be the common pathway. These findings demonstrate a novel understanding of the mechanism of insulin resistance and highlight the pivotal role of mitochondrial ROS generation and mitochondrial dysfunction in the pathogenesis of metabolic disorder.}, } @article {pmid26462158, year = {2015}, author = {Garcia-Heredia, JM and Carnero, A}, title = {Decoding Warburg's hypothesis: tumor-related mutations in the mitochondrial respiratory chain.}, journal = {Oncotarget}, volume = {6}, number = {39}, pages = {41582-41599}, pmid = {26462158}, issn = {1949-2553}, mesh = {Animals ; Cell Transformation, Neoplastic/*genetics/metabolism/pathology ; Electron Transport Chain Complex Proteins/*genetics/metabolism ; Energy Metabolism/*genetics ; Genetic Predisposition to Disease ; Glycolysis/genetics ; Humans ; Mitochondria/*metabolism/pathology ; Mitochondrial Proteins/*genetics/metabolism ; *Mutation ; Neoplasms/*genetics/metabolism/pathology ; Oxidative Phosphorylation ; Phenotype ; Risk Factors ; }, abstract = {Otto Warburg observed that cancer cells derived their energy from aerobic glycolysis by converting glucose to lactate. This mechanism is in opposition to the higher energy requirements of cancer cells because oxidative phosphorylation (OxPhos) produces more ATP from glucose. Warburg hypothesized that this phenomenon occurs due to the malfunction of mitochondria in cancer cells. The rediscovery of Warburg's hypothesis coincided with the discovery of mitochondrial tumor suppressor genes that may conform to Warburg's hypothesis along with the demonstrated negative impact of HIF-1 on PDH activity and the activation of HIF-1 by oncogenic signals such as activated AKT. This work summarizes the alterations in mitochondrial respiratory chain proteins that have been identified and their involvement in cancer. Also discussed is the fact that most of the mitochondrial mutations have been found in homoplasmy, indicating a positive selection during tumor evolution, thereby supporting their causal role.}, } @article {pmid26421611, year = {2015}, author = {Lopes-Marques, M and Delgado, IL and Ruivo, R and Torres, Y and Sainath, SB and Rocha, E and Cunha, I and Santos, MM and Castro, LF}, title = {The Origin and Diversity of Cpt1 Genes in Vertebrate Species.}, journal = {PloS one}, volume = {10}, number = {9}, pages = {e0138447}, pmid = {26421611}, issn = {1932-6203}, mesh = {Animals ; Carnitine O-Palmitoyltransferase/*genetics ; Energy Metabolism/physiology ; *Evolution, Molecular ; Humans ; *Phylogeny ; }, abstract = {The Carnitine palmitoyltransferase I (Cpt1) gene family plays a crucial role in energy homeostasis since it is required for the occurrence of fatty acid β-oxidation in the mitochondria. The exact gene repertoire in different vertebrate lineages is variable. Presently, four genes are documented: Cpt1a, also known as Cpt1a1, Cpt1a2; Cpt1b and Cpt1c. The later is considered a mammalian innovation resulting from a gene duplication event in the ancestor of mammals, after the divergence of sauropsids. In contrast, Cpt1a2 has been found exclusively in teleosts. Here, we reassess the overall evolutionary relationships of Cpt1 genes using a combination of approaches, including the survey of the gene repertoire in basal gnathostome lineages. Through molecular phylogenetics and synteny studies, we find that Cpt1c is most likely a rapidly evolving orthologue of Cpt1a2. Thus, Cpt1c is present in other lineages such as cartilaginous fish, reptiles, amphibians and the coelacanth. We show that genome duplications (2R) and variable rates of sequence evolution contribute to the history of Cpt1 genes in vertebrates. Finally, we propose that loss of Cpt1b is the likely cause for the unusual energy metabolism of elasmobranch.}, } @article {pmid26396189, year = {2015}, author = {Kassa, T and Jana, S and Strader, MB and Meng, F and Jia, Y and Wilson, MT and Alayash, AI}, title = {Sickle Cell Hemoglobin in the Ferryl State Promotes βCys-93 Oxidation and Mitochondrial Dysfunction in Epithelial Lung Cells (E10).}, journal = {The Journal of biological chemistry}, volume = {290}, number = {46}, pages = {27939-27958}, pmid = {26396189}, issn = {1083-351X}, support = {P01 HL110900/HL/NHLBI NIH HHS/United States ; P01-HL110900/HL/NHLBI NIH HHS/United States ; }, mesh = {Anemia, Hemolytic/enzymology ; Anemia, Sickle Cell/enzymology ; Catalysis ; Cyclic N-Oxides/chemistry ; Cysteine/*chemistry ; Energy Metabolism ; Heme/chemistry ; Heme Oxygenase (Decyclizing)/chemistry ; Hemoglobin, Sickle/*chemistry ; Humans ; Hydrogen Peroxide/chemistry ; Iron/*chemistry ; Lung/enzymology ; Methemoglobin/chemistry ; Mitochondria/*metabolism ; Oxidation-Reduction ; Oxygen Consumption ; Respiratory Mucosa/*enzymology/ultrastructure ; }, abstract = {Polymerization of intraerythrocytic deoxyhemoglobin S (HbS) is the primary molecular event that leads to hemolytic anemia in sickle cell disease (SCD). We reasoned that HbS may contribute to the complex pathophysiology of SCD in part due to its pseudoperoxidase activity. We compared oxidation reactions and the turnover of oxidation intermediates of purified human HbS and HbA. Hydrogen peroxide (H2O2) drives a catalytic cycle that includes the following three distinct steps: 1) initial oxidation of ferrous (oxy) to ferryl Hb; 2) autoreduction of the ferryl intermediate to ferric (metHb); and 3) reaction of metHb with an additional H2O2 molecule to regenerate the ferryl intermediate. Ferrous and ferric forms of both proteins underwent initial oxidation to the ferryl heme in the presence of H2O2 at equal rates. However, the rate of autoreduction of ferryl to the ferric form was slower in the HbS solutions. Using quantitative mass spectrometry and the spin trap, 5,5-dimethyl-1-pyrroline-N-oxide, we found more irreversibly oxidized βCys-93in HbS than in HbA. Incubation of the ferric or ferryl HbS with cultured lung epithelial cells (E10) induced a drop in mitochondrial oxygen consumption rate and impairment of cellular bioenergetics that was related to the redox state of the iron. Ferryl HbS induced a substantial drop in the mitochondrial transmembrane potential and increases in cytosolic heme oxygenase (HO-1) expression and mitochondrial colocalization in E10 cells. Thus, highly oxidizing ferryl Hb and heme, the product of oxidation, may be central to the evolution of vasculopathy in SCD and may suggest therapeutic modalities that interrupt heme-mediated inflammation.}, } @article {pmid26393435, year = {2016}, author = {Bremer, K and Kocha, KM and Snider, T and Moyes, CD}, title = {Sensing and responding to energetic stress: The role of the AMPK-PGC1α-NRF1 axis in control of mitochondrial biogenesis in fish.}, journal = {Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology}, volume = {199}, number = {}, pages = {4-12}, doi = {10.1016/j.cbpb.2015.09.005}, pmid = {26393435}, issn = {1879-1107}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Amino Acid Sequence ; Animals ; Enzyme Activation ; Fishes/*metabolism/physiology ; Humans ; Nuclear Respiratory Factor 1/*metabolism ; *Organelle Biogenesis ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/chemistry/*metabolism ; Rats ; *Stress, Physiological ; }, abstract = {Remodeling the muscle metabolic machinery in mammals in response to energetic challenges depends on the energy sensor AMP-activated protein kinase (AMPK) and its ability to phosphorylate PPAR γ coactivator 1 α (PGC1α), which in turn coactivates metabolic genes through direct and indirect association with DNA-binding proteins such as the nuclear respiratory factor 1 (NRF1) (Wu et al., 1999). The integrity of this axis in fish is uncertain because PGC1α i) lacks the critical Thr177 targeted by AMPK and ii) has mutations that may preclude binding NRF1. In this study we found no evidence that AMPK regulates mitochondrial gene expression through PGC1α in zebrafish and goldfish. AICAR treatment of zebrafish blastula cells increased phosphorylation of AMPK and led to changes in transcript levels of the AMPK targets mTOR and hexokinase 2. However, we saw no increases in mRNA levels for genes associated with mitochondrial biogenesis, including PGC1α, NRF1, and COX7C, a cytochrome c oxidase subunit. Further, AMPK phosphorylated mammalian peptides of PGC1α but not the corresponding region of zebrafish or goldfish in vitro. In vivo cold acclimation of goldfish caused an increase in mitochondrial enzymes, AMP and ADP levels, however AMPK phosphorylation decreased. In fish, the NRF1-PGC1α axis may be disrupted due to insertions in fish PGC1α orthologs within the region that serves as NRF1 binding domain in mammals. Immunocopurification showed that recombinant NRF1 protein binds mammalian but not fish PGC1α. Collectively, our studies suggest that fish have a disruption in the AMPK-PGC1α-NRF1 pathway due to structural differences between fish and mammalian PGC1α.}, } @article {pmid26350413, year = {2015}, author = {Stefano, GB and Mantione, KJ and Capellan, L and Casares, FM and Challenger, S and Ramin, R and Samuel, JM and Snyder, C and Kream, RM}, title = {Morphine stimulates nitric oxide release in human mitochondria.}, journal = {Journal of bioenergetics and biomembranes}, volume = {47}, number = {5}, pages = {409-417}, pmid = {26350413}, issn = {1573-6881}, mesh = {Autocrine Communication/*drug effects ; Cell Line ; Energy Metabolism/*drug effects ; Humans ; Mitochondria/*metabolism ; Morphine/*pharmacology ; Nitric Oxide/*biosynthesis ; Paracrine Communication/*drug effects ; }, abstract = {The expression of morphine by plants, invertebrate, and vertebrate cells and organ systems, strongly indicates a high level of evolutionary conservation of morphine and related morphinan alkaloids as required for life. The prototype catecholamine, dopamine, serves as an essential chemical intermediate in morphine biosynthesis, both in plants and animals. We surmise that, before the emergence of specialized plant and animal cells/organ systems, primordial multi-potential cell types required selective mechanisms to limit their responsiveness to environmental cues. Accordingly, cellular systems that emerged with the potential for recruitment of the free radical gas nitric oxide (NO) as a multi-faceted autocrine/paracrine signaling molecule, were provided with extremely positive evolutionary advantages. Endogenous morphinergic signaling, in concert with NO-coupled signaling systems, has evolved as an autocrine/paracrine regulator of metabolic homeostasis, energy metabolism, mitochondrial respiration and energy production. Basic physiological processes involving morphinergic/NO-coupled regulation of mitochondrial function, with special emphasis on the cardiovascular system, are critical to all organismic survival. Key to this concept may be the phenomenon of mitochondrial enslavement in eukaryotic evolution via endogenous morphine.}, } @article {pmid26347565, year = {2015}, author = {Roussel, D and Salin, K and Dumet, A and Romestaing, C and Rey, B and Voituron, Y}, title = {Oxidative phosphorylation efficiency, proton conductance and reactive oxygen species production of liver mitochondria correlates with body mass in frogs.}, journal = {The Journal of experimental biology}, volume = {218}, number = {Pt 20}, pages = {3222-3228}, doi = {10.1242/jeb.126086}, pmid = {26347565}, issn = {1477-9145}, mesh = {Animals ; Body Weight/*physiology ; Energy Metabolism ; Mitochondria, Liver/chemistry/*metabolism ; Oxidative Phosphorylation ; *Protons ; Ranidae/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Body size is a central biological parameter affecting most biological processes (especially energetics) and the mitochondrion is a key organelle controlling metabolism and is also the cell's main source of chemical energy. However, the link between body size and mitochondrial function is still unclear, especially in ectotherms. In this study, we investigated several parameters of mitochondrial bioenergetics in the liver of three closely related species of frog (the common frog Rana temporaria, the marsh frog Pelophylax ridibundus and the bull frog Lithobates catesbeiana). These particular species were chosen because of their differences in adult body mass. We found that mitochondrial coupling efficiency was markedly increased with animal size, which led to a higher ATP production (+70%) in the larger frogs (L. catesbeiana) compared with the smaller frogs (R. temporaria). This was essentially driven by a strong negative dependence of mitochondrial proton conductance on body mass. Liver mitochondria from the larger frogs (L. catesbeiana) displayed 50% of the proton conductance of mitochondria from the smaller frogs (R. temporaria). Contrary to our prediction, the low mitochondrial proton conductance measured in L. catesbeiana was not associated with higher reactive oxygen species production. Instead, liver mitochondria from the larger individuals produced significantly lower levels of radical oxygen species than those from the smaller frogs. Collectively, the data show that key bioenergetics parameters of mitochondria (proton leak, ATP production efficiency and radical oxygen species production) are correlated with body mass in frogs. This research expands our understanding of the relationship between mitochondrial function and the evolution of allometric scaling in ectotherms.}, } @article {pmid26323761, year = {2015}, author = {Martin, WF and Garg, S and Zimorski, V}, title = {Endosymbiotic theories for eukaryote origin.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {370}, number = {1678}, pages = {20140330}, pmid = {26323761}, issn = {1471-2970}, mesh = {*Biological Evolution ; Eukaryotic Cells/*classification/*cytology ; Organelles/genetics/physiology ; Symbiosis/*genetics/*physiology ; }, abstract = {For over 100 years, endosymbiotic theories have figured in thoughts about the differences between prokaryotic and eukaryotic cells. More than 20 different versions of endosymbiotic theory have been presented in the literature to explain the origin of eukaryotes and their mitochondria. Very few of those models account for eukaryotic anaerobes. The role of energy and the energetic constraints that prokaryotic cell organization placed on evolutionary innovation in cell history has recently come to bear on endosymbiotic theory. Only cells that possessed mitochondria had the bioenergetic means to attain eukaryotic cell complexity, which is why there are no true intermediates in the prokaryote-to-eukaryote transition. Current versions of endosymbiotic theory have it that the host was an archaeon (an archaebacterium), not a eukaryote. Hence the evolutionary history and biology of archaea increasingly comes to bear on eukaryotic origins, more than ever before. Here, we have compiled a survey of endosymbiotic theories for the origin of eukaryotes and mitochondria, and for the origin of the eukaryotic nucleus, summarizing the essentials of each and contrasting some of their predictions to the observations. A new aspect of endosymbiosis in eukaryote evolution comes into focus from these considerations: the host for the origin of plastids was a facultative anaerobe.}, } @article {pmid26323685, year = {2015}, author = {Lane, N and Powell, K}, title = {Nick Lane: Unearthing the first cellular innovations.}, journal = {The Journal of cell biology}, volume = {210}, number = {5}, pages = {684-685}, pmid = {26323685}, issn = {1540-8140}, mesh = {*Biological Evolution ; *Cell Biology ; Cell Membrane/physiology ; Energy Metabolism/physiology ; Humans ; Hydrothermal Vents ; Mitochondria/pathology/physiology ; Origin of Life ; }, abstract = {Lane’s unorthodox career stalks the origins of complex eukaryotic life.}, } @article {pmid26260178, year = {2016}, author = {Chen, L and Song, X and Chen, X and Dang, X and Wang, W}, title = {The complete mitochondrial genome of the Pundamilia nyererei (Perciformes, Cichlidae).}, journal = {Mitochondrial DNA. Part A, DNA mapping, sequencing, and analysis}, volume = {27}, number = {5}, pages = {3567-3568}, doi = {10.3109/19401736.2015.1074221}, pmid = {26260178}, issn = {2470-1408}, mesh = {Animals ; Base Composition ; Cichlids/*genetics ; Codon, Initiator ; Codon, Terminator ; DNA, Mitochondrial/genetics ; Fish Proteins/genetics ; *Genome, Mitochondrial ; Mitochondria/genetics ; Phylogeny ; RNA, Ribosomal/genetics ; RNA, Transfer/genetics ; Whole Genome Sequencing ; }, abstract = {Pundamilia nyererei (Perciformes, Cichlidae) is a member of Cichlid fishes that lives in the Great Lakes of East Africa. Fishes of the Cichlidae family can adapt spectacular trophic radiations and provide good potential examples of vertebrate adaptive radiations. Here, we firstly assembled the complete mitochondrial genome (mitogenome) of Pundamilia nyererei. The mitgenome was 16 761 bp in length, including 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 1 putative control region. Most of these protein-coding genes started with a traditional ATG codon except for COX1, which initiated with an infrequent start codon GTG instead, and terminated with the mitochondrial stop codon (TAA/AGG/AGA) or a single T base. The mitogenome structural organization is identical to other Cichlid fish. The overall GC content is 45.25%, which is lower than the AT content. According to these new determined mitogenome sequences and 10 other species under the same family or order, we have constructed the species phylogenetic tree to verify the accuracy of newly assembled mitogenome sequences. We accept that by taking the advantage of full mitogenome, we can address taxonomic issue and study the related evolutionary events. Our current data are going to provide important resources for the research of Cichlid fishes mitochondrial evolution and energy metabolism.}, } @article {pmid26243158, year = {2015}, author = {Matta, CF and Massa, L}, title = {Energy Equivalence of Information in the Mitochondrion and the Thermodynamic Efficiency of ATP Synthase.}, journal = {Biochemistry}, volume = {54}, number = {34}, pages = {5376-5378}, doi = {10.1021/acs.biochem.5b00834}, pmid = {26243158}, issn = {1520-4995}, mesh = {Adenosine Triphosphate/biosynthesis ; Animals ; Energy Metabolism ; Humans ; Kidney/metabolism ; Mitochondria/metabolism ; Mitochondrial Proton-Translocating ATPases/*chemistry/*metabolism ; Models, Biological ; Proton-Motive Force ; Thermodynamics ; }, abstract = {Half a century ago, Johnson and Knudsen resolved the puzzle of the apparent low efficiency of the kidney (∼ 0.5%) compared to most other bodily organs (∼ 40%) by taking into account the entropic cost of ion sorting, the principal function of this organ. Similarly, it is shown that the efficiency of energy transduction of the chemiosmotic proton-motive force by ATP synthase is closer to 90% instead of the oft-quoted textbook value of only 60% when information theoretic considerations are applied to the mitochondrion. This high efficiency is consistent with the mechanical energy transduction of ATP synthase known to be close to the 100% thermodynamic limit. It would have been wasteful for evolution to maximize the mechanical energy transduction to 100% while wasting 40% of the chemiosmotic free energy in the conversion of the proton-motive force into mechanical work before being captured as chemical energy in adenosine 5'-triphosphate.}, } @article {pmid26240360, year = {2015}, author = {Bauer, D and Merz, DR and Pelz, B and Theisen, KE and Yacyshyn, G and Mokranjac, D and Dima, RI and Rief, M and Žoldák, G}, title = {Nucleotides regulate the mechanical hierarchy between subdomains of the nucleotide binding domain of the Hsp70 chaperone DnaK.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {112}, number = {33}, pages = {10389-10394}, pmid = {26240360}, issn = {1091-6490}, mesh = {Actins/chemistry ; Adenosine Triphosphatases/chemistry ; Amino Acid Sequence ; Computer Simulation ; Elasticity ; Escherichia coli Proteins/*chemistry ; HSP70 Heat-Shock Proteins/*chemistry ; Lasers ; Mitochondria/metabolism ; Models, Molecular ; Molecular Chaperones ; Molecular Sequence Data ; Nucleotides/*chemistry ; Phylogeny ; Protein Binding ; Protein Denaturation ; Protein Folding ; Protein Structure, Tertiary ; Saccharomyces cerevisiae Proteins/*chemistry ; Signal Transduction ; }, abstract = {The regulation of protein function through ligand-induced conformational changes is crucial for many signal transduction processes. The binding of a ligand alters the delicate energy balance within the protein structure, eventually leading to such conformational changes. In this study, we elucidate the energetic and mechanical changes within the subdomains of the nucleotide binding domain (NBD) of the heat shock protein of 70 kDa (Hsp70) chaperone DnaK upon nucleotide binding. In an integrated approach using single molecule optical tweezer experiments, loop insertions, and steered coarse-grained molecular simulations, we find that the C-terminal helix of the NBD is the major determinant of mechanical stability, acting as a glue between the two lobes. After helix unraveling, the relative stability of the two separated lobes is regulated by ATP/ADP binding. We find that the nucleotide stays strongly bound to lobe II, thus reversing the mechanical hierarchy between the two lobes. Our results offer general insights into the nucleotide-induced signal transduction within members of the actin/sugar kinase superfamily.}, } @article {pmid26203001, year = {2015}, author = {Salin, K and Auer, SK and Rey, B and Selman, C and Metcalfe, NB}, title = {Variation in the link between oxygen consumption and ATP production, and its relevance for animal performance.}, journal = {Proceedings. Biological sciences}, volume = {282}, number = {1812}, pages = {20151028}, pmid = {26203001}, issn = {1471-2954}, mesh = {Adenosine Triphosphate/*metabolism ; Animals ; Biological Evolution ; *Energy Metabolism ; Invertebrates/metabolism ; Mitochondria/*metabolism ; *Oxygen Consumption ; Vertebrates/metabolism ; }, abstract = {It is often assumed that an animal's metabolic rate can be estimated through measuring the whole-organism oxygen consumption rate. However, oxygen consumption alone is unlikely to be a sufficient marker of energy metabolism in many situations. This is due to the inherent variability in the link between oxidation and phosphorylation; that is, the amount of adenosine triphosphate (ATP) generated per molecule of oxygen consumed by mitochondria (P/O ratio). In this article, we describe how the P/O ratio can vary within and among individuals, and in response to a number of environmental parameters, including diet and temperature. As the P/O ratio affects the efficiency of cellular energy production, its variability may have significant consequences for animal performance, such as growth rate and reproductive output. We explore the adaptive significance of such variability and hypothesize that while a reduction in the P/O ratio is energetically costly, it may be associated with advantages in terms of somatic maintenance through reduced production of reactive oxygen species. Finally, we discuss how considering variation in mitochondrial efficiency, together with whole-organism oxygen consumption, can permit a better understanding of the relationship between energy metabolism and life history for studies in evolutionary ecology.}, } @article {pmid26073494, year = {2015}, author = {Chandel, NS}, title = {Evolution of Mitochondria as Signaling Organelles.}, journal = {Cell metabolism}, volume = {22}, number = {2}, pages = {204-206}, doi = {10.1016/j.cmet.2015.05.013}, pmid = {26073494}, issn = {1932-7420}, support = {5P01HL071643/HL/NHLBI NIH HHS/United States ; R01CA123067/CA/NCI NIH HHS/United States ; R01HL12206201/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Energy Metabolism/*physiology ; *Evolution, Molecular ; Humans ; Mitochondria/*physiology ; Signal Transduction/*physiology ; *Stress, Physiological ; }, abstract = {Mitochondria have primarily been viewed as bioenergetic and biosynthetic organelles that autonomously co-exist within the cell. However, the past two decades have provided evidence that mitochondria function as signaling organelles, constantly communicating with the cytosol to initiate biological events under homeostatic and stress conditions. Thus, the signaling function of the mitochondria may have been selected by nature from the inception of the early eukaryote, as discussed in this essay.}, } @article {pmid26070000, year = {2015}, author = {Hubbard, WJ and Bland, KI and Chaudry, IH}, title = {The ERRor of Our Ways: Estrogen-Related Receptors are About Energy, Not Hormones, and are Potential New Targets for Trauma and Shock.}, journal = {Shock (Augusta, Ga.)}, volume = {44}, number = {1}, pages = {3-15}, doi = {10.1097/SHK.0000000000000364}, pmid = {26070000}, issn = {1540-0514}, mesh = {Animals ; *Energy Metabolism ; *Evolution, Molecular ; Humans ; *Mitochondria/genetics/metabolism ; PPAR gamma/genetics/metabolism ; *Receptors, Estrogen/genetics/metabolism ; *Shock/genetics/metabolism ; Transcription Factors/genetics/metabolism ; *Wounds and Injuries/genetics/metabolism ; }, abstract = {As with sharks and horseshoe crabs, some designs of nature need only minor evolutionary adjustments during the millennia to remain superbly adapted. Such is the case at the molecular level for the nuclear receptors (NRs), which seem to have originated concomitantly with the earliest metazoan lineage of animals. A wide array of NRs persists today throughout all animal phyla with many different functions, yet they share a highly conserved protein structure, a testament to their having evolved through numerous gene duplications. Of particular interest for this readership are the estrogen-related receptors (ERRs), which have significant supportive roles in energy creation and regulation, mitochondrial function and biogenesis, development, tissue repair, hypoxia, and cancer. Thus, placed at the nexus of energetics and homeostasis, ERR (in association with the coregulatory molecules peroxisome proliferator-activated receptor-γ coactivator-1α and -β) can facilitate repair from injury and adaptations to stressful environments. Whereas it is curious that ERRs and some other NRs exist as "orphans" by virtue of having no known cognate ligand, increasing interest in the estrogen receptor has led to the development of synthetic ligands and screening for naturally occurring molecules, either capable of modulating ERR activity. Thus, what is needed now is a nomenclature update for the ERR to focus the mind on energetics and metabolism, the most compromised and crucial systems after trauma and shock.}, } @article {pmid26041663, year = {2015}, author = {Virmani, A and Pinto, L and Bauermann, O and Zerelli, S and Diedenhofen, A and Binienda, ZK and Ali, SF and van der Leij, FR}, title = {The Carnitine Palmitoyl Transferase (CPT) System and Possible Relevance for Neuropsychiatric and Neurological Conditions.}, journal = {Molecular neurobiology}, volume = {52}, number = {2}, pages = {826-836}, pmid = {26041663}, issn = {1559-1182}, mesh = {Animals ; Brain/enzymology ; Cardiovascular Diseases/enzymology ; Carnitine/metabolism ; Carnitine O-Palmitoyltransferase/deficiency/genetics/*physiology ; Ceramides/metabolism ; Diabetes Mellitus, Type 2/enzymology ; Disease Progression ; Eating/physiology ; Endocannabinoids/metabolism ; Energy Metabolism/physiology ; Fatty Acids/metabolism ; Humans ; Hypoglycemia ; Insulin/metabolism ; Learning/physiology ; Lipid Metabolism, Inborn Errors ; Malonyl Coenzyme A/metabolism ; Metabolic Syndrome/enzymology ; Mitochondria/*enzymology ; Mitochondria, Liver/enzymology ; Mitochondria, Muscle/enzymology ; Multienzyme Complexes/physiology ; Neurodegenerative Diseases/*enzymology ; Oxidation-Reduction ; Protein Isoforms ; }, abstract = {The carnitine palmitoyl transferase (CPT) system is a multiprotein complex with catalytic activity localized within a core represented by CPT1 and CPT2 in the outer and inner membrane of the mitochondria, respectively. Two proteins, the acyl-CoA synthase and a translocase also form part of this system. This system is crucial for the mitochondrial beta-oxidation of long-chain fatty acids. CPT1 has two well-known isoforms, CPT1a and CPT1b. CPT1a is the hepatic isoform and CPT1b is typically muscular; both are normally utilized by the organism for metabolic processes throughout the body. There is a strong evidence for their involvement in various disease states, e.g., metabolic syndrome, cardiovascular diseases, and in diabetes mellitus type 2. Recently, a new, third isoform of CPT was described, CPT1c. This is a neuronal isoform and is prevalently localized in brain regions such as hypothalamus, amygdala, and hippocampus. These brain regions play an important role in control of food intake and neuropsychiatric and neurological diseases. CPT activity has been implicated in several neurological and social diseases mainly related to the alteration of insulin equilibrium in the brain. These pathologies include Parkinson's disease, Alzheimer's disease, and schizophrenia. Evolution of both Parkinson's disease and Alzheimer's disease is in some way linked to brain insulin and related metabolic dysfunctions with putative links also with the diabetes type 2. Studies show that in the CNS, CPT1c affects ceramide levels, endocannabionoids, and oxidative processes and may play an important role in various brain functions such as learning.}, } @article {pmid26004364, year = {2015}, author = {Ilkun, O and Wilde, N and Tuinei, J and Pires, KM and Zhu, Y and Bugger, H and Soto, J and Wayment, B and Olsen, C and Litwin, SE and Abel, ED}, title = {Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome.}, journal = {Journal of molecular and cellular cardiology}, volume = {85}, number = {}, pages = {104-116}, pmid = {26004364}, issn = {1095-8584}, support = {R01 HL073167/HL/NHLBI NIH HHS/United States ; T32DK091317/DK/NIDDK NIH HHS/United States ; U54 HL112311/HL/NHLBI NIH HHS/United States ; U01 HL070525/HL/NHLBI NIH HHS/United States ; R01HL73167/HL/NHLBI NIH HHS/United States ; UO1HL70525/HL/NHLBI NIH HHS/United States ; T32 DK091317/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*pharmacology/therapeutic use ; Drug Evaluation, Preclinical ; Energy Metabolism ; Fatty Acids/metabolism ; Homeostasis ; Insulin/blood ; Insulin Resistance ; Metabolic Syndrome/blood/*drug therapy ; Metalloporphyrins/*pharmacology/therapeutic use ; Mice, Inbred C57BL ; Mice, Obese ; Mitochondria, Heart/*metabolism ; Myocardium/metabolism ; Oxidative Stress ; Signal Transduction ; }, abstract = {Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism.}, } @article {pmid25997954, year = {2015}, author = {Stefano, GB and Kream, RM}, title = {Hypoxia defined as a common culprit/initiation factor in mitochondrial-mediated proinflammatory processes.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {21}, number = {}, pages = {1478-1484}, pmid = {25997954}, issn = {1643-3750}, mesh = {Adenosine Triphosphate/biosynthesis ; Animals ; Biological Evolution ; Cell Hypoxia/*physiology ; Cellular Microenvironment ; Cellular Senescence ; Cytokines/metabolism ; Energy Metabolism ; Gene Expression Regulation ; Humans ; Immunity, Innate ; Immunocompetence ; Inflammation/*etiology/physiopathology ; Invertebrates/physiology ; Microglia/*physiology ; Mitochondria/*physiology ; *Models, Biological ; Neuroimmunomodulation/*physiology ; Nitric Oxide/*physiology ; Nitrites/metabolism ; Opioid Peptides/metabolism ; Signal Transduction ; Vertebrates/physiology ; }, abstract = {In mammals and invertebrates, the activities of neuro- and immuno-competent cells, e.g., glia, which are present in nervous tissues, are deemed of critical importance to normative neuronal function. The responsiveness of invertebrate and vertebrate immuno-competent glia to a common set of signal molecules, such as nitric oxide and endogenous morphine, is functionally linked to physiologically driven innate immunological and neuronal activities. Importantly, the presence of a common, evolutionarily conserved, set of signal molecules in comparative animal groups strongly suggests an expansive intermediate metabolic profile dependent on high output mitochondrial ATP production and utilization. Normative bidirectional neural-immune communication across invertebrate and vertebrate species requires common anatomical and biochemical substrates and pathways involved in energy production and mitochondrial integrity. Within this closed-loop system, abnormal perturbation of the respective tissue functions will have profound ramifications in functionally altering associated nervous and vascular systems and it is highly likely that the initial trigger to the induction of a physiologically debilitating pro-inflammatory state is a micro-environmental hypoxic event. This is surmised by the need for an unwavering constant oxygen supply. In this case, temporal perturbations of normative oxygen tension may be tolerated for short, but not extended, periods and ischemic/hypoxic perturbations in oxygen delivery represent significant physiological challenges to overall cellular and multiple organ system viability. Hence, hypoxic triggering of multiple pro-inflammatory events, if not corrected, will promote pathophysiological amplification leading to a deleterious cascade of bio-senescent cellular and molecular signaling pathways, which converge to markedly impair mitochondrial energy utilization and ATP production.}, } @article {pmid25966796, year = {2015}, author = {Oelkrug, R and Polymeropoulos, ET and Jastroch, M}, title = {Brown adipose tissue: physiological function and evolutionary significance.}, journal = {Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology}, volume = {185}, number = {6}, pages = {587-606}, pmid = {25966796}, issn = {1432-136X}, mesh = {Adipose Tissue, Brown/anatomy & histology/cytology/*physiology ; Animals ; Animals, Newborn ; Antioxidants/metabolism ; *Biological Evolution ; Body Weight ; Female ; Humans ; Ion Channels/metabolism ; Mammals/physiology ; Marsupialia/physiology ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Phylogeny ; Reproduction/physiology ; Rodentia/physiology ; Thermogenesis/*physiology ; Uncoupling Protein 1 ; }, abstract = {In modern eutherian (placental) mammals, brown adipose tissue (BAT) evolved as a specialized thermogenic organ that is responsible for adaptive non-shivering thermogenesis (NST). For NST, energy metabolism of BAT mitochondria is increased by activation of uncoupling protein 1 (UCP1), which dissipates the proton motive force as heat. Despite the presence of UCP1 orthologues prior to the divergence of teleost fish and mammalian lineages, UCP1's significance for thermogenic adipose tissue emerged at later evolutionary stages. Recent studies on the presence of BAT in metatherians (marsupials) and eutherians of the afrotherian clade provide novel insights into the evolution of adaptive NST in mammals. In particular studies on the 'protoendothermic' lesser hedgehog tenrec (Afrotheria) suggest an evolutionary scenario linking BAT to the onset of eutherian endothermy. Here, we review the physiological function and distribution of BAT in an evolutionary context by focusing on the latest research on phylogenetically distinct species.}, } @article {pmid25948649, year = {2016}, author = {Xavier, JM and Rodrigues, CM and Solá, S}, title = {Mitochondria: Major Regulators of Neural Development.}, journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry}, volume = {22}, number = {4}, pages = {346-358}, doi = {10.1177/1073858415585472}, pmid = {25948649}, issn = {1089-4098}, mesh = {Animals ; Apoptosis ; Bile Acids and Salts ; Cell Cycle ; DNA, Mitochondrial/metabolism/physiology ; Energy Metabolism ; Humans ; Mitochondria/metabolism/*physiology ; Neural Stem Cells/metabolism/*physiology ; *Neurogenesis ; Neuronal Plasticity ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondria are organelles derived from primitive symbiosis between archeon ancestors and prokaryotic α-proteobacteria species, which lost the capacity of synthetizing most proteins encoded the bacterial DNA, along the evolutionary process of eukaryotes. Nowadays, mitochondria are constituted by small circular mitochondrial DNA of 16 kb, responsible for the control of several proteins, including polypeptides of the electron transport chain. Throughout evolution, these organelles acquired the capacity of regulating energy production and metabolism, thus becoming central modulators of cell fate. In fact, mitochondria are crucial for a variety of cellular processes, including adenosine triphosphate production by oxidative phosphorylation, intracellular Ca(2+) homeostasis, generation of reactive oxygen species, and also cellular specialization in a variety of tissues that ultimately relies on specific mitochondrial specialization and maturation. In this review, we discuss recent evidence extending the importance of mitochondrial function and energy metabolism to the context of neuronal development and adult neurogenesis.}, } @article {pmid25916587, year = {2015}, author = {Levin, L and Mishmar, D}, title = {A genetic view of the mitochondrial role in ageing: killing us softly.}, journal = {Advances in experimental medicine and biology}, volume = {847}, number = {}, pages = {89-106}, doi = {10.1007/978-1-4939-2404-2_4}, pmid = {25916587}, issn = {0065-2598}, mesh = {*Aging/genetics ; Animals ; DNA, Mitochondrial/physiology ; Energy Metabolism ; Humans ; Mitochondria/*physiology ; }, abstract = {In contrast to the nuclear genome, the mitochondrial DNA (mtDNA) is maternally inherited and resides in multiple cellular copies that may vary in sequence (heteroplasmy). Although the interaction between mtDNA and nuclear DNA-encoded factors (mito-nuclear interaction) is vital, the mtDNA accumulates mutations an order of magnitude faster than the nuclear genome both during evolution and during the lifetime of the individual, thus requiring tight mito-nuclear co-evolution. These unique features drew the attention of many to suggest a role for the mitochondria in ageing. Although an excess of mtDNA mutations has been found in aged humans and animal models, most of these mutations had minor functional potential. Moreover, there are mtDNA mutations that recur in aged humans, but do not have any clear functionality. Nevertheless, accumulation of recurrent private mutations with minor functionality in the fast-ageing, mtDNA polymerase mutated mice (Pol-gamma), suggested that these very mtDNA alterations participate in ageing. This introduces a paradox: how would either single or recurrent mutations with negligible functionality play a role in a major chronic phenotype such as ageing?Here, we propose a hypothesis to partially resolve this paradox: accumulation of mitochondrial mutations with subtle functionality, which was overlooked by the mechanisms of selection, supplemented by slightly affected fusion-fission cycles, will hamper mitochondrial functional complementation within cells, disrupt mito-nuclear interactions and lead to ageing. Since certain mito-nuclear genotypes are less functionally compatible than others, and since the mtDNA and the nuclear genome segregate independently among generations, mild functionality of mutations will have differential effect on individuals in the population thus explaining the large variability in the ageing phenotype even within ethnic groups. We emphasize the role of recurrent mtDNA mutations with functional potential during evolution and during the lifetime of the individual.}, } @article {pmid25883267, year = {2015}, author = {Booth, A and Doolittle, WF}, title = {Eukaryogenesis, how special really?.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {112}, number = {33}, pages = {10278-10285}, pmid = {25883267}, issn = {1091-6490}, mesh = {Animals ; *Biological Evolution ; Energy Metabolism ; Escherichia coli/metabolism ; Eukaryota/*metabolism ; Eukaryotic Cells/cytology ; Evolution, Molecular ; Genome, Bacterial ; Humans ; Introns ; Mitochondria/metabolism/physiology ; *Origin of Life ; Phenotype ; Phylogeny ; Plants ; Prokaryotic Cells/cytology ; Spliceosomes/physiology ; }, abstract = {Eukaryogenesis is widely viewed as an improbable evolutionary transition uniquely affecting the evolution of life on this planet. However, scientific and popular rhetoric extolling this event as a singularity lacks rigorous evidential and statistical support. Here, we question several of the usual claims about the specialness of eukaryogenesis, focusing on both eukaryogenesis as a process and its outcome, the eukaryotic cell. We argue in favor of four ideas. First, the criteria by which we judge eukaryogenesis to have required a genuinely unlikely series of events 2 billion years in the making are being eroded by discoveries that fill in the gaps of the prokaryote:eukaryote "discontinuity." Second, eukaryogenesis confronts evolutionary theory in ways not different from other evolutionary transitions in individuality; parallel systems can be found at several hierarchical levels. Third, identifying which of several complex cellular features confer on eukaryotes a putative richer evolutionary potential remains an area of speculation: various keys to success have been proposed and rejected over the five-decade history of research in this area. Fourth, and perhaps most importantly, it is difficult and may be impossible to eliminate eukaryocentric bias from the measures by which eukaryotes as a whole are judged to have achieved greater success than prokaryotes as a whole. Overall, we question whether premises of existing theories about the uniqueness of eukaryogenesis and the greater evolutionary potential of eukaryotes have been objectively formulated and whether, despite widespread acceptance that eukaryogenesis was "special," any such notion has more than rhetorical value.}, } @article {pmid25865816, year = {2015}, author = {Kake-Guena, SA and Touisse, K and Vergilino, R and Dufresne, F and Blier, PU and Lemieux, H}, title = {Assessment of mitochondrial functions in Daphnia pulex clones using high-resolution respirometry.}, journal = {Journal of experimental zoology. Part A, Ecological genetics and physiology}, volume = {323}, number = {5}, pages = {292-300}, doi = {10.1002/jez.1913}, pmid = {25865816}, issn = {1932-5231}, mesh = {Animals ; Biological Evolution ; DNA, Mitochondrial/genetics/metabolism ; Daphnia/genetics/*metabolism ; Energy Metabolism ; Environment ; Genetic Variation ; Haplotypes ; Mitochondria/genetics/*metabolism ; Oxidative Phosphorylation ; Ploidies ; Sequence Analysis, DNA ; }, abstract = {The objectives of our study were to adapt a method to measure mitochondrial function in intact mitochondria from the small crustacean Daphnia pulex and to validate if this method was sensitive enough to characterize mitochondrial metabolism in clones of the pulex complex differing in ploidy levels, mitochondrial DNA haplotypes, and geographic origins. Daphnia clones belonging to the Daphnia pulex complex represent a powerful model to delineate the link between mitochondrial DNA evolution and mitochondrial phenotypes, as single genotypes with divergent mtDNA can be grown under various experimental conditions. Our study included two diploid clones from temperate environments and two triploid clones from subarctic environments. The whole animal permeabilization and measurement of respiration with high-resolution respirometry enabled the measurement of the functional capacity of specific mitochondrial complexes in four clones. When expressing the activity as ratios, our method detected significant interclonal variations. In the triploid subarctic clone from Kuujjurapik, a higher proportion of the maximal physiological oxidative phosphorylation (OXPHOS) capacity of mitochondria was supported by complex II, and a lower proportion by complex I. The triploid subarctic clone from Churchill (Manitoba) showed the lowest proportion of the maximal OXPHOS supported by complex II. Additional studies are required to determine if these differences in mitochondrial functions are related to differences in mitochondrial haplotypes or ploidy level and if they might be associated with fitness divergences and therefore selective value.}, } @article {pmid25835781, year = {2015}, author = {Báez, AL and Reynoso, MN and Lo Presti, MS and Bazán, PC and Strauss, M and Miler, N and Pons, P and Rivarola, HW and Paglini-Oliva, P}, title = {Mitochondrial dysfunction in skeletal muscle during experimental Chagas disease.}, journal = {Experimental and molecular pathology}, volume = {98}, number = {3}, pages = {467-475}, doi = {10.1016/j.yexmp.2015.03.034}, pmid = {25835781}, issn = {1096-0945}, mesh = {Animals ; Chagas Disease/*metabolism/pathology ; Electron Transport Chain Complex Proteins/metabolism ; Female ; Male ; Mice ; Mitochondria, Muscle/*metabolism/ultrastructure ; Muscle, Skeletal/*metabolism/ultrastructure ; }, abstract = {Trypanosoma cruzi invasion and replication in cardiomyocytes and other tissues induce cellular injuries and cytotoxic reactions, with the production of inflammatory cytokines and nitric oxide, both sources of reactive oxygen species. The myocyte response to oxidative stress involves the progression of cellular changes primarily targeting mitochondria. Similar alterations could be taking place in mitochondria from the skeletal muscle; if that is the case, a simple skeletal muscle biopsy would give information about the cardiac energetic production that could be used as a predictor of the chagasic cardiopathy evolution. Therefore, in the present paper we studied skeletal muscle mitochondrial structure and the enzymatic activity of citrate synthase and respiratory chain complexes I to IV (CI-CIV), in Albino Swiss mice infected with T. cruzi, Tulahuen strain and SGO Z12 and Lucky isolates, along the infection. Changes in the mitochondrial structure were detected in 100% of the mitochondria analyzed from the infected groups: they all presented at least 1 significant abnormality such as increase in their matrix or disorganization of their cristae, which are probably related to the enzymatic dysfunction. When we studied the Krebs cycle functionality through the measurement of the specific citrate synthase activity, we found it to be significantly diminished during the acute phase of the infection in Tulahuen and SGO Z12 infected groups with respect to the control one; citrate synthase activity from the Lucky group was significantly increased (p<0.05). The activity of this enzyme was reduced in all the infected groups during the chronic asymptomatic phase (p<0.001) and return to normal values (Tulahuen and SGO Z12) or increased its activity (Lucky) by day 365 post-infection (p.i.). When the mitochondrial respiratory chain was analyzed from the acute to the chronic phase of the infection through the measurement of the activity of complexes I to IV, the activity of CI remained similar to control in Tulahuen and Lucky groups, but was significantly augmented in the SGO Z12 one in the acute and chronic phases (p<0.05). CII increased its activity in Tulahuen and Lucky groups by day 75 p.i. and in SGO Z12 by day 365 p.i. (p<0.05). CIII showed a similar behavior in the 3 infected groups, remaining similar to control values in the first two stages of the infection and significantly increasing later on (p<0.0001). CIV showed an increase in its activity in Lucky throughout all stages of infection (p<0.0001) and an increase in Tulahuen by day 365days p.i. (p<0.0001); SGO Z12 on the other hand, showed a decreased CIV activity at the same time. The structural changes in skeletal muscle mitochondria and their altered enzyme activity began in the acute phase of infection, probably modifying the ability of mitochondria to generate energy; these changes were not compensated in the rest of the phases of the infection. Chagas is a systemic disease, which produces not only heart damage but also permanent skeletal muscle alterations.}, } @article {pmid25826417, year = {2015}, author = {Kotakis, C}, title = {Non-coding RNAs' partitioning in the evolution of photosynthetic organisms via energy transduction and redox signaling.}, journal = {RNA biology}, volume = {12}, number = {1}, pages = {101-104}, pmid = {25826417}, issn = {1555-8584}, mesh = {*Energy Metabolism ; *Evolution, Molecular ; Oxidation-Reduction ; Photosynthesis ; Plant Cells/*classification/*metabolism ; RNA, Untranslated/*metabolism ; Signal Transduction ; }, abstract = {Ars longa, vita brevis -Hippocrates Chloroplasts and mitochondria are genetically semi-autonomous organelles inside the plant cell. These constructions formed after endosymbiosis and keep evolving throughout the history of life. Experimental evidence is provided for active non-coding RNAs (ncRNAs) in these prokaryote-like structures, and a possible functional imprinting on cellular electrophysiology by those RNA entities is described. Furthermore, updated knowledge on RNA metabolism of organellar genomes uncovers novel inter-communication bridges with the nucleus. This class of RNA molecules is considered as a unique ontogeny which transforms their biological role as a genetic rheostat into a synchronous biochemical one that can affect the energetic charge and redox homeostasis inside cells. A hypothesis is proposed where such modulation by non-coding RNAs is integrated with genetic signals regulating gene transfer. The implications of this working hypothesis are discussed, with particular reference to ncRNAs involvement in the organellar and nuclear genomes evolution since their integrity is functionally coupled with redox signals in photosynthetic organisms.}, } @article {pmid25748711, year = {2015}, author = {Bai, X and Kim, TI and Lee, JY and Dai, F and Hong, SJ}, title = {Identification and molecular characterization of Parkin in Clonorchis sinensis.}, journal = {The Korean journal of parasitology}, volume = {53}, number = {1}, pages = {65-75}, pmid = {25748711}, issn = {1738-0006}, mesh = {Amino Acid Sequence ; Animals ; Clonorchis sinensis/*enzymology ; Cluster Analysis ; Conserved Sequence ; DNA, Complementary/genetics ; Energy Metabolism ; Gene Expression Profiling ; Mitochondria/metabolism ; Models, Molecular ; Molecular Weight ; Phylogeny ; Protein Conformation ; Sequence Homology, Amino Acid ; Ubiquitin-Protein Ligases/chemistry/*genetics/*metabolism ; }, abstract = {Clonorchis sinensis habitating in the bile duct of mammals causes clonorchiasis endemic in East Asian countries. Parkin is a RING-between-RING protein and has E3-ubiquitin ligase activity catalyzing ubiquitination and degradation of substrate proteins. A cDNA clone of C. sinensis was predicted to encode a polypeptide homologous to parkin (CsParkin) including 5 domains (Ubl, RING0, RING1, IBR, and RING2). The cysteine and histidine residues binding to Zn(2+) were all conserved and participated in formation of tertiary structural RINGs. Conserved residues were also an E2-binding site in RING1 domain and a catalytic cysteine residue in the RING2 domain. Native CsParkin was determined to have an estimated molecular weight of 45.7 kDa from C. sinensis adults by immunoblotting. CsParkin revealed E3-ubiquitin ligase activity and higher expression in metacercariae than in adults. CsParkin was localized in the locomotive and male reproductive organs of C. sinensis adults, and extensively in metacercariae. Parkin has been found to participate in regulating mitochondrial function and energy metabolism in mammalian cells. From these results, it is suggested that CsParkin play roles in energy metabolism of the locomotive organs, and possibly in protein metabolism of the reproductive organs of C. sinensis.}, } @article {pmid25710177, year = {2015}, author = {Erives, AJ and Fassler, JS}, title = {Metabolic and chaperone gene loss marks the origin of animals: evidence for Hsp104 and Hsp78 chaperones sharing mitochondrial enzymes as clients.}, journal = {PloS one}, volume = {10}, number = {2}, pages = {e0117192}, pmid = {25710177}, issn = {1932-6203}, mesh = {Aconitate Hydratase/classification/genetics ; Animals ; Bayes Theorem ; Choanoflagellata/genetics ; Endopeptidase Clp/classification/genetics ; Heat-Shock Proteins/*genetics/metabolism ; Likelihood Functions ; Mitochondria/*enzymology/metabolism ; Mutation ; Phylogeny ; Promoter Regions, Genetic ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; }, abstract = {The evolution of animals involved acquisition of an emergent gene repertoire for gastrulation. Whether loss of genes also co-evolved with this developmental reprogramming has not yet been addressed. Here, we identify twenty-four genetic functions that are retained in fungi and choanoflagellates but undetectable in animals. These lost genes encode: (i) sixteen distinct biosynthetic functions; (ii) the two ancestral eukaryotic ClpB disaggregases, Hsp78 and Hsp104, which function in the mitochondria and cytosol, respectively; and (iii) six other assorted functions. We present computational and experimental data that are consistent with a joint function for the differentially localized ClpB disaggregases, and with the possibility of a shared client/chaperone relationship between the mitochondrial Fe/S homoaconitase encoded by the lost LYS4 gene and the two ClpBs. Our analyses lead to the hypothesis that the evolution of gastrulation-based multicellularity in animals led to efficient extraction of nutrients from dietary sources, loss of natural selection for maintenance of energetically expensive biosynthetic pathways, and subsequent loss of their attendant ClpB chaperones.}, } @article {pmid25706746, year = {2015}, author = {Diaz-Muñoz, MD and Bell, SE and Fairfax, K and Monzon-Casanova, E and Cunningham, AF and Gonzalez-Porta, M and Andrews, SR and Bunik, VI and Zarnack, K and Curk, T and Heggermont, WA and Heymans, S and Gibson, GE and Kontoyiannis, DL and Ule, J and Turner, M}, title = {The RNA-binding protein HuR is essential for the B cell antibody response.}, journal = {Nature immunology}, volume = {16}, number = {4}, pages = {415-425}, pmid = {25706746}, issn = {1529-2916}, support = {BBS/E/B/000C0409/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J001457/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/L009986/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; P01 AG014930/AG/NIA NIH HHS/United States ; BBS/E/B/000C0407/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J00152X/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Acyltransferases/genetics/immunology ; Alternative Splicing/immunology ; Animals ; Antigens/administration & dosage/immunology ; B-Lymphocytes/cytology/drug effects/*immunology ; Cell Death ; Cell Differentiation ; Cell Proliferation ; ELAV Proteins/genetics/*immunology ; Erythrocytes/immunology ; Germinal Center/cytology/drug effects/*immunology ; *Immunity, Humoral ; Immunization ; Immunoglobulin Class Switching ; Immunoglobulins/*biosynthesis ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/genetics/immunology ; RNA, Messenger/genetics/*immunology ; Reactive Oxygen Species/immunology/metabolism ; Sheep ; }, abstract = {Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells.}, } @article {pmid25616281, year = {2015}, author = {Gnipová, A and Šubrtová, K and Panicucci, B and Horváth, A and Lukeš, J and Zíková, A}, title = {The ADP/ATP carrier and its relationship to oxidative phosphorylation in ancestral protist trypanosoma brucei.}, journal = {Eukaryotic cell}, volume = {14}, number = {3}, pages = {297-310}, pmid = {25616281}, issn = {1535-9786}, mesh = {*Evolution, Molecular ; Mitochondrial ADP, ATP Translocases/chemistry/genetics/*metabolism ; *Oxidative Phosphorylation ; Protozoan Proteins/chemistry/genetics/*metabolism ; Trypanosoma brucei brucei/*genetics/metabolism ; }, abstract = {The highly conserved ADP/ATP carrier (AAC) is a key energetic link between the mitochondrial (mt) and cytosolic compartments of all aerobic eukaryotic cells, as it exchanges the ATP generated inside the organelle for the cytosolic ADP. Trypanosoma brucei, a parasitic protist of medical and veterinary importance, possesses a single functional AAC protein (TbAAC) that is related to the human and yeast ADP/ATP carriers. However, unlike previous studies performed with these model organisms, this study showed that TbAAC is most likely not a stable component of either the respiratory supercomplex III+IV or the ATP synthasome but rather functions as a physically separate entity in this highly diverged eukaryote. Therefore, TbAAC RNA interference (RNAi) ablation in the insect stage of T. brucei does not impair the activity or arrangement of the respiratory chain complexes. Nevertheless, RNAi silencing of TbAAC caused a severe growth defect that coincides with a significant reduction of mt ATP synthesis by both substrate and oxidative phosphorylation. Furthermore, TbAAC downregulation resulted in a decreased level of cytosolic ATP, a higher mt membrane potential, an elevated amount of reactive oxygen species, and a reduced consumption of oxygen in the mitochondria. Interestingly, while TbAAC has previously been demonstrated to serve as the sole ADP/ATP carrier for ADP influx into the mitochondria, our data suggest that a second carrier for ATP influx may be present and active in the T. brucei mitochondrion. Overall, this study provides more insight into the delicate balance of the functional relationship between TbAAC and the oxidative phosphorylation (OXPHOS) pathway in an early diverged eukaryote.}, } @article {pmid25605644, year = {2015}, author = {Wilson, DF}, title = {Programming and regulation of metabolic homeostasis.}, journal = {American journal of physiology. Endocrinology and metabolism}, volume = {308}, number = {6}, pages = {E506-17}, doi = {10.1152/ajpendo.00544.2014}, pmid = {25605644}, issn = {1522-1555}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Cell Respiration ; Electron Transport Complex IV/metabolism ; Energy Metabolism/*physiology ; Eukaryotic Cells/*metabolism ; Homeostasis/*physiology ; Humans ; Mitochondria/metabolism ; Models, Theoretical ; Oxidative Phosphorylation ; }, abstract = {Evidence is presented that the rate and equilibrium constants in mitochondrial oxidative phosphorylation set and maintain metabolic homeostasis in eukaryotic cells. These internal constants determine the energy state ([ATP]/[ADP][Pi]), and the energy state maintains homeostasis through a bidirectional sensory/signaling control network that reaches every aspect of cellular metabolism. The energy state is maintained with high precision (to ∼1 part in 10(10)), and the control system can respond to transient changes in energy demand (ATP utilization) of more than 100 times the resting rate. Epigenetic and environmental factors are able to "fine-tune" the programmed set point over a narrow range to meet the special needs associated with cell differentiation and chronic changes in metabolic requirements. The result is robust across-platform control of metabolism, which is essential to cellular differentiation and the evolution of complex organisms. A model of oxidative phosphorylation is presented, for which the steady-state rate expression has been derived and computer programmed. The behavior of oxidative phosphorylation predicted by the model is shown to fit the experimental data available for isolated mitochondria as well as for cells and tissues. This includes measurements from several different mammalian tissues as well as from insect flight muscle and plants. The respiratory chain and oxidative phosphorylation is remarkably similar for all higher plants and animals. This is consistent with the efficient synthesis of ATP and precise control of metabolic homeostasis provided by oxidative phosphorylation being a key to cellular differentiation and the evolution of structures with specialized function.}, } @article {pmid25573905, year = {2015}, author = {Nývltová, E and Stairs, CW and Hrdý, I and Rídl, J and Mach, J and Pačes, J and Roger, AJ and Tachezy, J}, title = {Lateral gene transfer and gene duplication played a key role in the evolution of Mastigamoeba balamuthi hydrogenosomes.}, journal = {Molecular biology and evolution}, volume = {32}, number = {4}, pages = {1039-1055}, pmid = {25573905}, issn = {1537-1719}, support = {MOP-62809//Canadian Institutes of Health Research/Canada ; }, mesh = {Anaerobiosis/genetics ; Archamoebae/enzymology/*genetics/metabolism ; Cell Membrane Structures/genetics/metabolism ; Energy Metabolism/*genetics ; Enzymes/genetics/isolation & purification ; *Evolution, Molecular ; *Gene Duplication ; *Gene Transfer, Horizontal ; Organelles/enzymology/*genetics/metabolism ; }, abstract = {Lateral gene transfer (LGT) is an important mechanism of evolution for protists adapting to oxygen-poor environments. Specifically, modifications of energy metabolism in anaerobic forms of mitochondria (e.g., hydrogenosomes) are likely to have been associated with gene transfer from prokaryotes. An interesting question is whether the products of transferred genes were directly targeted into the ancestral organelle or initially operated in the cytosol and subsequently acquired organelle-targeting sequences. Here, we identified key enzymes of hydrogenosomal metabolism in the free-living anaerobic amoebozoan Mastigamoeba balamuthi and analyzed their cellular localizations, enzymatic activities, and evolutionary histories. Additionally, we characterized 1) several canonical mitochondrial components including respiratory complex II and the glycine cleavage system, 2) enzymes associated with anaerobic energy metabolism, including an unusual D-lactate dehydrogenase and acetyl CoA synthase, and 3) a sulfate activation pathway. Intriguingly, components of anaerobic energy metabolism are present in at least two gene copies. For each component, one copy possesses an mitochondrial targeting sequence (MTS), whereas the other lacks an MTS, yielding parallel cytosolic and hydrogenosomal extended glycolysis pathways. Experimentally, we confirmed that the organelle targeting of several proteins is fully dependent on the MTS. Phylogenetic analysis of all extended glycolysis components suggested that these components were acquired by LGT. We propose that the transformation from an ancestral organelle to a hydrogenosome in the M. balamuthi lineage involved the lateral acquisition of genes encoding extended glycolysis enzymes that initially operated in the cytosol and that established a parallel hydrogenosomal pathway after gene duplication and MTS acquisition.}, } @article {pmid25488255, year = {2014}, author = {Wang, SP and Yang, H and Wu, JW and Gauthier, N and Fukao, T and Mitchell, GA}, title = {Metabolism as a tool for understanding human brain evolution: lipid energy metabolism as an example.}, journal = {Journal of human evolution}, volume = {77}, number = {}, pages = {41-49}, doi = {10.1016/j.jhevol.2014.06.013}, pmid = {25488255}, issn = {1095-8606}, support = {178978//Canadian Institutes of Health Research/Canada ; 221920//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; *Biological Evolution ; *Brain/metabolism/physiology ; Humans ; Ketone Bodies ; Lipid Metabolism/*physiology ; Mice ; Mitochondria/physiology ; Triglycerides ; }, abstract = {Genes and the environment both influence the metabolic processes that determine fitness. To illustrate the importance of metabolism for human brain evolution and health, we use the example of lipid energy metabolism, i.e. the use of fat (lipid) to produce energy and the advantages that this metabolic pathway provides for the brain during environmental energy shortage. We briefly describe some features of metabolism in ancestral organisms, which provided a molecular toolkit for later development. In modern humans, lipid energy metabolism is a regulated multi-organ pathway that links triglycerides in fat tissue to the mitochondria of many tissues including the brain. Three important control points are each suppressed by insulin. (1) Lipid reserves in adipose tissue are released by lipolysis during fasting and stress, producing fatty acids (FAs) which circulate in the blood and are taken up by cells. (2) FA oxidation. Mitochondrial entry is controlled by carnitine palmitoyl transferase 1 (CPT1). Inside the mitochondria, FAs undergo beta oxidation and energy production in the Krebs cycle and respiratory chain. (3) In liver mitochondria, the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) pathway produces ketone bodies for the brain and other organs. Unlike most tissues, the brain does not capture and metabolize circulating FAs for energy production. However, the brain can use ketone bodies for energy. We discuss two examples of genetic metabolic traits that may be advantageous under most conditions but deleterious in others. (1) A CPT1A variant prevalent in Inuit people may allow increased FA oxidation under nonfasting conditions but also predispose to hypoglycemic episodes. (2) The thrifty genotype theory, which holds that energy expenditure is efficient so as to maximize energy stores, predicts that these adaptations may enhance survival in periods of famine but predispose to obesity in modern dietary environments.}, } @article {pmid25482773, year = {2014}, author = {Wang, M and Ma, X and Shen, J and Li, C and Zhang, W}, title = {The ongoing story: the mitochondria pyruvate carrier 1 in plant stress response in Arabidopsis.}, journal = {Plant signaling & behavior}, volume = {9}, number = {10}, pages = {e973810}, pmid = {25482773}, issn = {1559-2324}, mesh = {Anion Transport Proteins ; Arabidopsis/genetics/*physiology ; Arabidopsis Proteins ; Gene Expression Regulation, Plant ; Membrane Transport Proteins/genetics/*metabolism ; Mitochondria/*metabolism ; Mitochondrial Proteins ; Monocarboxylic Acid Transporters ; Phylogeny ; Protein Interaction Mapping ; Protein Transport ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins ; *Stress, Physiological ; Subcellular Fractions/metabolism ; }, abstract = {Abscisic acid (ABA) is an important regulator of guard cell ion channels and stomatal movements in response to drought stress. Pyruvate is the final product of glycolysis in the cytosol, and could be transported by mitochondrial pyruvate carriers (MPCs) into mitochondrion for consequent cellular substance and energy metabolism. We recently characterized the first putative mitochondrial pyruvate carrier, NRGA1, in planta, and found that this small protein is involved in the negative regulation of drought and ABA induced guard cell signaling in Arabidopsis thaliana. The findings revealed a probable link between mitochondrial pyruvate transport and guard cell signaling. It has also been shown that NRGA1 protein product was directed to the mitochondria, and co-expression of MPC1 and NRGA1 functionally complement the absence of a native pyruvate transport protein in yeast. Here, we further demonstrated that MPC1 showed similar sub-cellular localization pattern to NRGA1. Quantitative RT-PCR analysis showed that the transcription of both NRGA1 and MPC1 were induced by pyruvate or ABA, and pyruvate strengthened the ABA induced transcription of these 2 genes. The similarity in subcellular localization and gene expression to ABA strongly suggests that MPC1 may associate with NRGA1 for mitochondrial pyruvate transport and is involved in ABA mediated stomatal movements in Arabidopsis.}, } @article {pmid25432941, year = {2014}, author = {Degli Esposti, M}, title = {Bioenergetic evolution in proteobacteria and mitochondria.}, journal = {Genome biology and evolution}, volume = {6}, number = {12}, pages = {3238-3251}, pmid = {25432941}, issn = {1759-6653}, mesh = {*Energy Metabolism ; *Evolution, Molecular ; Methanol/metabolism ; Mitochondria/*genetics/metabolism ; Proteobacteria/*genetics/metabolism/ultrastructure ; Symbiosis ; }, abstract = {Mitochondria are the energy-producing organelles of our cells and derive from bacterial ancestors that became endosymbionts of microorganisms from a different lineage, together with which they formed eukaryotic cells. For a long time it has remained unclear from which bacteria mitochondria actually evolved, even if these organisms in all likelihood originated from the α lineage of proteobacteria. A recent article (Degli Esposti M, et al. 2014. Evolution of mitochondria reconstructed from the energy metabolism of living bacteria. PLoS One 9:e96566) has presented novel evidence indicating that methylotrophic bacteria could be among the closest living relatives of mitochondrial ancestors. Methylotrophs are ubiquitous bacteria that live on single carbon sources such as methanol and methane; in the latter case they are called methanotrophs. In this review, I examine their possible ancestry to mitochondria within a survey of the common features that can be found in the central and terminal bioenergetic systems of proteobacteria and mitochondria. I also discuss previously overlooked information on methanotrophic bacteria, in particular their intracytoplasmic membranes resembling mitochondrial cristae and their capacity of establishing endosymbiotic relationships with invertebrate animals and archaic plants. This information appears to sustain the new idea that mitochondrial ancestors could be related to extant methanotrophic proteobacteria, a possibility that the genomes of methanotrophic endosymbionts will hopefully clarify.}, } @article {pmid25341790, year = {2014}, author = {Schwarzländer, M and Wagner, S and Ermakova, YG and Belousov, VV and Radi, R and Beckman, JS and Buettner, GR and Demaurex, N and Duchen, MR and Forman, HJ and Fricker, MD and Gems, D and Halestrap, AP and Halliwell, B and Jakob, U and Johnston, IG and Jones, NS and Logan, DC and Morgan, B and Müller, FL and Nicholls, DG and Remington, SJ and Schumacker, PT and Winterbourn, CC and Sweetlove, LJ and Meyer, AJ and Dick, TP and Murphy, MP}, title = {The 'mitoflash' probe cpYFP does not respond to superoxide.}, journal = {Nature}, volume = {514}, number = {7523}, pages = {E12-4}, pmid = {25341790}, issn = {1476-4687}, support = {P30 ES005605/ES/NIEHS NIH HHS/United States ; R01 GM073929/GM/NIGMS NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; R01 AG027349/AG/NIA NIH HHS/United States ; R01 CA169046/CA/NCI NIH HHS/United States ; MC_U105663142/MRC_/Medical Research Council/United Kingdom ; 098565//Wellcome Trust/United Kingdom ; R21 AG046799/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Caenorhabditis elegans/*metabolism ; *Longevity ; Male ; Mitochondria/*metabolism ; Superoxides/*metabolism ; }, abstract = {Ageing and lifespan of organisms are determined by complicated interactions between their genetics and the environment, but the cellular mechanisms remain controversial. There have been a number of studies suggesting that cellular energy metabolism and free radical dynamics affect lifespan, implicating mitochondrial function. Recently, Shen et al. provided apparent mechanistic insight by reporting that mitochondrial oscillations of ‘free radical production’, called ‘mitoflashes’, in the pharynx of 3-day old Caenorhabditis elegans correlated inversely with lifespan. The interpretation of ‘mitoflashes’ as ‘bursts of superoxide’ radicals assumes that circularly permuted yellow fluorescent protein (cpYFP) is a reliable indicator of mitochondrial superoxide. This interpretation has been criticised because experiments and theoretical considerations both show that changes in cpYFP fluorescence are due to alterations in pH, not superoxide[-]. We now provide direct evidence that purified cpYFP is completely unresponsive to superoxide. Therefore ‘mitoflashes’ do not reflect superoxide generation and are not evidence for a link between mitochondrial free radical dynamics and lifespan.}, } @article {pmid25333787, year = {2014}, author = {Wang, Z and Wu, M}, title = {Phylogenomic reconstruction indicates mitochondrial ancestor was an energy parasite.}, journal = {PloS one}, volume = {9}, number = {10}, pages = {e110685}, pmid = {25333787}, issn = {1932-6203}, mesh = {Alphaproteobacteria/genetics/metabolism ; Biological Evolution ; Cell Respiration ; *Energy Metabolism ; Eukaryotic Cells/physiology ; *Evolution, Molecular ; Flagella/genetics/metabolism ; *Genome, Mitochondrial ; *Genomics ; Lipid Metabolism ; Metabolic Networks and Pathways ; Mitochondria/*genetics/*metabolism ; *Phylogeny ; }, abstract = {Reconstruction of mitochondrial ancestor has great impact on our understanding of the origin of mitochondria. Previous studies have largely focused on reconstructing the last common ancestor of all contemporary mitochondria (proto-mitochondria), but not on the more informative pre-mitochondria (the last common ancestor of mitochondria and their alphaproteobacterial sister clade). Using a phylogenomic approach and leveraging on the increased taxonomic sampling of alphaproteobacterial and eukaryotic genomes, we reconstructed the metabolisms of both proto-mitochondria and pre-mitochondria. Our reconstruction depicts a more streamlined proto-mitochondrion than these predicted by previous studies, and revealed several novel insights into the mitochondria-derived eukaryotic metabolisms including the lipid metabolism. Most strikingly, pre-mitochondrion was predicted to possess a plastid/parasite type of ATP/ADP translocase that imports ATP from the host, which posits pre-mitochondrion as an energy parasite that directly contrasts with the current role of mitochondria as the cell's energy producer. In addition, pre-mitochondrion was predicted to encode a large number of flagellar genes and several cytochrome oxidases functioning under low oxygen level, strongly supporting the previous finding that the mitochondrial ancestor was likely motile and capable of oxidative phosphorylation under microoxic condition.}, } @article {pmid25313038, year = {2014}, author = {Haag, KL and James, TY and Pombert, JF and Larsson, R and Schaer, TM and Refardt, D and Ebert, D}, title = {Evolution of a morphological novelty occurred before genome compaction in a lineage of extreme parasites.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {111}, number = {43}, pages = {15480-15485}, pmid = {25313038}, issn = {1091-6490}, mesh = {Animals ; *Evolution, Molecular ; Genome, Fungal/*genetics ; Genomics ; Microsporidia/*genetics/ultrastructure ; Molecular Sequence Annotation ; Molecular Sequence Data ; Parasites/*anatomy & histology/*genetics/ultrastructure ; *Phylogeny ; Sequence Analysis, DNA ; Species Specificity ; }, abstract = {Intracellular parasitism results in extreme adaptations, whose evolutionary history is difficult to understand, because the parasites and their known free-living relatives are so divergent from one another. Microsporidia are intracellular parasites of humans and other animals, which evolved highly specialized morphological structures, but also extreme physiologic and genomic simplification. They are suggested to be an early-diverging branch on the fungal tree, but comparisons to other species are difficult because their rates of molecular evolution are exceptionally high. Mitochondria in microsporidia have degenerated into organelles called mitosomes, which have lost a genome and the ability to produce ATP. Here we describe a gut parasite of the crustacean Daphnia that despite having remarkable morphological similarity to the microsporidia, has retained genomic features of its fungal ancestors. This parasite, which we name Mitosporidium daphniae gen. et sp. nov., possesses a mitochondrial genome including genes for oxidative phosphorylation, yet a spore stage with a highly specialized infection apparatus--the polar tube--uniquely known only from microsporidia. Phylogenomics places M. daphniae at the root of the microsporidia. A comparative genomic analysis suggests that the reduction in energy metabolism, a prominent feature of microsporidian evolution, was preceded by a reduction in the machinery controlling cell cycle, DNA recombination, repair, and gene expression. These data show that the morphological features unique to M. daphniae and other microsporidia were already present before the lineage evolved the extreme host metabolic dependence and loss of mitochondrial respiration for which microsporidia are well known.}, } @article {pmid25312050, year = {2015}, author = {Gonçalves, VF and Andreazza, AC and Kennedy, JL}, title = {Mitochondrial dysfunction in schizophrenia: an evolutionary perspective.}, journal = {Human genetics}, volume = {134}, number = {1}, pages = {13-21}, pmid = {25312050}, issn = {1432-1203}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Humans ; Mitochondria/*pathology ; Mitochondrial Diseases/*complications ; Schizophrenia/*etiology/*pathology ; }, abstract = {Schizophrenia (SCZ) is a severe psychiatric illness with a lifetime prevalence of 0.4 %. A disturbance of energy metabolism has been suggested as part of the etiopathogenesis of the disorder. Several lines of evidence have proposed a connection between etiopathogenesis of SCZ and human brain evolution, which was characterized by an increase in the energy requirement, demanding a co-evolution of the mitochondrial system. Mitochondria are key players in brain energy homeostasis and multiple lines of evidence suggest that the system is disrupted in SCZ. In this review, we will describe the current knowledge on pathways/system involved in the human brain evolution as well as the main theories regarding the evolutionary origin of SCZ. We will furthermore discuss the role of mitochondria in the context of brain energy metabolism and its role in the etiopathogenesis of SCZ. Understanding SCZ in the context of human brain evolution opens a new perspective to elucidate pathophysiological mechanisms involved in the origin and/or portions of the complex symptomatology of this severe mental disorder.}, } @article {pmid25271376, year = {2014}, author = {Ju, YS and Alexandrov, LB and Gerstung, M and Martincorena, I and Nik-Zainal, S and Ramakrishna, M and Davies, HR and Papaemmanuil, E and Gundem, G and Shlien, A and Bolli, N and Behjati, S and Tarpey, PS and Nangalia, J and Massie, CE and Butler, AP and Teague, JW and Vassiliou, GS and Green, AR and Du, MQ and Unnikrishnan, A and Pimanda, JE and Teh, BT and Munshi, N and Greaves, M and Vyas, P and El-Naggar, AK and Santarius, T and Collins, VP and Grundy, R and Taylor, JA and Hayes, DN and Malkin, D and , and , and , and Foster, CS and Warren, AY and Whitaker, HC and Brewer, D and Eeles, R and Cooper, C and Neal, D and Visakorpi, T and Isaacs, WB and Bova, GS and Flanagan, AM and Futreal, PA and Lynch, AG and Chinnery, PF and McDermott, U and Stratton, MR and Campbell, PJ}, title = {Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.}, journal = {eLife}, volume = {3}, number = {}, pages = {}, pmid = {25271376}, issn = {2050-084X}, support = {101876//Wellcome Trust/United Kingdom ; MR/K000608/1/MRC_/Medical Research Council/United Kingdom ; G0900871/MRC_/Medical Research Council/United Kingdom ; 088340//Wellcome Trust/United Kingdom ; P01 CA155258/CA/NCI NIH HHS/United States ; 096919//Wellcome Trust/United Kingdom ; 095663//Wellcome Trust/United Kingdom ; G1000729/MRC_/Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Base Composition ; DNA/*genetics ; DNA Replication ; DNA, Mitochondrial/*genetics ; DNA, Neoplasm/*genetics ; Data Mining ; Evolution, Molecular ; *Genome, Mitochondrial ; High-Throughput Nucleotide Sequencing ; Humans ; Mitochondria/genetics/pathology ; *Mutation ; Neoplasms/classification/*genetics/pathology ; Polymorphism, Single Nucleotide ; }, abstract = {Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.}, } @article {pmid25188293, year = {2014}, author = {Koumandou, VL and Kossida, S}, title = {Evolution of the F0F1 ATP synthase complex in light of the patchy distribution of different bioenergetic pathways across prokaryotes.}, journal = {PLoS computational biology}, volume = {10}, number = {9}, pages = {e1003821}, pmid = {25188293}, issn = {1553-7358}, mesh = {Archaea/classification/*genetics ; Bacteria/classification/*genetics ; DNA, Archaeal/*analysis/chemistry ; DNA, Bacterial/*analysis/chemistry ; Energy Metabolism/genetics ; Phylogeny ; Proton-Translocating ATPases/*chemistry ; RNA, Ribosomal, 16S ; Sequence Analysis, DNA ; }, abstract = {Bacteria and archaea are characterized by an amazing metabolic diversity, which allows them to persist in diverse and often extreme habitats. Apart from oxygenic photosynthesis and oxidative phosphorylation, well-studied processes from chloroplasts and mitochondria of plants and animals, prokaryotes utilize various chemo- or lithotrophic modes, such as anoxygenic photosynthesis, iron oxidation and reduction, sulfate reduction, and methanogenesis. Most bioenergetic pathways have a similar general structure, with an electron transport chain composed of protein complexes acting as electron donors and acceptors, as well as a central cytochrome complex, mobile electron carriers, and an ATP synthase. While each pathway has been studied in considerable detail in isolation, not much is known about their relative evolutionary relationships. Wanting to address how this metabolic diversity evolved, we mapped the distribution of nine bioenergetic modes on a phylogenetic tree based on 16S rRNA sequences from 272 species representing the full diversity of prokaryotic lineages. This highlights the patchy distribution of many pathways across different lineages, and suggests either up to 26 independent origins or 17 horizontal gene transfer events. Next, we used comparative genomics and phylogenetic analysis of all subunits of the F0F1 ATP synthase, common to most bacterial lineages regardless of their bioenergetic mode. Our results indicate an ancient origin of this protein complex, and no clustering based on bioenergetic mode, which suggests that no special modifications are needed for the ATP synthase to work with different electron transport chains. Moreover, examination of the ATP synthase genetic locus indicates various gene rearrangements in the different bacterial lineages, ancient duplications of atpI and of the beta subunit of the F0 subcomplex, as well as more recent stochastic lineage-specific and species-specific duplications of all subunits. We discuss the implications of the overall pattern of conservation and flexibility of the F0F1 ATP synthase genetic locus.}, } @article {pmid25118050, year = {2014}, author = {Mentel, M and Röttger, M and Leys, S and Tielens, AG and Martin, WF}, title = {Of early animals, anaerobic mitochondria, and a modern sponge.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {36}, number = {10}, pages = {924-932}, doi = {10.1002/bies.201400060}, pmid = {25118050}, issn = {1521-1878}, support = {232975/ERC_/European Research Council/International ; }, mesh = {Anaerobiosis/genetics ; Animals ; Energy Metabolism/genetics ; Metabolic Networks and Pathways ; Mitochondria/genetics/*metabolism ; *Phylogeny ; Porifera/*metabolism ; }, abstract = {The origin and early evolution of animals marks an important event in life's history. This event is historically associated with an important variable in Earth history - oxygen. One view has it that an increase in oceanic oxygen levels at the end of the Neoproterozoic Era (roughly 600 million years ago) allowed animals to become large and leave fossils. How important was oxygen for the process of early animal evolution? New data show that some modern sponges can survive for several weeks at low oxygen levels. Many groups of animals have mechanisms to cope with low oxygen or anoxia, and very often, mitochondria - organelles usually associated with oxygen - are involved in anaerobic energy metabolism in animals. It is a good time to refresh our memory about the anaerobic capacities of mitochondria in modern animals and how that might relate to the ecology of early metazoans.}, } @article {pmid25002117, year = {2014}, author = {Hess, KC and Liu, J and Manfredi, G and Mühlschlegel, FA and Buck, J and Levin, LR and Barrientos, A}, title = {A mitochondrial CO2-adenylyl cyclase-cAMP signalosome controls yeast normoxic cytochrome c oxidase activity.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {28}, number = {10}, pages = {4369-4380}, pmid = {25002117}, issn = {1530-6860}, support = {R01 GM105781/GM/NIGMS NIH HHS/United States ; R01 GM107442/GM/NIGMS NIH HHS/United States ; R01 GM062328/GM/NIGMS NIH HHS/United States ; GM-071775/GM/NIGMS NIH HHS/United States ; R01 HD059913/HD/NICHD NIH HHS/United States ; GM-088999A/GM/NIGMS NIH HHS/United States ; R01 GM071775/GM/NIGMS NIH HHS/United States ; R01 GM088999/GM/NIGMS NIH HHS/United States ; HD-059913/HD/NICHD NIH HHS/United States ; GM-062328/GM/NIGMS NIH HHS/United States ; }, mesh = {Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Allosteric Regulation ; Carbon Dioxide/metabolism ; *Cell Hypoxia ; Cyclic AMP/*metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Electron Transport Complex IV/genetics/*metabolism ; Mitochondrial Proteins/genetics/*metabolism ; Mutation ; Phosphorylation ; Saccharomyces cerevisiae/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; }, abstract = {Mitochondria, the major source of cellular energy in the form of ATP, respond to changes in substrate availability and bioenergetic demands by employing rapid, short-term, metabolic adaptation mechanisms, such as phosphorylation-dependent protein regulation. In mammalian cells, an intramitochondrial CO2-adenylyl cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway regulates aerobic energy production. One target of this pathway involves phosphorylation of cytochrome c oxidase (COX) subunit 4-isoform 1 (COX4i1), which modulates COX allosteric regulation by ATP. However, the role of the CO2-sAC-cAMP-PKA signalosome in regulating COX activity and mitochondrial metabolism and its evolutionary conservation remain to be fully established. We show that in Saccharomyces cerevisiae, normoxic COX activity measured in the presence of ATP is 55% lower than in the presence of ADP. Moreover, the adenylyl cyclase Cyr1 activity is present in mitochondria, and it contributes to the ATP-mediated regulation of COX through the normoxic subunit Cox5a, homologue of human COX4i1, in a bicarbonate-sensitive manner. Furthermore, we have identified 2 phosphorylation targets in Cox5a (T65 and S43) that modulate its allosteric regulation by ATP. These residues are not conserved in the Cox5b-containing hypoxic enzyme, which is not regulated by ATP. We conclude that across evolution, a CO2-sAC-cAMP-PKA axis regulates normoxic COX activity.}, } @article {pmid24982758, year = {2014}, author = {Epstein, T and Xu, L and Gillies, RJ and Gatenby, RA}, title = {Separation of metabolic supply and demand: aerobic glycolysis as a normal physiological response to fluctuating energetic demands in the membrane.}, journal = {Cancer & metabolism}, volume = {2}, number = {}, pages = {7}, pmid = {24982758}, issn = {2049-3002}, support = {P30 CA076292/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Cancer cells, and a variety of normal cells, exhibit aerobic glycolysis, high rates of glucose fermentation in the presence of normal oxygen concentrations, also known as the Warburg effect. This metabolism is considered abnormal because it violates the standard model of cellular energy production that assumes glucose metabolism is predominantly governed by oxygen concentrations and, therefore, fermentative glycolysis is an emergency back-up for periods of hypoxia. Though several hypotheses have been proposed for the origin of aerobic glycolysis, its biological basis in cancer and normal cells is still not well understood.

RESULTS: We examined changes in glucose metabolism following perturbations in membrane activity in different normal and tumor cell lines and found that inhibition or activation of pumps on the cell membrane led to reduction or increase in glycolysis, respectively, while oxidative phosphorylation remained unchanged. Computational simulations demonstrated that these findings are consistent with a new model of normal physiological cellular metabolism in which efficient mitochondrial oxidative phosphorylation supplies chronic energy demand primarily for macromolecule synthesis and glycolysis is necessary to supply rapid energy demands primarily to support membrane pumps. A specific model prediction was that the spatial distribution of ATP-producing enzymes in the glycolytic pathway must be primarily localized adjacent to the cell membrane, while mitochondria should be predominantly peri-nuclear. The predictions were confirmed experimentally.

CONCLUSIONS: Our results show that glycolytic metabolism serves a critical physiological function under normoxic conditions by responding to rapid energetic demand, mainly from membrane transport activities, even in the presence of oxygen. This supports a new model for glucose metabolism in which glycolysis and oxidative phosphorylation supply different types of energy demand. Cells use efficient but slow-responding aerobic metabolism to meet baseline, steady energy demand and glycolytic metabolism, which is inefficient but can rapidly increase adenosine triphosphate (ATP) production, to meet short-timescale energy demands, mainly from membrane transport activities. In this model, the origin of the Warburg effect in cancer cells and aerobic glycolysis in general represents a normal physiological function due to enhanced energy demand for membrane transporters activity required for cell division, growth, and migration.}, } @article {pmid24918926, year = {2014}, author = {Yang, Y and Xu, S and Xu, J and Guo, Y and Yang, G}, title = {Adaptive evolution of mitochondrial energy metabolism genes associated with increased energy demand in flying insects.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e99120}, pmid = {24918926}, issn = {1932-6203}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; DNA, Mitochondrial/genetics ; *Energy Metabolism ; *Evolution, Molecular ; *Flight, Animal ; Insecta/*genetics/physiology ; Mitochondria/*metabolism ; }, abstract = {Insects are unique among invertebrates for their ability to fly, which raises intriguing questions about how energy metabolism in insects evolved and changed along with flight. Although physiological studies indicated that energy consumption differs between flying and non-flying insects, the evolution of molecular energy metabolism mechanisms in insects remains largely unexplored. Considering that about 95% of adenosine triphosphate (ATP) is supplied by mitochondria via oxidative phosphorylation, we examined 13 mitochondrial protein-encoding genes to test whether adaptive evolution of energy metabolism-related genes occurred in insects. The analyses demonstrated that mitochondrial DNA protein-encoding genes are subject to positive selection from the last common ancestor of Pterygota, which evolved primitive flight ability. Positive selection was also found in insects with flight ability, whereas no significant sign of selection was found in flightless insects where the wings had degenerated. In addition, significant positive selection was also identified in the last common ancestor of Neoptera, which changed its flight mode from direct to indirect. Interestingly, detection of more positively selected genes in indirect flight rather than direct flight insects suggested a stronger selective pressure in insects having higher energy consumption. In conclusion, mitochondrial protein-encoding genes involved in energy metabolism were targets of adaptive evolution in response to increased energy demands that arose during the evolution of flight ability in insects.}, } @article {pmid24911874, year = {2014}, author = {Kitazoe, Y and Tanaka, M}, title = {Evolution of mitochondrial power in vertebrate metazoans.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e98188}, pmid = {24911874}, issn = {1932-6203}, mesh = {Animals ; *Computational Biology ; *Energy Metabolism ; *Evolution, Molecular ; Humans ; Hydrophobic and Hydrophilic Interactions ; Mitochondria/*metabolism ; Mitochondrial Proteins/chemistry/metabolism ; Protein Stability ; Protein Structure, Secondary ; *Vertebrates ; }, abstract = {BACKGROUND: Basal metabolic rate (BMR) has a very strong body-mass (M) dependence in an individual animal group, and BMR per unit mass (msBMR) converges on a markedly narrow range even across major taxonomic groups. However, it is here a basic question in metazoan biology how much BMR per unit mitochondrion (mtBMR) changes, and then whether mtBMR can be related to the original molecular mechanism of action of mt-encoded membrane proteins (MMPs) playing a central role in cellular energy production.

Analyzing variations of amino-acid compositions of MMPs across 13 metazoan animal groups, incorporating 2022 sequences, we found a strong inverse correlation between Ser/Thr composition (STC) and hydrophobicity (HYD). A majority of animal groups showed an evolutionary pathway of a gradual increase in HYD and decrease in STC, whereas only the deuterostome lineage revealed a rapid decrease in HYD and increase in STC. The strongest correlations appeared in 5 large subunits (ND4, ND5, ND2, CO1, and CO3) undergoing dynamic conformational changes for the proton-pumping function. The pathway of the majority groups is well understood as reflecting natural selection to reduce mtBMR, since simply raising HYD in MMPs (surrounded by the lipid bilayer) weakens their mobility and strengthens their stability. On the other hand, the marked decrease in HYD of the deuterostome elevates mtBMR, but is accompanied with their instability heightening a turnover rate of mitochondria and then cells. Interestingly, cooperative networks of interhelical hydrogen-bonds between motifs involving Ser and Thr residues can enhance MMP stability.

CONCLUSION/SIGNIFICANCE: This stability enhancement lowers turnover rates of mitochondria/cells and may prolong even longevity, and was indeed founded by strong positive correlations of STC with both mtBMR and longevity. The lowest HYD and highest STC in Aves and Mammals are congruent with their very high mtBMR and long longevity.}, } @article {pmid24883254, year = {2014}, author = {Pochon, X and Putnam, HM and Gates, RD}, title = {Multi-gene analysis of Symbiodinium dinoflagellates: a perspective on rarity, symbiosis, and evolution.}, journal = {PeerJ}, volume = {2}, number = {}, pages = {e394}, pmid = {24883254}, issn = {2167-8359}, abstract = {Symbiodinium, a large group of dinoflagellates, live in symbiosis with marine protists, invertebrate metazoans, and free-living in the environment. Symbiodinium are functionally variable and play critical energetic roles in symbiosis. Our knowledge of Symbiodinium has been historically constrained by the limited number of molecular markers available to study evolution in the genus. Here we compare six functional genes, representing three cellular compartments, in the nine known Symbiodinium lineages. Despite striking similarities among the single gene phylogenies from distinct organelles, none were evolutionarily identical. A fully concatenated reconstruction, however, yielded a well-resolved topology identical to the current benchmark nr28S gene. Evolutionary rates differed among cellular compartments and clades, a pattern largely driven by higher rates of evolution in the chloroplast genes of Symbiodinium clades D2 and I. The rapid rates of evolution observed amongst these relatively uncommon Symbiodinium lineages in the functionally critical chloroplast may translate into potential innovation for the symbiosis. The multi-gene analysis highlights the potential power of assessing genome-wide evolutionary patterns using recent advances in sequencing technology and emphasizes the importance of integrating ecological data with more comprehensive sampling of free-living and symbiotic Symbiodinium in assessing the evolutionary adaptation of this enigmatic dinoflagellate.}, } @article {pmid24804722, year = {2014}, author = {Degli Esposti, M and Chouaia, B and Comandatore, F and Crotti, E and Sassera, D and Lievens, PM and Daffonchio, D and Bandi, C}, title = {Evolution of mitochondria reconstructed from the energy metabolism of living bacteria.}, journal = {PloS one}, volume = {9}, number = {5}, pages = {e96566}, pmid = {24804722}, issn = {1932-6203}, mesh = {Bacteria/genetics/*metabolism ; Energy Metabolism/*physiology ; *Evolution, Molecular ; Mitochondria/genetics/*metabolism ; *Phylogeny ; }, abstract = {The ancestors of mitochondria, or proto-mitochondria, played a crucial role in the evolution of eukaryotic cells and derived from symbiotic α-proteobacteria which merged with other microorganisms - the basis of the widely accepted endosymbiotic theory. However, the identity and relatives of proto-mitochondria remain elusive. Here we show that methylotrophic α-proteobacteria could be the closest living models for mitochondrial ancestors. We reached this conclusion after reconstructing the possible evolutionary pathways of the bioenergy systems of proto-mitochondria with a genomic survey of extant α-proteobacteria. Results obtained with complementary molecular and genetic analyses of diverse bioenergetic proteins converge in indicating the pathway stemming from methylotrophic bacteria as the most probable route of mitochondrial evolution. Contrary to other α-proteobacteria, methylotrophs show transition forms for the bioenergetic systems analysed. Our approach of focusing on these bioenergetic systems overcomes the phylogenetic impasse that has previously complicated the search for mitochondrial ancestors. Moreover, our results provide a new perspective for experimentally re-evolving mitochondria from extant bacteria and in the future produce synthetic mitochondria.}, } @article {pmid24789818, year = {2014}, author = {Lane, N}, title = {Bioenergetic constraints on the evolution of complex life.}, journal = {Cold Spring Harbor perspectives in biology}, volume = {6}, number = {5}, pages = {a015982}, pmid = {24789818}, issn = {1943-0264}, mesh = {Animals ; *Biological Evolution ; Carbon Dioxide/metabolism ; *Energy Metabolism ; Gene Dosage ; Humans ; Mitochondria/metabolism ; Origin of Life ; Proteins/metabolism ; Symbiosis ; }, abstract = {All morphologically complex life on Earth, beyond the level of cyanobacteria, is eukaryotic. All eukaryotes share a common ancestor that was already a complex cell. Despite their biochemical virtuosity, prokaryotes show little tendency to evolve eukaryotic traits or large genomes. Here I argue that prokaryotes are constrained by their membrane bioenergetics, for fundamental reasons relating to the origin of life. Eukaryotes arose in a rare endosymbiosis between two prokaryotes, which broke the energetic constraints on prokaryotes and gave rise to mitochondria. Loss of almost all mitochondrial genes produced an extreme genomic asymmetry, in which tiny mitochondrial genomes support, energetically, a massive nuclear genome, giving eukaryotes three to five orders of magnitude more energy per gene than prokaryotes. The requirement for endosymbiosis radically altered selection on eukaryotes, potentially explaining the evolution of unique traits, including the nucleus, sex, two sexes, speciation, and aging.}, } @article {pmid24782883, year = {2014}, author = {Rigas, S and Daras, G and Tsitsekian, D and Alatzas, A and Hatzopoulos, P}, title = {Evolution and significance of the Lon gene family in Arabidopsis organelle biogenesis and energy metabolism.}, journal = {Frontiers in plant science}, volume = {5}, number = {}, pages = {145}, pmid = {24782883}, issn = {1664-462X}, abstract = {Lon is the first identified ATP-dependent protease highly conserved across all kingdoms. Model plant species Arabidopsis thaliana has a small Lon gene family of four members. Although these genes share common structural features, they have distinct properties in terms of gene expression profile, subcellular targeting and substrate recognition motifs. This supports the notion that their functions under different environmental conditions are not necessarily redundant. This article intends to unravel the biological role of Lon proteases in energy metabolism and plant growth through an evolutionary perspective. Given that plants are sessile organisms exposed to diverse environmental conditions and plant organelles are semi-autonomous, it is tempting to suggest that Lon genes in Arabidopsis are paralogs. Adaptive evolution through repetitive gene duplication events of a single archaic gene led to Lon genes with complementing sets of subfunctions providing to the organism rapid adaptability for canonical development under different environmental conditions. Lon1 function is adequately characterized being involved in mitochondrial biogenesis, modulating carbon metabolism, oxidative phosphorylation and energy supply, all prerequisites for seed germination and seedling establishment. Lon is not a stand-alone proteolytic machine in plant organelles. Lon in association with other nuclear-encoded ATP-dependent proteases builds up an elegant nevertheless, tight interconnected circuit. This circuitry channels properly and accurately, proteostasis and protein quality control among the distinct subcellular compartments namely mitochondria, chloroplasts, and peroxisomes.}, } @article {pmid24702837, year = {2014}, author = {Du, J}, title = {Hypothesis of mitochondrial oncogenesis as the trigger of normal cells to cancer cells.}, journal = {Medical hypotheses}, volume = {82}, number = {6}, pages = {744-747}, doi = {10.1016/j.mehy.2014.02.032}, pmid = {24702837}, issn = {1532-2777}, mesh = {*Biological Evolution ; Carcinogenesis/*metabolism ; Cell Transformation, Neoplastic/*metabolism ; Energy Metabolism/*physiology ; Humans ; Mitochondria/*metabolism ; *Models, Biological ; }, abstract = {The Warburg Effect showed that energy metabolism of cancer cells was similar to prokaryotic cells, which were different from normal eucaryotic cells. The Endosymbiotic Theory offered a plausible explanation that the eucaryotic cells were evolved from prokaryotic cells, by which host cells (ancient prokaryotic cells) had ingested mitochondria (ancient aerobic bacteria), which depended on oxidative phosphorylation rather than glycolysis for generating energy. The alteration of energy metabolism might mean that the survival style of cancer cells were the re-evolution from eucaryotic cells to prokaryotic cells. But how this alteration happened was still unknown. This hypothesis tries to explain how mitochondria take part in the re-evolution from normal cell to cancer cell.}, } @article {pmid24650628, year = {2014}, author = {Grüber, G and Manimekalai, MS and Mayer, F and Müller, V}, title = {ATP synthases from archaea: the beauty of a molecular motor.}, journal = {Biochimica et biophysica acta}, volume = {1837}, number = {6}, pages = {940-952}, doi = {10.1016/j.bbabio.2014.03.004}, pmid = {24650628}, issn = {0006-3002}, mesh = {Archaea/*enzymology ; Archaeal Proteins/chemistry/*physiology ; Binding Sites ; Biocatalysis ; Catalytic Domain ; Mitochondrial Proton-Translocating ATPases/chemistry/*physiology ; Models, Molecular ; Molecular Motor Proteins/chemistry/*physiology ; }, abstract = {Archaea live under different environmental conditions, such as high salinity, extreme pHs and cold or hot temperatures. How energy is conserved under such harsh environmental conditions is a major question in cellular bioenergetics of archaea. The key enzymes in energy conservation are the archaeal A1AO ATP synthases, a class of ATP synthases distinct from the F1FO ATP synthase ATP synthase found in bacteria, mitochondria and chloroplasts and the V1VO ATPases of eukaryotes. A1AO ATP synthases have distinct structural features such as a collar-like structure, an extended central stalk, and two peripheral stalks possibly stabilizing the A1AO ATP synthase during rotation in ATP synthesis/hydrolysis at high temperatures as well as to provide the storage of transient elastic energy during ion-pumping and ATP synthesis/-hydrolysis. High resolution structures of individual subunits and subcomplexes have been obtained in recent years that shed new light on the function and mechanism of this unique class of ATP synthases. An outstanding feature of archaeal A1AO ATP synthases is their diversity in size of rotor subunits and the coupling ion used for ATP synthesis with H(+), Na(+) or even H(+) and Na(+) using enzymes. The evolution of the H(+) binding site to a Na(+) binding site and its implications for the energy metabolism and physiology of the cell are discussed.}, } @article {pmid24438310, year = {2015}, author = {Feng, P and Zhao, H and Lu, X}, title = {Evolution of mitochondrial DNA and its relation to basal metabolic rate.}, journal = {Mitochondrial DNA}, volume = {26}, number = {4}, pages = {566-571}, doi = {10.3109/19401736.2013.873895}, pmid = {24438310}, issn = {1940-1744}, mesh = {Animals ; Basal Metabolism/*genetics ; DNA, Mitochondrial/*chemistry ; *Evolution, Molecular ; Likelihood Functions ; Locomotion/genetics ; Mammals/*genetics ; Phylogeny ; Selection, Genetic ; }, abstract = {Energy metabolism is essential for the survival of animals, which can be characterized by maximum metabolic rate (MMR) and basal metabolic rate (BMR). Because of the crucial roles of mitochondria in energy metabolism, mitochondrial DNA (mtDNA) has been subjected to stronger purifying selection in strongly locomotive than weakly locomotive birds and mammals. Although maximum locomotive speed (an indicator of MMR) showed a negative correlation with the evolutionary rate of mtDNA, it is unclear whether BMR has driven the evolution of mtDNA. Here, we take advantage of the large amount of mtDNA and BMR data in 106 mammals to test whether BMR has influenced the mtDNA evolution. Our results showed that, in addition to the locomotive speed, mammals with higher BMR have subjected to stronger purifying selection on mtDNA than did those with lower BMR. The evolution of mammalian mtDNA has been modified by two levels of energy metabolism, including MMR and BMR. Our study provides a more comprehensive view of mtDNA evolution in relation to energy metabolism.}, } @article {pmid24434588, year = {2014}, author = {Zhang, Y and Pan, YH and Yin, Q and Yang, T and Dong, D and Liao, CC and Zhang, S}, title = {Critical roles of mitochondria in brain activities of torpid Myotis ricketti bats revealed by a proteomic approach.}, journal = {Journal of proteomics}, volume = {105}, number = {}, pages = {266-284}, doi = {10.1016/j.jprot.2014.01.006}, pmid = {24434588}, issn = {1876-7737}, mesh = {Animals ; Brain/*metabolism ; Chiroptera/*metabolism ; Gene Expression Regulation/*physiology ; Mitochondria/*metabolism ; Mitochondrial Proteins/*biosynthesis ; Protein Processing, Post-Translational/*physiology ; Proteomics/methods ; Synaptic Transmission/physiology ; }, abstract = {UNLABELLED: Bats are the only mammals that fly and hibernate. Little is known about their overall metabolism in the brain during hibernation. In this study, brain proteins of torpid and active Myotis ricketti bats were fractionated and compared using a proteomic approach. Results showed that 21% (23 proteins) of identified proteins with significant expression changes were associated with amino acid metabolism and proteostasis. The expression levels of proteins involved in energy metabolism (15 proteins), cytoskeletal structure (18 proteins), and stress response (13 proteins) were also significantly altered in torpid bats. Over 30% (34 proteins) of differentially expressed proteins were associated with mitochondrial functions. Various post-translational modifications (PTMs) on PDHB, DLD, and ARG1 were detected, suggesting that bats use PTMs to regulate protein functions during torpor. Antioxidation and stress responses in torpid bats were similar to those of hibernated squirrels, suggesting a common strategy adopted by small hibernators against brain dysfunction. Since many amino acids that metabolize in mitochondria modulate neuronal transmissions, results of this study reveal pivotal roles of mitochondria in neural communication, metabolic regulation, and brain cell survival during bat hibernation. This article is part of a Special Issue entitled: Proteomics of non-model organisms.

BIOLOGICAL SIGNIFICANCE: This study reveals the mechanisms used by bats to regulate brain activities during torpor. These mechanisms include post-translational modifications and differential expression of proteins involved in mitochondrial electron transport, anaerobic glycolysis, TCA cycle efflux, cytoskeletal plasticity, amino acid metabolism, vesicle structure, antioxidation defense, stress response, and proteostasis. Our study provides insights in metabolic regulation of flying mammals during torpor and common strategies used by small hibernators in response to hibernation. This article is part of a Special Issue entitled: Proteomics of non-model organisms.}, } @article {pmid24379079, year = {2014}, author = {Yin, Y and Qu, F and Yang, Z and Zhang, X and Yue, B}, title = {Structural characteristics and phylogenetic analysis of the mitochondrial genome of the rice leafroller, Cnaphalocrocis medinalis (Lepidoptera: Crambidae).}, journal = {Molecular biology reports}, volume = {41}, number = {2}, pages = {1109-1116}, pmid = {24379079}, issn = {1573-4978}, mesh = {Animals ; Base Sequence ; DNA, Mitochondrial/genetics ; Genome, Mitochondrial/*genetics ; Lepidoptera/*genetics/ultrastructure ; Oryza/genetics ; Pest Control ; *Phylogeny ; }, abstract = {The rice leafroller, Cnaphalocrocis medinalis, is one of the most important pests on rice and possesses striking flight ability. We have determined the nucleotide sequence of the 15,377 bp of a C. medinalis mitochondrial genome (mtDNA). The mtDNA encodes 37 genes and shows a unique lepidopteran CR-M-I-Q arrangement. Three possible substructures were detected in C. medinalis and some other lepidopteran insects' control region. The findings might be relevant to the regulation of mtDNA replication and transcription. Phylogenetic relationships were reconstructed among 19 families in Lepidoptera so far. Cnaphalocrocis medinalis forms a reciprocal monophyletic group with Ostrinia in clade Crambidae instead of Pyralidae. The topology between Papilionoidea and other superfamilies showed an apparent contradiction with traditional Lepidopteran classification. As a well-known migratory insect, the molecular information contained in C. medinalis mtDNA may provide a further insight into the evolution of mitochondria genes and insect species, and may help to better understanding the energy metabolism of invertebrates.}, } @article {pmid24334395, year = {2013}, author = {Angione, C and Carapezza, G and Costanza, J and Lió, P and Nicosia, G}, title = {Pareto optimality in organelle energy metabolism analysis.}, journal = {IEEE/ACM transactions on computational biology and bioinformatics}, volume = {10}, number = {4}, pages = {1032-1044}, doi = {10.1109/TCBB.2013.95}, pmid = {24334395}, issn = {1557-9964}, mesh = {Adenosine Triphosphate/metabolism ; Algorithms ; Anaerobiosis ; Computational Biology ; Energy Metabolism/*physiology ; *Models, Biological ; Organelles/*metabolism ; Trichomonas vaginalis ; }, abstract = {In low and high eukaryotes, energy is collected or transformed in compartments, the organelles. The rich variety of size, characteristics, and density of the organelles makes it difficult to build a general picture. In this paper, we make use of the Pareto-front analysis to investigate the optimization of energy metabolism in mitochondria and chloroplasts. Using the Pareto optimality principle, we compare models of organelle metabolism on the basis of single- and multiobjective optimization, approximation techniques (the Bayesian Automatic Relevance Determination), robustness, and pathway sensitivity analysis. Finally, we report the first analysis of the metabolic model for the hydrogenosome of Trichomonas vaginalis, which is found in several protozoan parasites. Our analysis has shown the importance of the Pareto optimality for such comparison and for insights into the evolution of the metabolism from cytoplasmic to organelle bound, involving a model order reduction. We report that Pareto fronts represent an asymptotic analysis useful to describe the metabolism of an organism aimed at maximizing concurrently two or more metabolite concentrations.}, } @article {pmid24265196, year = {2013}, author = {Bonini, MG and Gantner, BN}, title = {The multifaceted activities of AMPK in tumor progression--why the "one size fits all" definition does not fit at all?.}, journal = {IUBMB life}, volume = {65}, number = {11}, pages = {889-896}, doi = {10.1002/iub.1213}, pmid = {24265196}, issn = {1521-6551}, support = {1S10RR027848-01A1/RR/NCRR NIH HHS/United States ; 5T32HL072742-09/HL/NHLBI NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases/*metabolism ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/physiology ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Disease Progression ; Enzyme Activation ; Epithelial-Mesenchymal Transition/physiology ; Glycolysis ; Humans ; Metformin/pharmacology ; Mitochondria/drug effects ; Neoplasms/*physiopathology ; Neoplastic Stem Cells/drug effects/physiology ; Proto-Oncogene Proteins c-akt/metabolism ; Tumor Suppressor Proteins/physiology ; }, abstract = {AMP-activated kinase (AMPK) is a central cellular energetic biosensor and regulator of a broad array of cellular metabolic routes activated by nutrient deprivation, mitochondrial dysfunction, oxidative stress, and cytokines. The activation of AMPK maintains ATP levels in response to hypoxia, mitochondrial dysfunction, and shortage of essential metabolic fuels. Activated AMPK turns on energy sparing pathways and promotes antiapoptotic functions thereby permitting cells to survive extremely hostile conditions for prolonged periods of time. Cancer cells in solid tumors are generally subjected to such harsh conditions; however, they manage to efficiently survive and proliferate. This is likely due, in great part, to a peculiar form of metabolism that is heavily reliant on glycolysis and which promotes cancer cell adaptation and tumor progression. AMPK controls the influx and utilization of glucose by cancer cells and therefore has emerged as an attractive target to treat cancer. Investigations exploring this possibility demonstrated that activators or inhibitors of AMPK impact cancer cell viability and possibly cancer progression. For example, the AMPK activator metformin induces apoptosis in a variety of cancer cell lines and models. A major problem with many of the studies on metformin is that little effort has been invested in unraveling how metformin activates AMPK in the many contexts it has been tested. This is significant because many AMPK-independent effects of metformin have been documented. The notion that AMPK acts solely as a tumor suppressor also conflicts with findings that it confers resistance to nutrient deprivation, sustains NADPH levels in cancer cells, facilitates stress-induced gene transcription, promotes cell survival via antiapoptotic function upregulation, intermediates epithelial-to-mesenchymal transition, and increases malignant transformation. These are all recognized steps necessary for the successful evolution of tumors. This review highlights some of these findings and proposes that the role of AMPK in cancer should be reconsidered in light of the complex roles of AMPK under different metabolic conditions.}, } @article {pmid24259312, year = {2013}, author = {Maier, UG and Zauner, S and Woehle, C and Bolte, K and Hempel, F and Allen, JF and Martin, WF}, title = {Massively convergent evolution for ribosomal protein gene content in plastid and mitochondrial genomes.}, journal = {Genome biology and evolution}, volume = {5}, number = {12}, pages = {2318-2329}, pmid = {24259312}, issn = {1759-6653}, mesh = {Biological Evolution ; Cell Membrane/genetics ; Chlorophyta/genetics ; Chloroplasts/genetics ; Cyanobacteria/*genetics ; Electron Transport Chain Complex Proteins/genetics ; Energy Metabolism/genetics ; Eukaryotic Cells/cytology ; Evolution, Molecular ; *Genome, Mitochondrial ; Membrane Proteins/genetics ; Mitochondria/*genetics ; Photosynthesis/genetics ; Plastids/*genetics ; Respiration/genetics ; Ribosomal Proteins/*genetics ; Ribosomes/*genetics ; }, abstract = {Plastid and mitochondrial genomes have undergone parallel evolution to encode the same functional set of genes. These encode conserved protein components of the electron transport chain in their respective bioenergetic membranes and genes for the ribosomes that express them. This highly convergent aspect of organelle genome evolution is partly explained by the redox regulation hypothesis, which predicts a separate plastid or mitochondrial location for genes encoding bioenergetic membrane proteins of either photosynthesis or respiration. Here we show that convergence in organelle genome evolution is far stronger than previously recognized, because the same set of genes for ribosomal proteins is independently retained by both plastid and mitochondrial genomes. A hitherto unrecognized selective pressure retains genes for the same ribosomal proteins in both organelles. On the Escherichia coli ribosome assembly map, the retained proteins are implicated in 30S and 50S ribosomal subunit assembly and initial rRNA binding. We suggest that ribosomal assembly imposes functional constraints that govern the retention of ribosomal protein coding genes in organelles. These constraints are subordinate to redox regulation for electron transport chain components, which anchor the ribosome to the organelle genome in the first place. As organelle genomes undergo reduction, the rRNAs also become smaller. Below size thresholds of approximately 1,300 nucleotides (16S rRNA) and 2,100 nucleotides (26S rRNA), all ribosomal protein coding genes are lost from organelles, while electron transport chain components remain organelle encoded as long as the organelles use redox chemistry to generate a proton motive force.}, } @article {pmid24195633, year = {2014}, author = {Tao, M and You, CP and Zhao, RR and Liu, SJ and Zhang, ZH and Zhang, C and Liu, Y}, title = {Animal mitochondria: evolution, function, and disease.}, journal = {Current molecular medicine}, volume = {14}, number = {1}, pages = {115-124}, doi = {10.2174/15665240113136660081}, pmid = {24195633}, issn = {1875-5666}, mesh = {Aging/genetics/metabolism ; Animals ; Biological Evolution ; DNA, Mitochondrial/genetics/metabolism ; Energy Metabolism ; Humans ; Mitochondria/*physiology ; Mitochondrial Diseases/genetics/metabolism ; Neoplasms/genetics/metabolism ; Signal Transduction ; }, abstract = {Mitochondria are sub-cellular organelles responsible for producing the majority of cellular energy through the process of oxidative phosphorylation (OXPHOS), and are found in nearly all eukaryotic cells. Mitochondria have a unique genetic system, mitochondrial DNA (mtDNA), which is a small, self-replicating and diverse genome. In the past 30 years, mtDNA has made significant contribution to molecular ecology and phylogeography. Mitochondria also represent a unique system of mitochondrial-nuclear genomic cooperation. Additionally, mitochondrial dysfunction can be fatal. In this paper, we review several aspects of mitochondria, including evolution and the origin of mitochondria, energy supply and the central role of mitochondria in apoptosis, and mitochondrial dysfunction. It is shown that mitochondria play a critical role in many aspects of life.}, } @article {pmid24141138, year = {2014}, author = {Tan, AS and Baty, JW and Berridge, MV}, title = {The role of mitochondrial electron transport in tumorigenesis and metastasis.}, journal = {Biochimica et biophysica acta}, volume = {1840}, number = {4}, pages = {1454-1463}, doi = {10.1016/j.bbagen.2013.10.016}, pmid = {24141138}, issn = {0006-3002}, mesh = {Animals ; Carcinogenesis/*genetics ; Electron Transport/*genetics ; Humans ; Mitochondria/*genetics ; Mutation ; Neoplasm Metastasis/*genetics ; Tumor Microenvironment ; }, abstract = {BACKGROUND: Tumor formation and spread via the circulatory and lymphatic drainage systems is associated with metabolic reprogramming that often includes increased glycolytic metabolism relative to mitochondrial energy production. However, cells within a tumor are not identical due to genetic change, clonal evolution and layers of epigenetic reprogramming. In addition, cell hierarchy impinges on metabolic status while tumor cell phenotype and metabolic status will be influenced by the local microenvironment including stromal cells, developing blood and lymphatic vessels and innate and adaptive immune cells. Mitochondrial mutations and changes in mitochondrial electron transport contribute to metabolic remodeling in cancer in ways that are poorly understood.

SCOPE OF REVIEW: This review concerns the role of mitochondria, mitochondrial mutations and mitochondrial electron transport function in tumorigenesis and metastasis.

MAJOR CONCLUSIONS: It is concluded that mitochondrial electron transport is required for tumor initiation, growth and metastasis. Nevertheless, defects in mitochondrial electron transport that compromise mitochondrial energy metabolism can contribute to tumor formation and spread. These apparently contradictory phenomena can be reconciled by cells in individual tumors in a particular environment adapting dynamically to optimally balance mitochondrial genome changes and bioenergetic status.

GENERAL SIGNIFICANCE: Tumors are complex evolving biological systems characterized by genetic and adaptive epigenetic changes. Understanding the complexity of these changes in terms of bioenergetics and metabolic changes will permit the development of better combination anticancer therapies. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.}, } @article {pmid24114701, year = {2013}, author = {Wilson, DF}, title = {Regulation of cellular metabolism: programming and maintaining metabolic homeostasis.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {115}, number = {11}, pages = {1583-1588}, doi = {10.1152/japplphysiol.00894.2013}, pmid = {24114701}, issn = {1522-1601}, mesh = {Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Cells/*metabolism ; *Energy Metabolism ; Homeostasis ; Humans ; Metabolic Networks and Pathways ; Mitochondria/metabolism ; *Oxidative Phosphorylation ; }, abstract = {Mitochondrial oxidative phosphorylation is programmed to set and maintain metabolic homeostasis. This is accomplished through an intrinsic program that determines the metabolic [ATP]/[ADP]/[Pi], where [Pi] is the concentration of inorganic phosphate (energy state) and maintains it through a bidirectional sensory/signaling control network that reaches every aspect of cellular metabolism. The program sets the energy state with high precision (to better than one part in 10(9)) and can respond to transient changes in energy demand (ATP use) to more than 100 times the resting rate. Epigenetic and environmental factors are able to "fine tune" the programmed set point over a narrow range to meet the special needs associated with cell differentiation and chronic changes in metabolic requirements. The result is robust, across platform control of metabolism, essential to cellular differentiation and the evolution of complex organisms.}, } @article {pmid24086244, year = {2013}, author = {Leger, MM and Gawryluk, RM and Gray, MW and Roger, AJ}, title = {Evidence for a hydrogenosomal-type anaerobic ATP generation pathway in Acanthamoeba castellanii.}, journal = {PloS one}, volume = {8}, number = {9}, pages = {e69532}, pmid = {24086244}, issn = {1932-6203}, support = {U54 HG002051/HG/NHGRI NIH HHS/United States ; MOP-62809/CAPMC/CIHR/Canada ; MOP-4124/CAPMC/CIHR/Canada ; U01 HG02051/HG/NHGRI NIH HHS/United States ; }, mesh = {Acanthamoeba castellanii/enzymology/genetics/*metabolism ; Adenosine Triphosphate/*biosynthesis ; Amino Acid Sequence ; Anaerobiosis ; Electron Transport ; Enzymes/chemistry/metabolism ; Expressed Sequence Tags ; Genome, Protozoan ; Hydrogen/*metabolism ; Molecular Sequence Data ; Phylogeny ; Tandem Mass Spectrometry ; }, abstract = {Diverse, distantly-related eukaryotic lineages have adapted to low-oxygen environments, and possess mitochondrion-related organelles that have lost the capacity to generate adenosine triphosphate (ATP) through oxidative phosphorylation. A subset of these organelles, hydrogenosomes, has acquired a set of characteristic ATP generation enzymes commonly found in anaerobic bacteria. The recipient of these enzymes could not have survived prior to their acquisition had it not still possessed the electron transport chain present in the ancestral mitochondrion. In the divergence of modern hydrogenosomes from mitochondria, a transitional organelle must therefore have existed that possessed both an electron transport chain and an anaerobic ATP generation pathway. Here, we report a modern analog of this organelle in the habitually aerobic opportunistic pathogen, Acanthamoeba castellanii. This organism possesses a complete set of enzymes comprising a hydrogenosome-like ATP generation pathway, each of which is predicted to be targeted to mitochondria. We have experimentally confirmed the mitochondrial localizations of key components of this pathway using tandem mass spectrometry. This evidence is the first supported by localization and proteome data of a mitochondrion possessing both an electron transport chain and hydrogenosome-like energy metabolism enzymes. Our work provides insight into the first steps that might have occurred in the course of the emergence of modern hydrogenosomes.}, } @article {pmid24050258, year = {2013}, author = {Ghanta, S and Grossmann, RE and Brenner, C}, title = {Mitochondrial protein acetylation as a cell-intrinsic, evolutionary driver of fat storage: chemical and metabolic logic of acetyl-lysine modifications.}, journal = {Critical reviews in biochemistry and molecular biology}, volume = {48}, number = {6}, pages = {561-574}, pmid = {24050258}, issn = {1549-7798}, support = {K01 GM109309/GM/NIGMS NIH HHS/United States ; T32 DK007734/DK/NIDDK NIH HHS/United States ; K01GM109309/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylation ; Animals ; Caloric Restriction ; *Energy Metabolism ; Humans ; *Lipid Metabolism ; Lipids ; *Lipogenesis ; Lysine/chemistry/metabolism ; Mitochondria/*metabolism ; Mitochondrial Proteins/*metabolism ; Niacinamide/analogs & derivatives/metabolism ; Oxaloacetic Acid/chemistry ; Oxidation-Reduction ; Pyridinium Compounds ; Sirtuin 3/metabolism ; }, abstract = {Hormone systems evolved over 500 million years of animal natural history to motivate feeding behavior and convert excess calories to fat. These systems produced vertebrates, including humans, who are famine-resistant but sensitive to obesity in environments of persistent overnutrition. We looked for cell-intrinsic metabolic features, which might have been subject to an evolutionary drive favoring lipogenesis. Mitochondrial protein acetylation appears to be such a system. Because mitochondrial acetyl-coA is the central mediator of fuel oxidation and is saturable, this metabolite is postulated to be the fundamental indicator of energy excess, which imprints a memory of nutritional imbalances by covalent modification. Fungal and invertebrate mitochondria have highly acetylated mitochondrial proteomes without an apparent mitochondrially targeted protein lysine acetyltransferase. Thus, mitochondrial acetylation is hypothesized to have evolved as a nonenzymatic phenomenon. Because the pKa of a nonperturbed Lys is 10.4 and linkage of a carbonyl carbon to an ε amino group cannot be formed with a protonated Lys, we hypothesize that acetylation occurs on residues with depressed pKa values, accounting for the propensity of acetylation to hit active sites and suggesting that regulatory Lys residues may have been under selective pressure to avoid or attract acetylation throughout animal evolution. In addition, a shortage of mitochondrial oxaloacetate under ketotic conditions can explain why macronutrient insufficiency also produces mitochondrial hyperacetylation. Reduced mitochondrial activity during times of overnutrition and undernutrition would improve fitness by virtue of resource conservation. Micronutrient insufficiency is predicted to exacerbate mitochondrial hyperacetylation. Nicotinamide riboside and Sirt3 activity are predicted to relieve mitochondrial inhibition.}, } @article {pmid24045017, year = {2013}, author = {Ng, S and Ivanova, A and Duncan, O and Law, SR and Van Aken, O and De Clercq, I and Wang, Y and Carrie, C and Xu, L and Kmiec, B and Walker, H and Van Breusegem, F and Whelan, J and Giraud, E}, title = {A membrane-bound NAC transcription factor, ANAC017, mediates mitochondrial retrograde signaling in Arabidopsis.}, journal = {The Plant cell}, volume = {25}, number = {9}, pages = {3450-3471}, pmid = {24045017}, issn = {1532-298X}, mesh = {Arabidopsis/cytology/*genetics/growth & development/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Binding Sites ; Cell Nucleus/metabolism ; Endoplasmic Reticulum/metabolism ; Gene Expression Profiling ; *Gene Expression Regulation, Plant ; Genes, Reporter ; Hydrogen Peroxide/pharmacology ; Mitochondria/metabolism ; Mitochondrial Proteins/genetics/metabolism ; Mutation ; Oligonucleotide Array Sequence Analysis ; Oxidoreductases/genetics/metabolism ; Phenotype ; Phylogeny ; Plant Proteins/genetics/metabolism ; Protein Structure, Tertiary ; Recombinant Fusion Proteins ; Seedlings/cytology/genetics/growth & development/metabolism ; *Signal Transduction ; Stress, Physiological ; Transcription Factors/genetics/metabolism ; Transcriptome ; }, abstract = {Plants require daily coordinated regulation of energy metabolism for optimal growth and survival and therefore need to integrate cellular responses with both mitochondrial and plastid retrograde signaling. Using a forward genetic screen to characterize regulators of alternative oxidase1a (rao) mutants, we identified RAO2/Arabidopsis NAC domain-containing protein17 (ANAC017) as a direct positive regulator of AOX1a. RAO2/ANAC017 is targeted to connections and junctions in the endoplasmic reticulum (ER) and F-actin via a C-terminal transmembrane (TM) domain. A consensus rhomboid protease cleavage site is present in ANAC017 just prior to the predicted TM domain. Furthermore, addition of the rhomboid protease inhibitor N-p-Tosyl-l-Phe chloromethyl abolishes the induction of AOX1a upon antimycin A treatment. Simultaneous fluorescent tagging of ANAC017 with N-terminal red fluorescent protein (RFP) and C-terminal green fluorescent protein (GFP) revealed that the N-terminal RFP domain migrated into the nucleus, while the C-terminal GFP tag remained in the ER. Genome-wide analysis of the transcriptional network regulated by RAO2/ANAC017 under stress treatment revealed that RAO2/ANAC017 function was necessary for >85% of the changes observed as a primary response to cytosolic hydrogen peroxide (H2O2), but only ~33% of transcriptional changes observed in response to antimycin A treatment. Plants with mutated rao2/anac017 were more stress sensitive, whereas a gain-of-function mutation resulted in plants that had lower cellular levels of H2O2 under untreated conditions.}, } @article {pmid24026098, year = {2013}, author = {Hoekstra, LA and Siddiq, MA and Montooth, KL}, title = {Pleiotropic effects of a mitochondrial-nuclear incompatibility depend upon the accelerating effect of temperature in Drosophila.}, journal = {Genetics}, volume = {195}, number = {3}, pages = {1129-1139}, pmid = {24026098}, issn = {1943-2631}, mesh = {Animals ; Base Sequence ; Cell Nucleus/genetics/metabolism ; DNA, Mitochondrial/genetics ; Drosophila/*genetics/growth & development/*physiology ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/*genetics/growth & development/*physiology ; Epistasis, Genetic ; Evolution, Molecular ; Female ; Fertility/genetics/physiology ; Genes, Insect ; Genetic Fitness ; Hot Temperature ; Larva/genetics/growth & development/metabolism ; Male ; Mitochondria/genetics/metabolism ; Mutation ; RNA, Transfer, Tyr/chemistry/genetics/metabolism ; Selection, Genetic ; Species Specificity ; Tyrosine-tRNA Ligase/genetics/metabolism ; }, abstract = {Interactions between mitochondrial and nuclear gene products that underlie eukaryotic energy metabolism can cause the fitness effects of mutations in one genome to be conditional on variation in the other genome. In ectotherms, the effects of these interactions are likely to depend upon the thermal environment, because increasing temperature accelerates molecular rates. We find that temperature strongly modifies the pleiotropic phenotypic effects of an incompatible interaction between a Drosophila melanogaster polymorphism in the nuclear-encoded, mitochondrial tyrosyl-transfer (t)RNA synthetase and a D. simulans polymorphism in the mitochondrially encoded tRNA(Tyr). The incompatible mitochondrial-nuclear genotype extends development time, decreases larval survivorship, and reduces pupation height, indicative of decreased energetic performance. These deleterious effects are ameliorated when larvae develop at 16° and exacerbated at warmer temperatures, leading to complete sterility in both sexes at 28°. The incompatible genotype has a normal metabolic rate at 16° but a significantly elevated rate at 25°, consistent with the hypothesis that inefficient energy metabolism extends development in this genotype at warmer temperatures. Furthermore, the incompatibility decreases metabolic plasticity of larvae developed at 16°, indicating that cooler development temperatures do not completely mitigate the deleterious effects of this genetic interaction. Our results suggest that the epistatic fitness effects of metabolic mutations may generally be conditional on the thermal environment. The expression of epistatic interactions in some environments, but not others, weakens the efficacy of selection in removing deleterious epistatic variants from populations and may promote the accumulation of incompatibilities whose fitness effects will depend upon the environment in which hybrids occur.}, } @article {pmid24019145, year = {2013}, author = {Martínez-Fábregas, J and Díaz-Moreno, I and González-Arzola, K and Janocha, S and Navarro, JA and Hervás, M and Bernhardt, R and Díaz-Quintana, A and De la Rosa, MÁ}, title = {New Arabidopsis thaliana cytochrome c partners: a look into the elusive role of cytochrome c in programmed cell death in plants.}, journal = {Molecular & cellular proteomics : MCP}, volume = {12}, number = {12}, pages = {3666-3676}, pmid = {24019145}, issn = {1535-9484}, mesh = {Apoptosis/*genetics ; Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Chromatography, Affinity ; Cytochromes c/genetics/*metabolism ; Cytosol/chemistry/metabolism ; Energy Metabolism ; Evolution, Molecular ; *Gene Expression Regulation, Plant ; HEK293 Cells ; Humans ; Mass Spectrometry ; Mitochondria/chemistry/metabolism ; Molecular Sequence Annotation ; Oxidative Stress ; Protein Binding ; Protein Interaction Mapping ; Protein Transport ; Protoplasts/chemistry/metabolism ; RNA, Messenger/genetics/metabolism ; Signal Transduction ; Surface Plasmon Resonance ; }, abstract = {Programmed cell death is an event displayed by many different organisms along the evolutionary scale. In plants, programmed cell death is necessary for development and the hypersensitive response to stress or pathogenic infection. A common feature in programmed cell death across organisms is the translocation of cytochrome c from mitochondria to the cytosol. To better understand the role of cytochrome c in the onset of programmed cell death in plants, a proteomic approach was developed based on affinity chromatography and using Arabidopsis thaliana cytochrome c as bait. Using this approach, ten putative new cytochrome c partners were identified. Of these putative partners and as indicated by bimolecular fluorescence complementation, nine of them bind the heme protein in plant protoplasts and human cells as a heterologous system. The in vitro interaction between cytochrome c and such soluble cytochrome c-targets was further corroborated using surface plasmon resonance. Taken together, the results obtained in the study indicate that Arabidopsis thaliana cytochrome c interacts with several distinct proteins involved in protein folding, translational regulation, cell death, oxidative stress, DNA damage, energetic metabolism, and mRNA metabolism. Interestingly, some of these novel Arabidopsis thaliana cytochrome c-targets are closely related to those for Homo sapiens cytochrome c (Martínez-Fábregas et al., unpublished). These results indicate that the evolutionarily well-conserved cytosolic cytochrome c, appearing in organisms from plants to mammals, interacts with a wide range of targets on programmed cell death. The data have been deposited to the ProteomeXchange with identifier PXD000280.}, } @article {pmid24018281, year = {2013}, author = {Navarrete, ML and Cerdeño, MC and Serra, MC and Conejero, R}, title = {[Mitochondrial and microcirculatory distress syndrome in the critical patient. Therapeutic implications].}, journal = {Medicina intensiva}, volume = {37}, number = {7}, pages = {476-484}, doi = {10.1016/j.medin.2013.03.001}, pmid = {24018281}, issn = {1578-6749}, mesh = {Animals ; Antioxidants/therapeutic use ; Cell Hypoxia ; Disease Progression ; Electron Transport/drug effects ; Energy Metabolism/drug effects ; Free Radical Scavengers/therapeutic use ; Hemodynamics ; Hibernation ; Humans ; Hypothermia, Induced ; Microcirculation/*physiology ; Mitochondria/drug effects/physiology ; Mitochondrial Diseases/diagnosis/*etiology/physiopathology ; Models, Animal ; Multiple Organ Failure/etiology/physiopathology/prevention & control ; Nitric Oxide/physiology/therapeutic use ; Oxidative Phosphorylation/drug effects ; Reactive Oxygen Species ; Syndrome ; Systemic Inflammatory Response Syndrome/*complications/physiopathology ; }, abstract = {Mitochondrial and microcirculatory distress syndrome (MMDS) can occur during systemic inflammatory response syndrome (SIRS), and is characterized by cytopathic tissue hypoxia uncorrected by oxygen transport optimization, and associated with an acquired defect in the use of oxygen and energy production in mitochondria, leading to multiple organ dysfunction (MOD). We examine the pathogenesis of MMDS, new diagnostic methods, and recent therapeutic approaches adapted to each of the three phases in the evolution of the syndrome. In the initial phase, the aim is prevention and early reversal of mitochondrial dysfunction. Once the latter is established, the aim is to restore flow of the electron chain, mitochondrial respiration, and to avoid cellular energy collapse. Finally, in the third (resolution) stage, treatment should focus on stimulating mitochondrial biogenesis and the repair or replacement of damaged mitochondria.}, } @article {pmid23995460, year = {2013}, author = {Zhang, F and Broughton, RE}, title = {Mitochondrial-nuclear interactions: compensatory evolution or variable functional constraint among vertebrate oxidative phosphorylation genes?.}, journal = {Genome biology and evolution}, volume = {5}, number = {10}, pages = {1781-1791}, pmid = {23995460}, issn = {1759-6653}, mesh = {Animals ; Catalytic Domain/genetics ; Cell Nucleus/*genetics ; Energy Metabolism/*genetics ; Evolution, Molecular ; Mitochondria/*genetics ; Mitochondrial Proteins/genetics/metabolism ; *Oxidative Phosphorylation ; Vertebrates/genetics ; }, abstract = {Oxidative phosphorylation (OXPHOS), the major energy-producing pathway in aerobic organisms, includes protein subunits encoded by both mitochondrial (mt) and nuclear (nu) genomes. How these independent genomes have coevolved is a long-standing question in evolutionary biology. Although mt genes evolve faster than most nu genes, maintenance of OXPHOS structural stability and functional efficiency may involve correlated evolution of mt and nu OXPHOS genes. The nu OXPHOS genes might be predicted to exhibit accelerated evolutionary rates to accommodate the elevated substitution rates of mt OXPHOS subunits with which they interact. Evolutionary rates of nu OXPHOS genes should, therefore, be higher than that of nu genes that are not involved in OXPHOS (nu non-OXPHOS). We tested the compensatory evolution hypothesis by comparing the evolutionary rates (synonymous substitution rate dS and nonsynonymous substitution rate dN) among 13 mt OXPHOS genes, 60 nu OXPHOS genes, and 77 nu non-OXPHOS genes in vertebrates (7 fish and 40 mammal species). The results from a combined analysis of all OXPHOS subunits fit the predictions of the hypothesis. However, results from two OXPHOS complexes did not fit this pattern when analyzed separately. We found that the d(N) of nu OXPHOS genes for "core" subunits (those involved in the major catalytic activity) was lower than that of "noncore" subunits, whereas there was no significant difference in d(N) between genes for nu non-OXPHOS and core subunits. This latter finding suggests that compensatory changes play a minor role in the evolution of OXPHOS genes and that the observed accelerated nu substitution rates are due largely to reduced functional constraint on noncore subunits.}, } @article {pmid23943303, year = {2013}, author = {Mitra, K}, title = {Mitochondrial fission-fusion as an emerging key regulator of cell proliferation and differentiation.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {35}, number = {11}, pages = {955-964}, doi = {10.1002/bies.201300011}, pmid = {23943303}, issn = {1521-1878}, mesh = {Animals ; Cell Cycle ; *Cell Differentiation ; *Cell Proliferation ; Cyclin E/genetics/metabolism ; Evolution, Molecular ; Mitochondria/physiology ; Mitochondrial Dynamics/*physiology ; Models, Molecular ; Signal Transduction ; Stem Cells ; Yeasts/genetics/metabolism ; }, abstract = {Mitochondrial shape change, brought about by molecules that promote either fission or fusion between individual mitochondria, has been documented in several model systems. However, the deeper significance of mitochondrial shape change has only recently begun to emerge: among others, it appears to play a role in the regulation of cell proliferation. Here, I review the emerging interplay between mitochondrial fission-fusion components with cell cycle regulatory machineries and how that may impact cell differentiation. Regulation of mitochondrial shape may modulate mitochondrial metabolism and/or energetics to promote crosstalk between signaling components and the cell cycle machinery. Focused research in this area will reveal the exact role of mitochondria in development and disease, specifically in stem cell regulation and tumorigenesis. Such research may also reveal whether and how the endosymbiotic event that gave rise to the mitochondrion was crucial for the evolution of cell cycle regulatory mechanisms in eukaryotes that are absent in prokaryotes.}, } @article {pmid23876871, year = {2013}, author = {Ali, V and Nozaki, T}, title = {Iron-sulphur clusters, their biosynthesis, and biological functions in protozoan parasites.}, journal = {Advances in parasitology}, volume = {83}, number = {}, pages = {1-92}, doi = {10.1016/B978-0-12-407705-8.00001-X}, pmid = {23876871}, issn = {2163-6079}, mesh = {Blastocystis/*physiology ; Cell Physiological Phenomena ; Entamoeba/*physiology ; Gene Expression Regulation ; Giardia/*physiology ; Iron/metabolism ; Metalloproteins/*metabolism ; Microsporidia/*physiology ; Protozoan Proteins/*metabolism ; Sulfur/metabolism ; Trichomonas/*physiology ; }, abstract = {Fe-S clusters are ensembles of sulphide-linked di-, tri-, and tetra-iron centres of a variety of metalloproteins that play important roles in reduction and oxidation of mitochondrial electron transport, energy metabolism, regulation of gene expression, cell survival, nitrogen fixation, and numerous other metabolic pathways. The Fe-S clusters are assembled by one of four distinct systems: NIF, SUF, ISC, and CIA machineries. The ISC machinery is a house-keeping system conserved widely from prokaryotes to higher eukaryotes, while the other systems are present in a limited range of organisms and play supplementary roles under certain conditions such as stress. Fe-S cluster-containing proteins and the components required for Fe-S cluster biosynthesis are modulated under stress conditions, drug resistance, and developmental stages. It is also known that a defect in Fe-S proteins and Fe-S cluster biogenesis leads to many genetic disorders in humans, which indicates the importance of the systems. In this review, we describe the biological and physiological significance of Fe-S cluster-containing proteins and their biosynthesis in parasitic protozoa including Plasmodium, Trypanosoma, Leishmania, Giardia, Trichomonas, Entamoeba, Cryptosporidium, Blastocystis, and microsporidia. We also discuss the roles of Fe-S cluster biosynthesis in proliferation, differentiation, and stress response in protozoan parasites. The heterogeneity of the systems and the compartmentalization of Fe-S cluster biogenesis in the protozoan parasites likely reflect divergent evolution under highly diverse environmental niches, and influence their parasitic lifestyle and pathogenesis. Finally, both Fe-S cluster-containing proteins and their biosynthetic machinery in protozoan parasites are remarkably different from those in their mammalian hosts. Thus, they represent a rational target for the development of novel chemotherapeutic and prophylactic agents against protozoan infections.}, } @article {pmid23754818, year = {2013}, author = {Wallace, DC}, title = {Bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {368}, number = {1622}, pages = {20120267}, pmid = {23754818}, issn = {1471-2970}, support = {NS21328/NS/NINDS NIH HHS/United States ; NS070298/NS/NINDS NIH HHS/United States ; R01 NS070298/NS/NINDS NIH HHS/United States ; DK73691/DK/NIDDK NIH HHS/United States ; AG24373/AG/NIA NIH HHS/United States ; R01 AG024373/AG/NIA NIH HHS/United States ; R01 DK073691/DK/NIDDK NIH HHS/United States ; R01 NS021328/NS/NINDS NIH HHS/United States ; }, mesh = {*Biological Evolution ; Energy Metabolism/*genetics ; Gene Expression Regulation ; *Genetic Predisposition to Disease ; *Genetic Variation ; Humans ; }, abstract = {Two major inconsistencies exist in the current neo-Darwinian evolutionary theory that random chromosomal mutations acted on by natural selection generate new species. First, natural selection does not require the evolution of ever increasing complexity, yet this is the hallmark of biology. Second, human chromosomal DNA sequence variation is predominantly either neutral or deleterious and is insufficient to provide the variation required for speciation or for predilection to common diseases. Complexity is explained by the continuous flow of energy through the biosphere that drives the accumulation of nucleic acids and information. Information then encodes complex forms. In animals, energy flow is primarily mediated by mitochondria whose maternally inherited mitochondrial DNA (mtDNA) codes for key genes for energy metabolism. In mammals, the mtDNA has a very high mutation rate, but the deleterious mutations are removed by an ovarian selection system. Hence, new mutations that subtly alter energy metabolism are continuously introduced into the species, permitting adaptation to regional differences in energy environments. Therefore, the most phenotypically significant gene variants arise in the mtDNA, are regional, and permit animals to occupy peripheral energy environments where rarer nuclear DNA (nDNA) variants can accumulate, leading to speciation. The neutralist-selectionist debate is then a consequence of mammals having two different evolutionary strategies: a fast mtDNA strategy for intra-specific radiation and a slow nDNA strategy for speciation. Furthermore, the missing genetic variation for common human diseases is primarily mtDNA variation plus regional nDNA variants, both of which have been missed by large, inter-population association studies.}, } @article {pmid23754817, year = {2013}, author = {Blackstone, NW}, title = {Why did eukaryotes evolve only once? Genetic and energetic aspects of conflict and conflict mediation.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {368}, number = {1622}, pages = {20120266}, pmid = {23754817}, issn = {1471-2970}, mesh = {*Biological Evolution ; *Energy Metabolism ; Eukaryota/*genetics/*physiology ; Genetic Variation ; Genome ; Mitochondria ; }, abstract = {According to multi-level theory, evolutionary transitions require mediating conflicts between lower-level units in favour of the higher-level unit. By this view, the origin of eukaryotes and the origin of multicellularity would seem largely equivalent. Yet, eukaryotes evolved only once in the history of life, whereas multicellular eukaryotes have evolved many times. Examining conflicts between evolutionary units and mechanisms that mediate these conflicts can illuminate these differences. Energy-converting endosymbionts that allow eukaryotes to transcend surface-to-volume constraints also can allocate energy into their own selfish replication. This principal conflict in the origin of eukaryotes can be mediated by genetic or energetic mechanisms. Genome transfer diminishes the heritable variation of the symbiont, but requires the de novo evolution of the protein-import apparatus and was opposed by selection for selfish symbionts. By contrast, metabolic signalling is a shared primitive feature of all cells. Redox state of the cytosol is an emergent feature that cannot be subverted by an individual symbiont. Hypothetical scenarios illustrate how metabolic regulation may have mediated the conflicts inherent at different stages in the origin of eukaryotes. Aspects of metabolic regulation may have subsequently been coopted from within-cell to between-cell pathways, allowing multicellularity to emerge repeatedly.}, } @article {pmid23754807, year = {2013}, author = {Lane, N and Martin, WF and Raven, JA and Allen, JF}, title = {Energy, genes and evolution: introduction to an evolutionary synthesis.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {368}, number = {1622}, pages = {20120253}, pmid = {23754807}, issn = {1471-2970}, mesh = {Animals ; *Biological Evolution ; Energy Metabolism/*genetics/*physiology ; Gene Expression Regulation/*physiology ; Genome ; }, abstract = {Life is the harnessing of chemical energy in such a way that the energy-harnessing device makes a copy of itself. No energy, no evolution. The 'modern synthesis' of the past century explained evolution in terms of genes, but this is only part of the story. While the mechanisms of natural selection are correct, and increasingly well understood, they do little to explain the actual trajectories taken by life on Earth. From a cosmic perspective-what is the probability of life elsewhere in the Universe, and what are its probable traits?-a gene-based view of evolution says almost nothing. Irresistible geological and environmental changes affected eukaryotes and prokaryotes in very different ways, ones that do not relate to specific genes or niches. Questions such as the early emergence of life, the morphological and genomic constraints on prokaryotes, the singular origin of eukaryotes, and the unique and perplexing traits shared by all eukaryotes but not found in any prokaryote, are instead illuminated by bioenergetics. If nothing in biology makes sense except in the light of evolution, nothing in evolution makes sense except in the light of energetics. This Special Issue of Philosophical Transactions examines the interplay between energy transduction and genome function in the major transitions of evolution, with implications ranging from planetary habitability to human health. We hope that these papers will contribute to a new evolutionary synthesis of energetics and genetics.}, } @article {pmid23615204, year = {2013}, author = {Seufferheld, MJ and Caetano-Anollés, G}, title = {Phylogenomics supports a cellularly structured urancestor.}, journal = {Journal of molecular microbiology and biotechnology}, volume = {23}, number = {1-2}, pages = {178-191}, doi = {10.1159/000346552}, pmid = {23615204}, issn = {1660-2412}, support = {AI079478-02/AI/NIAID NIH HHS/United States ; }, mesh = {Archaea/cytology/genetics/metabolism ; Bacteria/cytology/genetics/metabolism ; *Biological Evolution ; *Cell Compartmentation ; Cell Membrane ; *Energy Metabolism ; Eukaryota/cytology/genetics/metabolism ; *Evolution, Molecular ; Genomics ; Organelles/metabolism/ultrastructure ; *Origin of Life ; Phylogeny ; }, abstract = {Cells and viruses are structured and harbor complex organization. This manifests in intra- and extracellular compartments such as reticuli and periplasmic spaces, storage and energy-harvesting organelles such as acidocalcisomes and mitochondria, and specialized structures that hold genomic repositories such as nuclei and capsids. Structural phylogenomic reconstruction of the protein repertoire of the common ancestor of life, the urancestor, suggests these entities that existed 2.9 billion years ago were not only complex from a structural and functional point of view, but were also cellularly structured. We also provide support to the existence of urancestral storage organelles that were analogous to acidocalcisomes. These cellular structures probably accumulated compounds that stored energy in their phosphoanhydride bonds, such as polyphosphates. These energy-rich compounds necessary for thioester and pyrophosphate intermediates would have channeled the abundant redox energy of early Earth to the early metabolic needs of the primordial cells. Our findings are compatible with a relatively complex urancestral cell and with abundant microfossil evidence supporting the existence of primordial microbial communities as far back as 3.4 billion years ago. Results highlight the centrality of the cellular compartment and bioenergetics in the early evolutionary stages of life.}, } @article {pmid23600852, year = {2013}, author = {Suraniti, E and Vajrala, VS and Goudeau, B and Bottari, SP and Rigoulet, M and Devin, A and Sojic, N and Arbault, S}, title = {Monitoring metabolic responses of single mitochondria within poly(dimethylsiloxane) wells: study of their endogenous reduced nicotinamide adenine dinucleotide evolution.}, journal = {Analytical chemistry}, volume = {85}, number = {10}, pages = {5146-5152}, doi = {10.1021/ac400494e}, pmid = {23600852}, issn = {1520-6882}, mesh = {Dimethylpolysiloxanes/*chemistry ; Microarray Analysis/*methods ; Mitochondria/*metabolism ; NAD/*metabolism ; Saccharomyces cerevisiae/cytology ; Spectrometry, Fluorescence ; }, abstract = {It is now demonstrated that mitochondria individually function differently because of specific energetic needs in cell compartments but also because of the genetic heterogeneity within the mitochondrial pool-network of a cell. Consequently, understanding mitochondrial functioning at the single organelle level is of high interest for biomedical research, therefore being a target for analyticians. In this context, we developed easy-to-build platforms of milli- to microwells for fluorescence microscopy of single isolated mitochondria. Poly(dimethylsiloxane) (PDMS) was determined to be an excellent material for mitochondrial deposition and observation of their NADH content. Because of NADH autofluorescence, the metabolic status of each mitochondrion was analyzed following addition of a respiratory substrate (stage 2), ethanol herein, and a respiratory inhibitor (stage 3), Antimycin A. Mean levels of mitochondrial NADH were increased by 32% and 62% under stages 2 and 3, respectively. Statistical studies of NADH value distributions evidenced different types of responses, at least three, to ethanol and Antimycin A within the mitochondrial population. In addition, we showed that mitochondrial ability to generate high levels of NADH, that is its metabolic performance, is not correlated either to the initial energetic state or to the respective size of each mitochondrion.}, } @article {pmid23538482, year = {2013}, author = {Elrod, JW and Molkentin, JD}, title = {Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore.}, journal = {Circulation journal : official journal of the Japanese Circulation Society}, volume = {77}, number = {5}, pages = {1111-1122}, pmid = {23538482}, issn = {1347-4820}, support = {/HHMI_/Howard Hughes Medical Institute/United States ; F32 HL092737/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis ; Cyclophilin D ; Cyclophilins/genetics/*metabolism ; Energy Metabolism ; Humans ; Mitochondria, Heart/*metabolism/pathology ; Mitochondrial Membrane Transport Proteins/*metabolism ; Mitochondrial Membranes/*metabolism/pathology ; Mitochondrial Permeability Transition Pore ; Myocardial Reperfusion Injury/metabolism/mortality ; Myocytes, Cardiac/*metabolism/pathology ; Necrosis ; Phylogeny ; Protein Processing, Post-Translational ; }, abstract = {This review focuses on the role of cyclophilin D (CypD) as a prominent mediator of the mitochondrial permeability transition pore (MPTP) and subsequent effects on cardiovascular physiology and pathology. Although a great number of reviews have been written on the MPTP and its effects on cell death, we focus on the biology surrounding CypD itself and the non-cell death physiologic functions of the MPTP. A greater understanding of the physiologic functions of the MPTP and its regulation by CypD will likely suggest novel therapeutic approaches for cardiovascular disease, both dependent and independent of programmed necrotic cell death mechanisms.}, } @article {pmid23520284, year = {2013}, author = {Perry, CG and Kane, DA and Lanza, IR and Neufer, PD}, title = {Methods for assessing mitochondrial function in diabetes.}, journal = {Diabetes}, volume = {62}, number = {4}, pages = {1041-1053}, pmid = {23520284}, issn = {1939-327X}, support = {R01-DK074825/DK/NIDDK NIH HHS/United States ; R01 DK074825/DK/NIDDK NIH HHS/United States ; R01 DK096907/DK/NIDDK NIH HHS/United States ; KL2 TR000136/TR/NCATS NIH HHS/United States ; R01-DK096907/DK/NIDDK NIH HHS/United States ; }, mesh = {Diabetes Mellitus/etiology/*metabolism ; Energy Metabolism ; Humans ; Mitochondria/*metabolism ; Oxygen Consumption ; }, abstract = {A growing body of research is investigating the potential contribution of mitochondrial function to the etiology of type 2 diabetes. Numerous in vitro, in situ, and in vivo methodologies are available to examine various aspects of mitochondrial function, each requiring an understanding of their principles, advantages, and limitations. This review provides investigators with a critical overview of the strengths, limitations and critical experimental parameters to consider when selecting and conducting studies on mitochondrial function. In vitro (isolated mitochondria) and in situ (permeabilized cells/tissue) approaches provide direct access to the mitochondria, allowing for study of mitochondrial bioenergetics and redox function under defined substrate conditions. Several experimental parameters must be tightly controlled, including assay media, temperature, oxygen concentration, and in the case of permeabilized skeletal muscle, the contractile state of the fibers. Recently developed technology now offers the opportunity to measure oxygen consumption in intact cultured cells. Magnetic resonance spectroscopy provides the most direct way of assessing mitochondrial function in vivo with interpretations based on specific modeling approaches. The continuing rapid evolution of these technologies offers new and exciting opportunities for deciphering the potential role of mitochondrial function in the etiology and treatment of diabetes.}, } @article {pmid23426914, year = {2013}, author = {Kasumovic, MM and Seebacher, F}, title = {The active metabolic rate predicts a male spider's proximity to females and expected fitness.}, journal = {Biology letters}, volume = {9}, number = {2}, pages = {20121164}, pmid = {23426914}, issn = {1744-957X}, mesh = {Animals ; Australia ; Basal Metabolism ; Behavior, Animal/*physiology ; Biological Evolution ; Body Size ; Citrate (si)-Synthase/*metabolism ; Energy Metabolism/*physiology ; Enzyme Activation ; Female ; *Genetic Fitness ; L-Lactate Dehydrogenase/metabolism ; Male ; Mitochondria/enzymology/physiology ; Oxygen Consumption ; Species Specificity ; Spiders/*metabolism/physiology ; }, abstract = {Conspicuous traits, such as weaponry and body size, are often correlated with fitness. By contrast, we understand less about how inconspicuous physiological traits affect fitness. Not only is linking physiology directly to fitness a challenge, but in addition, behavioural studies most often focus on resting or basal metabolic rates, resulting in a poor understanding of how active metabolic rates affect fitness. Here we use the golden orb-web spider (Nephila plumipes), a species for which proximity to a female on the web predicts a male's paternity share, to examine the role of resting and active metabolic rates in fitness. Using a semi-natural experimental set-up, we show that males closer to a female have higher active metabolic rates than males further from females. This higher metabolic activity is paralleled by increased citrate synthase activity, suggesting greater mitochondrial densities. Our results link both higher active metabolic rates and increased citrate synthase activity with fitness. Coupled with the behaviour and life history of N. plumipes, these results provide insight into the evolution of physiological systems.}, } @article {pmid23409181, year = {2013}, author = {Tahara, EB and Cunha, FM and Basso, TO and Della Bianca, BE and Gombert, AK and Kowaltowski, AJ}, title = {Calorie restriction hysteretically primes aging Saccharomyces cerevisiae toward more effective oxidative metabolism.}, journal = {PloS one}, volume = {8}, number = {2}, pages = {e56388}, pmid = {23409181}, issn = {1932-6203}, mesh = {Biomass ; Caloric Restriction ; Cell Respiration ; Cell Survival ; Culture Media/chemistry ; Energy Metabolism ; Glucose/metabolism ; Hydrogen-Ion Concentration ; Mitochondria/metabolism ; Oxidation-Reduction ; Oxygen/metabolism ; Saccharomyces cerevisiae/cytology/*metabolism ; Time Factors ; }, abstract = {Calorie restriction (CR) is an intervention known to extend the lifespan of a wide variety of organisms. In S. cerevisiae, chronological lifespan is prolonged by decreasing glucose availability in the culture media, a model for CR. The mechanism has been proposed to involve an increase in the oxidative (versus fermentative) metabolism of glucose. Here, we measured wild-type and respiratory incompetent (ρ(0)) S. cerevisiae biomass formation, pH, oxygen and glucose consumption, and the evolution of ethanol, glycerol, acetate, pyruvate and succinate levels during the course of 28 days of chronological aging, aiming to identify metabolic changes responsible for the effects of CR. The concomitant and quantitative measurements allowed for calculations of conversion factors between different pairs of substrates and products, maximum specific substrate consumption and product formation rates and maximum specific growth rates. Interestingly, we found that the limitation of glucose availability in CR S. cerevisiae cultures hysteretically increases oxygen consumption rates many hours after the complete exhaustion of glucose from the media. Surprisingly, glucose-to-ethanol conversion and cellular growth supported by glucose were not quantitatively altered by CR. Instead, we found that CR primed the cells for earlier, faster and more efficient metabolism of respiratory substrates, especially ethanol. Since lifespan-enhancing effects of CR are absent in respiratory incompetent ρ(0) cells, we propose that the hysteretic effect of glucose limitation on oxidative metabolism is central toward chronological lifespan extension by CR in this yeast.}, } @article {pmid23360288, year = {2013}, author = {Loureiro, R and Mesquita, KA and Oliveira, PJ and Vega-Naredo, I}, title = {Mitochondria in cancer stem cells: a target for therapy.}, journal = {Recent patents on endocrine, metabolic & immune drug discovery}, volume = {7}, number = {2}, pages = {102-114}, doi = {10.2174/18722148113079990006}, pmid = {23360288}, issn = {2212-3334}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Drug Design ; Energy Metabolism/drug effects ; Humans ; Mitochondria/*drug effects/metabolism/pathology ; Mitochondrial Membrane Transport Proteins/drug effects/metabolism ; Mitochondrial Permeability Transition Pore ; Neoplasms/*drug therapy/metabolism/pathology ; Neoplastic Stem Cells/*drug effects/metabolism/pathology ; Oxidation-Reduction ; Patents as Topic ; }, abstract = {Complete knowledge about the evolution of the carcinogenic process has to include cancer stem cells (CSCs), which are essential to understand tumor occurrence, recurrence, and also its reduction rate after radio- and/or chemotherapeutic treatments. Understanding CSCs physiology and metabolism may be crucial for the development of novel effective therapies. Therefore, being mitochondria an undeniable target for cancer therapy and a central hub in metabolism and cell and death decisions, it is essential to take this organelle into account and explore its actions and involvements in the context of CSCs physiology. In this review, we focus on recent patents and discoveries about mitochondrial bioenergetics and physiology of CSCs. A full understanding of the role of mitochondrial activity in CSCs and the creation of new strategies, methods and discoveries to support actual treatments with novel ones are of pivotal importance in order to ultimately eradicate cancer.}, } @article {pmid23282997, year = {2013}, author = {Rowe, M and Laskemoen, T and Johnsen, A and Lifjeld, JT}, title = {Evolution of sperm structure and energetics in passerine birds.}, journal = {Proceedings. Biological sciences}, volume = {280}, number = {1753}, pages = {20122616}, pmid = {23282997}, issn = {1471-2954}, mesh = {Adenosine Triphosphate/*metabolism ; Animals ; Bayes Theorem ; *Biological Evolution ; Luminescent Measurements ; Male ; Mitochondria/*metabolism ; Models, Biological ; Norway ; Songbirds/genetics/*physiology ; Species Specificity ; Sperm Motility ; Spermatozoa/*cytology/*physiology ; }, abstract = {Spermatozoa exhibit considerable interspecific variability in size and shape. Our understanding of the adaptive significance of this diversity, however, remains limited. Determining how variation in sperm structure translates into variation in sperm performance will contribute to our understanding of the evolutionary diversification of sperm form. Here, using data from passerine birds, we test the hypothesis that longer sperm swim faster because they have more available energy. We found that sperm with longer midpieces have higher levels of intracellular adenosine triphosphate (ATP), but that greater energy reserves do not translate into faster-swimming sperm. Additionally, we found that interspecific variation in sperm ATP concentration is not associated with the level of sperm competition faced by males. Finally, using Bayesian methods, we compared the evolutionary trajectories of sperm morphology and ATP content, and show that both traits have undergone directional evolutionary change. However, in contrast to recent suggestions in other taxa, we show that changes in ATP are unlikely to have preceded changes in morphology in passerine sperm. These results suggest that variable selective pressures are likely to have driven the evolution of sperm traits in different taxa, and highlight fundamental biological differences between taxa with internal and external fertilization, as well as those with and without sperm storage.}, } @article {pmid23266975, year = {2012}, author = {Chen, X and Shen, YY and Zhang, YP}, title = {[Review of mtDNA in molecular evolution studies].}, journal = {Dong wu xue yan jiu = Zoological research}, volume = {33}, number = {6}, pages = {566-573}, doi = {10.3724/SP.J.1141.2012.06566}, pmid = {23266975}, issn = {0254-5853}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; DNA, Mitochondrial/*genetics/metabolism ; *Evolution, Molecular ; Genome, Mitochondrial ; Humans ; Mitochondria/*genetics/metabolism ; }, abstract = {Mitochondria are old organelles found in most eukaryotic cells. Due to its rapid mutation ratio, mitochondrial DNA (mtDNA) has been widely used as a DNA marker in molecular studies and has long been suggested to undergo neutral evolution or purifying selection. Mitochondria produces 95% of the adenosine triphosphate (ATP) needed for locomotion, and heat for thermoregulation. Recent studies had found that mitochondria play critical roles in energy metabolism, and proved that functional constraints acting on mitochondria, due to energy metabolism and/or thermoregulation, influence the evolution of mtDNA. This review summarizes mitochondrial genome composition, evolution, and its applications in molecular evolution studies (reconstruction of species phylogenesis, the relationship between biological energy metabolism and mtDNA evolution, and the mtDNA codon reassignment influences the adaptation in different creatures).}, } @article {pmid23171165, year = {2012}, author = {Wylezich, C and Karpov, SA and Mylnikov, AP and Anderson, R and Jürgens, K}, title = {Ecologically relevant choanoflagellates collected from hypoxic water masses of the Baltic Sea have untypical mitochondrial cristae.}, journal = {BMC microbiology}, volume = {12}, number = {}, pages = {271}, pmid = {23171165}, issn = {1471-2180}, mesh = {Anaerobiosis ; Choanoflagellata/*classification/isolation & purification/physiology/*ultrastructure ; Cluster Analysis ; DNA, Protozoan/chemistry/genetics ; DNA, Ribosomal/chemistry/genetics ; Genes, rRNA ; Microscopy ; Mitochondria/*ultrastructure ; Molecular Sequence Data ; Phylogeny ; RNA, Protozoan/genetics ; RNA, Ribosomal, 18S/genetics ; RNA, Ribosomal, 28S/genetics ; Seawater/*parasitology ; Sequence Analysis, DNA ; }, abstract = {BACKGROUND: Protist communities inhabiting oxygen depleted waters have so far been characterized through both microscopical observations and sequence based techniques. However, the lack of cultures for abundant taxa severely hampers our knowledge on the morphology, ecology and energy metabolism of hypoxic protists. Cultivation of such protists has been unsuccessful in most cases, and has never yet succeeded for choanoflagellates, even though these small bacterivorous flagellates are known to be ecologically relevant components of aquatic protist communities.

RESULTS: Quantitative data for choanoflagellates and the vertical distribution of Codosiga spp. at Gotland and Landsort Deep (Baltic Sea) indicate its preference for oxygen-depleted zones. Strains isolated and cultivated from these habitats revealed ultrastructural peculiarities such as mitochondria showing tubular cristae never seen before for choanoflagellates, and the first observation of intracellular prokaryotes in choanoflagellates. Analysis of their partial 28S rRNA gene sequence complements the description of two new species, Codosiga minima n. sp. and C. balthica n. sp. These are closely related with but well separated from C. gracilis (C. balthica and C. minima p-distance to C. gracilis 4.8% and 11.6%, respectively). In phylogenetic analyses the 18S rRNA gene sequences branch off together with environmental sequences from hypoxic habitats resulting in a wide cluster of hypoxic Codosiga relatives so far only known from environmental sequencing approaches.

CONCLUSIONS: Here, we establish the morphological and ultrastructural identity of an environmental choanoflagellate lineage. Data from microscopical observations, supplemented by findings from previous culture-independent methods, indicate that C. balthica is likely an ecologically relevant player of Baltic Sea hypoxic waters. The possession of derived mitochondria could be an adaptation to life in hypoxic environments periodically influenced by small-scale mixing events and changing oxygen content allowing the reduction of oxygen consuming components. In view of the intricacy of isolating and cultivating choanoflagellates, the two new cultured species represent an important advance to the understanding of the ecology of this group, and mechanisms of adaptations to hypoxia in protists in general.}, } @article {pmid23133373, year = {2012}, author = {Heinz, E and Williams, TA and Nakjang, S and Noël, CJ and Swan, DC and Goldberg, AV and Harris, SR and Weinmaier, T and Markert, S and Becher, D and Bernhardt, J and Dagan, T and Hacker, C and Lucocq, JM and Schweder, T and Rattei, T and Hall, N and Hirt, RP and Embley, TM}, title = {The genome of the obligate intracellular parasite Trachipleistophora hominis: new insights into microsporidian genome dynamics and reductive evolution.}, journal = {PLoS pathogens}, volume = {8}, number = {10}, pages = {e1002979}, pmid = {23133373}, issn = {1553-7374}, support = {/WT_/Wellcome Trust/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Acquired Immunodeficiency Syndrome/microbiology ; Biological Evolution ; Energy Metabolism/*genetics ; Evolution, Molecular ; *Genome, Fungal ; Humans ; Microsporidia/*genetics/isolation & purification ; Mitochondria ; Phylogeny ; Proteome/*genetics ; Proteomics ; RNA Interference ; RNA, Small Interfering ; Sequence Analysis, DNA ; }, abstract = {The dynamics of reductive genome evolution for eukaryotes living inside other eukaryotic cells are poorly understood compared to well-studied model systems involving obligate intracellular bacteria. Here we present 8.5 Mb of sequence from the genome of the microsporidian Trachipleistophora hominis, isolated from an HIV/AIDS patient, which is an outgroup to the smaller compacted-genome species that primarily inform ideas of evolutionary mode for these enormously successful obligate intracellular parasites. Our data provide detailed information on the gene content, genome architecture and intergenic regions of a larger microsporidian genome, while comparative analyses allowed us to infer genomic features and metabolism of the common ancestor of the species investigated. Gene length reduction and massive loss of metabolic capacity in the common ancestor was accompanied by the evolution of novel microsporidian-specific protein families, whose conservation among microsporidians, against a background of reductive evolution, suggests they may have important functions in their parasitic lifestyle. The ancestor had already lost many metabolic pathways but retained glycolysis and the pentose phosphate pathway to provide cytosolic ATP and reduced coenzymes, and it had a minimal mitochondrion (mitosome) making Fe-S clusters but not ATP. It possessed bacterial-like nucleotide transport proteins as a key innovation for stealing host-generated ATP, the machinery for RNAi, key elements of the early secretory pathway, canonical eukaryotic as well as microsporidian-specific regulatory elements, a diversity of repetitive and transposable elements, and relatively low average gene density. Microsporidian genome evolution thus appears to have proceeded in at least two major steps: an ancestral remodelling of the proteome upon transition to intracellular parasitism that involved reduction but also selective expansion, followed by a secondary compaction of genome architecture in some, but not all, lineages.}, } @article {pmid24850385, year = {2014}, author = {Hardie, DG}, title = {AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels.}, journal = {Annual review of nutrition}, volume = {34}, number = {}, pages = {31-55}, pmid = {24850385}, issn = {1545-4312}, support = {//Wellcome Trust/United Kingdom ; 097726//Wellcome Trust/United Kingdom ; /CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; *Energy Intake ; *Energy Metabolism ; *Homeostasis ; Humans ; *Models, Biological ; *Signal Transduction ; }, abstract = {The adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway arose early during evolution of eukaryotic cells, when it appears to have been involved in the response to glucose starvation and perhaps also in monitoring the output of the newly acquired mitochondria. Due to the advent of hormonal regulation of glucose homeostasis, glucose starvation is a less frequent event for mammalian cells than for single-celled eukaryotes. Nevertheless, the AMPK system has been preserved in mammals where, by monitoring cellular AMP:adenosine triphosphate (ATP) and adenosine diphosphate (ADP):ATP ratios and balancing the rates of catabolism and ATP consumption, it maintains energy homeostasis at a cell-autonomous level. In addition, hormones involved in maintaining energy balance at the whole-body level interact with AMPK in the hypothalamus. AMPK is activated by two widely used clinical drugs, metformin and aspirin, and also by many natural products of plants that are either derived from traditional medicines or are promoted as "nutraceuticals."}, } @article {pmid22827366, year = {2012}, author = {Mukai, C and Travis, AJ}, title = {What sperm can teach us about energy production.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {47 Suppl 4}, number = {0 4}, pages = {164-169}, pmid = {22827366}, issn = {1439-0531}, support = {DP1 EB016541/EB/NIBIB NIH HHS/United States ; DP1 OD006431/OD/NIH HHS/United States ; 5DP1-OD-006431/OD/NIH HHS/United States ; }, mesh = {Animals ; Energy Metabolism/*physiology ; Male ; Mammals/*physiology ; Species Specificity ; Sperm Motility ; Spermatozoa/*physiology ; }, abstract = {Mammalian sperm have evolved under strict selection pressures that have resulted in a highly polarized and efficient design. A critical component of that design is the compartmentalization of specific metabolic pathways to specific regions of the cell. Although the restricted localization of mitochondria to the midpiece is the best known example of this design, the organization of the enzymes of glycolysis along the fibrous sheath is the primary focus of this review. Evolution of variants of these metabolic enzymes has allowed them to function when tethered, enabling localized energy production that is essential for sperm motility. We close by exploring how this design might be mimicked to provide an energy-producing platform technology for applications in nanobiotechnology.}, } @article {pmid22830417, year = {2012}, author = {Evans, ML and Bernatchez, L}, title = {Oxidative phosphorylation gene transcription in whitefish species pairs reveals patterns of parallel and nonparallel physiological divergence.}, journal = {Journal of evolutionary biology}, volume = {25}, number = {9}, pages = {1823-1834}, doi = {10.1111/j.1420-9101.2012.02570.x}, pmid = {22830417}, issn = {1420-9101}, mesh = {Adaptation, Biological ; Adenosine Triphosphate/genetics/metabolism ; Animals ; Base Sequence ; Cell Nucleus/genetics ; DNA, Mitochondrial/genetics ; Ecosystem ; Gene Expression Profiling/methods ; Gene Expression Regulation ; Genes, Mitochondrial ; Genetic Speciation ; Genetics, Population/methods ; Lakes ; Maine ; Mitochondria/genetics ; *Oxidative Phosphorylation ; Salmonidae/*genetics/metabolism/*physiology ; Species Specificity ; Statistics, Nonparametric ; Sympatry ; *Transcription, Genetic ; Up-Regulation ; }, abstract = {Across multiple lakes in North America, lake whitefish (Coregonus clupeaformis) have independently evolved 'dwarf' and 'normal' sympatric species pairs that exhibit pronounced phenotypic and genetic divergence. In particular, traits associated with metabolism have been shown to be highly differentiated between whitefish species. Here, we examine the transcription of genes associated with the five mitochondrial and nuclear genome-encoded oxidative phosphorylation (OXPHOS) complexes, the primary physiological mechanism responsible for the production of ATP, in whitefish species pairs from Cliff Lake and Webster Lake in Maine, USA. We observed OXPHOS gene transcription divergence between dwarf and normal whitefish in each of the two lakes, with the former exhibiting transcription upregulation for genes associated with each of the OXPHOS complexes. We also observed a significant influence of lake on transcription levels for some of the genes, indicating that inter-lake ecological or genetic differences are contributing to variation in OXPHOS gene transcription levels. Together, our results support the hypothesis that metabolic divergence is a critical adaptation involved in whitefish speciation and implicate OXPHOS gene upregulation as a factor involved in meeting the enhanced energetic demands of dwarf whitefish. Further studies are now needed to evaluate the contribution of genetically vs. plasticity driven variation in transcription associated with this critical physiological pathway.}, } @article {pmid22820118, year = {2012}, author = {Peng, Q and Tang, L and Tan, S and Li, Z and Wang, J and Zou, F}, title = {Mitogenomic analysis of the genus Pseudois: evidence of adaptive evolution of morphological variation in the ATP synthase genes.}, journal = {Mitochondrion}, volume = {12}, number = {5}, pages = {500-505}, doi = {10.1016/j.mito.2012.07.107}, pmid = {22820118}, issn = {1872-8278}, mesh = {Amino Acid Substitution ; Animals ; Asia, Central ; Cluster Analysis ; *Evolution, Molecular ; Mitochondrial Proton-Translocating ATPases/*genetics ; Molecular Sequence Data ; Mutation Rate ; Phylogeography ; Ruminants/*genetics ; Selection, Genetic ; Sequence Analysis, DNA ; }, abstract = {The genus Pseudois includes two variable taxa, blue sheep (Pseudois nayaur) and dwarf blue sheep (Pseudois schaeferi), that exhibit notable geographic variation in morphology and ecological niche, suggesting the potential for significant adaptive differentiation between these two goats. Blue sheep are broadly distributed in the Tibetan Plateau and peripheral mountains through Central Asia, while dwarf blue sheep are only found in the gorges of the upper Yangtze River (Jinsha River) near Batang county, Sichuan province and adjacent mountains. Although they are all adapted to high altitude environments, endangered dwarf blue sheep show unique morphological variation and niche shifts compared to blue sheep. Mitochondria play important roles in oxygen usage and energy metabolism. The energetically demanding lifestyles of these high altitude species may have altered the selective regimes on mitochondrial genes encoding proteins related to cellular respiration. Here, we compared the sequences of 13 protein-coding genes in the mitochondrial genome of dwarf blue sheep with those of blue sheep to understand the genetic basis of morphological variation. Using neighbor-joining, maximum-likelihood and Bayesian approaches, we estimated rates of synonymous (d(S)) and nonsynonymous (d(N)) substitutions. Independent analyses showed that no ω ratio was larger than 1, suggesting that all mitochondrial 13 genes were under the purifying selection. Surprisingly, we found that the ω ratio (d(N)/d(S)) of the ATP synthase complex (ATP6 and ATP8) in blue sheep is sixteen times that of dwarf blue sheep (0.340 compared to 0.021). This result was confirmed by a separate analysis of ATP synthase genes from two additional P. schaeferi individuals and two P. nayaur individuals. We hypothesize that the large body size and diverse feeding styles are factors influencing the nonsynonymous substitutions in the ATP synthase complex of blue sheep.}, } @article {pmid22804568, year = {2013}, author = {Winslow, RM}, title = {Oxygen: the poison is in the dose.}, journal = {Transfusion}, volume = {53}, number = {2}, pages = {424-437}, doi = {10.1111/j.1537-2995.2012.03774.x}, pmid = {22804568}, issn = {1537-2995}, mesh = {Animals ; Biological Evolution ; Cell Respiration/physiology ; Dose-Response Relationship, Drug ; Energy Metabolism/physiology ; Hemoglobins/adverse effects ; Humans ; Microcirculation/physiology ; Mitochondria/metabolism/physiology ; Oxygen/administration & dosage/metabolism/*poisoning/therapeutic use ; Oxygen Consumption/physiology ; }, abstract = {Cell-free hemoglobin (Hb) has been blamed for a spectrum of problems, including vasoconstriction pancreatitis, myocardial infarction, and pulmonary hypertension in hemolytic anemia, malaria, and sickle cell anemia, and from Hb-based oxygen carriers (HBOCs). Toxicities have been attributed to scavenging of nitric oxide (NO). However, while NO scavenging may explain many in vitro effects, and some effects in animal models and clinical trials with HBOCs, key inconsistencies in the theory require alternative explanations. This review considers the hypothesis that cell-free Hb oversupplies oxygen to tissues, leading to oxygen-related toxicity, possibly through formation of reactive oxygen species and local destruction of NO. Evidence for this hypothesis comes from various sources, establishing that tissue oxygen levels are maintained over very narrow (and low) levels, even at high oxygen consumption. Tissue is normally protected from excessive oxygen by its extremely low solubility in plasma, but introduction of cell-free Hb, even at low concentration, greatly augments oxygen supply, engaging protective mechanisms that include vasoconstriction and ischemia. The requirement to limit oxygen supply by cell-free Hb suggests novel ways to modify it to overcome vasoconstriction, independent of the intrinsic reaction of Hb with NO. This control is essential to the design of a safe and effective cell-free HBOC.}, } @article {pmid22776908, year = {2013}, author = {Hillman, SS and Hancock, TV and Hedrick, MS}, title = {A comparative meta-analysis of maximal aerobic metabolism of vertebrates: implications for respiratory and cardiovascular limits to gas exchange.}, journal = {Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology}, volume = {183}, number = {2}, pages = {167-179}, pmid = {22776908}, issn = {1432-136X}, mesh = {Animals ; *Biological Evolution ; Carbon Dioxide/*metabolism ; Energy Metabolism/*physiology ; *Models, Biological ; Oxygen/*metabolism ; Pulmonary Gas Exchange/*physiology ; Species Specificity ; Vertebrates/*metabolism ; }, abstract = {Maximal aerobic metabolic rates (MMR) in vertebrates are supported by increased conductive and diffusive fluxes of O(2) from the environment to the mitochondria necessitating concomitant increases in CO(2) efflux. A question that has received much attention has been which step, respiratory or cardiovascular, provides the principal rate limitation to gas flux at MMR? Limitation analyses have principally focused on O(2) fluxes, though the excess capacity of the lung for O(2) ventilation and diffusion remains unexplained except as a safety factor. Analyses of MMR normally rely upon allometry and temperature to define these factors, but cannot account for much of the variation and often have narrow phylogenetic breadth. The unique aspect of our comparative approach was to use an interclass meta-analysis to examine cardio-respiratory variables during the increase from resting metabolic rate to MMR among vertebrates from fish to mammals, independent of allometry and phylogeny. Common patterns at MMR indicate universal principles governing O(2) and CO(2) transport in vertebrate cardiovascular and respiratory systems, despite the varied modes of activities (swimming, running, flying), different cardio-respiratory architecture, and vastly different rates of metabolism (endothermy vs. ectothermy). Our meta-analysis supports previous studies indicating a cardiovascular limit to maximal O(2) transport and also implicates a respiratory system limit to maximal CO(2) efflux, especially in ectotherms. Thus, natural selection would operate on the respiratory system to enhance maximal CO(2) excretion and the cardiovascular system to enhance maximal O(2) uptake. This provides a possible evolutionary explanation for the conundrum of why the respiratory system appears functionally over-designed from an O(2) perspective, a unique insight from previous work focused solely on O(2) fluxes. The results suggest a common gas transport blueprint, or Bauplan, in the vertebrate clade.}, } @article {pmid22771735, year = {2012}, author = {Vianello, A and Casolo, V and Petrussa, E and Peresson, C and Patui, S and Bertolini, A and Passamonti, S and Braidot, E and Zancani, M}, title = {The mitochondrial permeability transition pore (PTP) - an example of multiple molecular exaptation?.}, journal = {Biochimica et biophysica acta}, volume = {1817}, number = {11}, pages = {2072-2086}, doi = {10.1016/j.bbabio.2012.06.620}, pmid = {22771735}, issn = {0006-3002}, mesh = {Animals ; Calcium/metabolism ; Evolution, Molecular ; Humans ; Mitochondrial Membrane Transport Proteins/genetics/*physiology ; Mitochondrial Permeability Transition Pore ; Phylogeny ; Potassium Channels/physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {The mitochondrial permeability transition (PT) is a well-recognized phenomenon that allows mitochondria to undergo a sudden increase of permeability to solutes with molecular mass ≤ 1500Da, leading to organelle swelling and structural modifications. The relevance of PT relies on its master role in the manifestation of programmed cell death (PCD). This function is performed by a mega-channel (in some cases inhibited by cyclosporin A) named permeability transition pore (PTP), whose function could derive from the assembly of different mitochondrial proteins. In this paper we examine the distribution and characteristics of PTP in mitochondria of eukaryotic organisms so far investigated in order to draw a hypothesis on the mechanism of its evolution. As a result, we suggest that PTP may have arisen as a new function linked to a multiple molecular exaptation of different mitochondrial proteins, even though they could nevertheless still play their original role. Furthermore, we suggest that the early appearance of PTP could have had a crucial role in the establishment of endosymbiosis in eukaryotic cells, by the coordinated balancing of ATP production by glycolysis (performed by the primary phagocyte) and oxidative phosphorylation (accomplished by the endosymbiont). Indeed, we argue on the possibility that this new energetic equilibrium could have opened the way to the subsequent evolution toward metazoans.}, } @article {pmid22729859, year = {2012}, author = {Pierron, D and Wildman, DE and Hüttemann, M and Letellier, T and Grossman, LI}, title = {Evolution of the couple cytochrome c and cytochrome c oxidase in primates.}, journal = {Advances in experimental medicine and biology}, volume = {748}, number = {}, pages = {185-213}, pmid = {22729859}, issn = {0065-2598}, support = {R01 GM089900/GM/NIGMS NIH HHS/United States ; R24 GM065580/GM/NIGMS NIH HHS/United States ; GM089900/GM/NIGMS NIH HHS/United States ; GM65580/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Brain/metabolism ; Cytochromes c/*physiology ; Electron Transport Complex IV/*physiology ; *Evolution, Molecular ; Humans ; Mutation ; Primates/*metabolism ; Protein Subunits ; Selection, Genetic ; }, abstract = {Mitochondrial energy metabolism has been affected by a broad set of ancient and recent evolutionary events. The oldest example is the endosymbiosis theory that led to mitochondria and a recently proposed example is adaptation to cold climate by anatomically modern human lineages. Mitochondrial energy metabolism has also been associated with an important area in anthropology and evolutionary biology, brain enlargement in human evolution. Indeed, several studies have pointed to the need for a major metabolic rearrangement to supply a sufficient amount of energy for brain development in primates.The genes encoding for the coupled cytochrome c (Cyt c) and cytochrome c oxidase (COX, complex IV, EC 1.9.3.1) seem to have an exceptional pattern of evolution in the anthropoid lineage. It has been proposed that this evolution was linked to the rearrangement of energy metabolism needed for brain enlargement. This hypothesis is reinforced by the fact that the COX enzyme was proposed to have a large role in control of the respiratory chain and thereby global energy production.After summarizing major events that occurred during the evolution of COX and cytochrome c on the primate lineage, we review the different evolutionary forces that could have influenced primate COX evolution and discuss the probable causes and consequences of this evolution. Finally, we discuss and review the co-occurring primate phenotypic evolution.}, } @article {pmid22688819, year = {2012}, author = {Müller, M and Mentel, M and van Hellemond, JJ and Henze, K and Woehle, C and Gould, SB and Yu, RY and van der Giezen, M and Tielens, AG and Martin, WF}, title = {Biochemistry and evolution of anaerobic energy metabolism in eukaryotes.}, journal = {Microbiology and molecular biology reviews : MMBR}, volume = {76}, number = {2}, pages = {444-495}, pmid = {22688819}, issn = {1098-5557}, support = {232975/ERC_/European Research Council/International ; R01 AI011942/AI/NIAID NIH HHS/United States ; AI 11942/AI/NIAID NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Anaerobiosis/physiology ; *Energy Metabolism ; Eukaryota/*metabolism ; *Evolution, Molecular ; Mitochondria/metabolism ; }, abstract = {Major insights into the phylogenetic distribution, biochemistry, and evolutionary significance of organelles involved in ATP synthesis (energy metabolism) in eukaryotes that thrive in anaerobic environments for all or part of their life cycles have accrued in recent years. All known eukaryotic groups possess an organelle of mitochondrial origin, mapping the origin of mitochondria to the eukaryotic common ancestor, and genome sequence data are rapidly accumulating for eukaryotes that possess anaerobic mitochondria, hydrogenosomes, or mitosomes. Here we review the available biochemical data on the enzymes and pathways that eukaryotes use in anaerobic energy metabolism and summarize the metabolic end products that they generate in their anaerobic habitats, focusing on the biochemical roles that their mitochondria play in anaerobic ATP synthesis. We present metabolic maps of compartmentalized energy metabolism for 16 well-studied species. There are currently no enzymes of core anaerobic energy metabolism that are specific to any of the six eukaryotic supergroup lineages; genes present in one supergroup are also found in at least one other supergroup. The gene distribution across lineages thus reflects the presence of anaerobic energy metabolism in the eukaryote common ancestor and differential loss during the specialization of some lineages to oxic niches, just as oxphos capabilities have been differentially lost in specialization to anoxic niches and the parasitic life-style. Some facultative anaerobes have retained both aerobic and anaerobic pathways. Diversified eukaryotic lineages have retained the same enzymes of anaerobic ATP synthesis, in line with geochemical data indicating low environmental oxygen levels while eukaryotes arose and diversified.}, } @article {pmid24298354, year = {2012}, author = {Trosko, JE and Kang, KS}, title = {Evolution of energy metabolism, stem cells and cancer stem cells: how the warburg and barker hypotheses might be linked.}, journal = {International journal of stem cells}, volume = {5}, number = {1}, pages = {39-56}, pmid = {24298354}, issn = {2005-3606}, abstract = {The evolutionary transition from single cells to the metazoan forced the appearance of adult stem cells and a hypoxic niche, when oxygenation of the environment forced the appearance of oxidative phosphorylation from that of glycolysis. The prevailing paradigm in the cancer field is that cancers start from the "immortalization" or "re-programming" of a normal, differentiated cell with many mitochondria, that metabolize via oxidative phosphorylation. This paradigm has been challenged with one that assumes that the target cell for carcinogenesis is the normal, immortal adult stem cell, with few mitochondria. This adult organ-specific stem cell is blocked from "mortalizing" or from "programming" to be terminally differentiated. Two hypotheses have been offered to explain cancers, namely, the "stem cell theory" and the "de-differentiation" or "re-programming" theory. This Commentary postulates that the paleochemistry of the oceans, which, initially, provided conditions for life' s energy to arise via glycolysis, changed to oxidative phosphorylation for life' s processes. In doing so, stem cells evolved, within hypoxic niches, to protect the species germinal and somatic genomes. This Commentary provides support for the "stem cell theory", in that cancer cells, which, unlike differentiated cells, have few mitochondria and metabolize via glycolysis. The major argument against the "de-differentiation theory" is that, if re-programming of a differentiated cell to an "induced pluri-potent stem cell" happened in an adult, teratomas, rather than carcinomas, should be the result.}, } @article {pmid22535382, year = {2012}, author = {Goda, N and Kanai, M}, title = {Hypoxia-inducible factors and their roles in energy metabolism.}, journal = {International journal of hematology}, volume = {95}, number = {5}, pages = {457-463}, pmid = {22535382}, issn = {1865-3774}, mesh = {Animals ; Carbohydrate Metabolism ; *Energy Metabolism ; Humans ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1/*metabolism ; Lactic Acid/metabolism ; Lipid Metabolism ; Oxygen Consumption ; Pyruvic Acid/metabolism ; }, abstract = {Over the course of evolution, aerobic organisms have developed sophisticated systems for responding to alterations in oxygen concentration, as oxygen acts as a final electron acceptor in oxidative phosphorylation for energy production. Hypoxia-inducible factor (HIF) plays a central role in the adaptive regulation of energy metabolism, by triggering a switch from mitochondrial oxidative phosphorylation to anaerobic glycolysis in hypoxic conditions. HIF also reduces oxygen consumption in mitochondria by inhibiting conversion of pyruvate to acetyl CoA, suppressing mitochondrial biogenesis and activating autophagy of mitochondria concomitantly with reduction in reactive oxygen species production. In addition, metabolic reprogramming in response to hypoxia through HIF activation is not limited to the regulation of carbohydrate metabolism; it occurs in lipid metabolism as well. Recent studies using in vivo gene-targeting technique have revealed unexpected, but novel functions of HIF in energy metabolism in a context- and cell type-specific manner, and shed light on the possibility of pharmaceutical targeting HIF as a new therapy against many diseases, including cancer, diabetes, and fatty liver.}, } @article {pmid22530989, year = {2012}, author = {McNulty, SN and Mullin, AS and Vaughan, JA and Tkach, VV and Weil, GJ and Fischer, PU}, title = {Comparing the mitochondrial genomes of Wolbachia-dependent and independent filarial nematode species.}, journal = {BMC genomics}, volume = {13}, number = {}, pages = {145}, pmid = {22530989}, issn = {1471-2164}, support = {R03 AI092306/AI/NIAID NIH HHS/United States ; T32-AI007172/AI/NIAID NIH HHS/United States ; R03-AI092306/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Filarioidea/classification/*genetics ; *Genome, Mitochondrial ; Loa/classification/genetics ; Mitochondrial Proteins/genetics/metabolism ; Nucleic Acid Conformation ; Onchocerca/classification/genetics ; Phylogeny ; RNA, Ribosomal/chemistry/metabolism ; RNA, Transfer/chemistry/metabolism ; Wuchereria bancrofti/classification/*genetics ; }, abstract = {BACKGROUND: Many species of filarial nematodes depend on Wolbachia endobacteria to carry out their life cycle. Other species are naturally Wolbachia-free. The biological mechanisms underpinning Wolbachia-dependence and independence in filarial nematodes are not known. Previous studies have indicated that Wolbachia have an impact on mitochondrial gene expression, which may suggest a role in energy metabolism. If Wolbachia can supplement host energy metabolism, reduced mitochondrial function in infected filarial species may account for Wolbachia-dependence. Wolbachia also have a strong influence on mitochondrial evolution due to vertical co-transmission. This could drive alterations in mitochondrial genome sequence in infected species. Comparisons between the mitochondrial genome sequences of Wolbachia-dependent and independent filarial worms may reveal differences indicative of altered mitochondrial function.

RESULTS: The mitochondrial genomes of 5 species of filarial nematodes, Acanthocheilonema viteae, Chandlerella quiscali, Loa loa, Onchocerca flexuosa, and Wuchereria bancrofti, were sequenced, annotated and compared with available mitochondrial genome sequences from Brugia malayi, Dirofilaria immitis, Onchocerca volvulus and Setaria digitata. B. malayi, D. immitis, O. volvulus and W. bancrofti are Wolbachia-dependent while A. viteae, C. quiscali, L. loa, O. flexuosa and S. digitata are Wolbachia-free. The 9 mitochondrial genomes were similar in size and AT content and encoded the same 12 protein-coding genes, 22 tRNAs and 2 rRNAs. Synteny was perfectly preserved in all species except C. quiscali, which had a different order for 5 tRNA genes. Protein-coding genes were expressed at the RNA level in all examined species. In phylogenetic trees based on mitochondrial protein-coding sequences, species did not cluster according to Wolbachia dependence.

CONCLUSIONS: Thus far, no discernable differences were detected between the mitochondrial genome sequences of Wolbachia-dependent and independent species. Additional research will be needed to determine whether mitochondria from Wolbachia-dependent filarial species show reduced function in comparison to the mitochondria of Wolbachia-independent species despite their sequence-level similarities.}, } @article {pmid22510273, year = {2012}, author = {Boudina, S and Sena, S and Sloan, C and Tebbi, A and Han, YH and O'Neill, BT and Cooksey, RC and Jones, D and Holland, WL and McClain, DA and Abel, ED}, title = {Early mitochondrial adaptations in skeletal muscle to diet-induced obesity are strain dependent and determine oxidative stress and energy expenditure but not insulin sensitivity.}, journal = {Endocrinology}, volume = {153}, number = {6}, pages = {2677-2688}, pmid = {22510273}, issn = {1945-7170}, support = {R01 HL73167/HL/NHLBI NIH HHS/United States ; R01 HL073167/HL/NHLBI NIH HHS/United States ; R01 DK081842/DK/NIDDK NIH HHS/United States ; P30 HL101310/HL/NHLBI NIH HHS/United States ; U01 HL087947/HL/NHLBI NIH HHS/United States ; }, mesh = {Adaptation, Physiological ; Adenosine Triphosphate/metabolism ; Animals ; Blood Glucose/metabolism ; Blotting, Western ; Diet, High-Fat/adverse effects ; Diglycerides/metabolism ; Energy Metabolism/*physiology ; Female ; Insulin/blood ; Ion Channels/genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Muscle/genetics/metabolism/*physiology ; Mitochondrial Proteins/genetics/metabolism ; Muscle, Skeletal/metabolism ; Obesity/etiology/metabolism/*physiopathology ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Time Factors ; Triglycerides/metabolism ; Uncoupling Protein 3 ; }, abstract = {This study sought to elucidate the relationship between skeletal muscle mitochondrial dysfunction, oxidative stress, and insulin resistance in two mouse models with differential susceptibility to diet-induced obesity. We examined the time course of mitochondrial dysfunction and insulin resistance in obesity-prone C57B and obesity-resistant FVB mouse strains in response to high-fat feeding. After 5 wk, impaired insulin-mediated glucose uptake in skeletal muscle developed in both strains in the absence of any impairment in proximal insulin signaling. Impaired mitochondrial oxidative capacity preceded the development of insulin resistant glucose uptake in C57B mice in concert with increased oxidative stress in skeletal muscle. By contrast, mitochondrial uncoupling in FVB mice, which prevented oxidative stress and increased energy expenditure, did not prevent insulin resistant glucose uptake in skeletal muscle. Preventing oxidative stress in C57B mice treated systemically with an antioxidant normalized skeletal muscle mitochondrial function but failed to normalize glucose tolerance and insulin sensitivity. Furthermore, high fat-fed uncoupling protein 3 knockout mice developed increased oxidative stress that did not worsen glucose tolerance. In the evolution of diet-induced obesity and insulin resistance, initial but divergent strain-dependent mitochondrial adaptations modulate oxidative stress and energy expenditure without influencing the onset of impaired insulin-mediated glucose uptake.}, } @article {pmid22430869, year = {2012}, author = {Olson, KR}, title = {Mitochondrial adaptations to utilize hydrogen sulfide for energy and signaling.}, journal = {Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology}, volume = {182}, number = {7}, pages = {881-897}, pmid = {22430869}, issn = {1432-136X}, mesh = {Adaptation, Biological/*physiology ; Adenosine Triphosphate/biosynthesis ; Energy Metabolism/*physiology ; Hydrogen Sulfide/*metabolism/toxicity ; Mitochondria/metabolism/*physiology ; Molecular Structure ; *Organelle Biogenesis ; Oxidation-Reduction ; Oxygen/*metabolism ; Signal Transduction/*physiology ; }, abstract = {Sulfur is a versatile molecule with oxidation states ranging from -2 to +6. From the beginning, sulfur has been inexorably entwined with the evolution of organisms. Reduced sulfur, prevalent in the prebiotic Earth and supplied from interstellar sources, was an integral component of early life as it could provide energy through oxidization, even in a weakly oxidizing environment, and it spontaneously reacted with iron to form iron-sulfur clusters that became the earliest biological catalysts and structural components of cells. The ability to cycle sulfur between reduced and oxidized states may have been key in the great endosymbiotic event that incorporated a sulfide-oxidizing α-protobacteria into a host sulfide-reducing Archea, resulting in the eukaryotic cell. As eukaryotes slowly adapted from a sulfidic and anoxic (euxinic) world to one that was highly oxidizing, numerous mechanisms developed to deal with increasing oxidants; namely, oxygen, and decreasing sulfide. Because there is rarely any reduced sulfur in the present-day environment, sulfur was historically ignored by biologists, except for an occasional report of sulfide toxicity. Twenty-five years ago, it became evident that the organisms in sulfide-rich environments could synthesize ATP from sulfide, 10 years later came the realization that animals might use sulfide as a signaling molecule, and only within the last 4 years did it become apparent that even mammals could derive energy from sulfide generated in the gastrointestinal tract. It has also become evident that, even in the present-day oxic environment, cells can exploit the redox chemistry of sulfide, most notably as a physiological transducer of oxygen availability. This review will examine how the legacy of sulfide metabolism has shaped natural selection and how some of these ancient biochemical pathways are still employed by modern-day eukaryotes.}, } @article {pmid22395773, year = {2012}, author = {Houtkooper, RH and Pirinen, E and Auwerx, J}, title = {Sirtuins as regulators of metabolism and healthspan.}, journal = {Nature reviews. Molecular cell biology}, volume = {13}, number = {4}, pages = {225-238}, pmid = {22395773}, issn = {1471-0080}, support = {231138/ERC_/European Research Council/International ; }, mesh = {Aging/genetics/*metabolism ; Animals ; Energy Metabolism ; Glucose/metabolism ; Histones/genetics/metabolism ; Homeostasis ; Humans ; Insulin/metabolism ; Insulin Secretion ; Lipid Metabolism ; Longevity/genetics ; Multigene Family ; NAD/metabolism ; Phylogeny ; Protein Processing, Post-Translational ; Resveratrol ; Sirtuins/*physiology ; Stilbenes/pharmacology ; }, abstract = {Since the beginning of the century, the mammalian sirtuin protein family (comprising SIRT1-SIRT7) has received much attention for its regulatory role, mainly in metabolism and ageing. Sirtuins act in different cellular compartments: they deacetylate histones and several transcriptional regulators in the nucleus, but also specific proteins in other cellular compartments, such as in the cytoplasm and in mitochondria. As a consequence, sirtuins regulate fat and glucose metabolism in response to physiological changes in energy levels, thereby acting as crucial regulators of the network that controls energy homeostasis and as such determines healthspan.}, } @article {pmid22355196, year = {2012}, author = {Thiergart, T and Landan, G and Schenk, M and Dagan, T and Martin, WF}, title = {An evolutionary network of genes present in the eukaryote common ancestor polls genomes on eukaryotic and mitochondrial origin.}, journal = {Genome biology and evolution}, volume = {4}, number = {4}, pages = {466-485}, pmid = {22355196}, issn = {1759-6653}, support = {232975/ERC_/European Research Council/International ; }, mesh = {Archaea/genetics ; Bacteria/genetics ; Eukaryota/classification/*genetics ; *Evolution, Molecular ; *Genome ; Mitochondria/*genetics ; Phylogeny ; }, abstract = {To test the predictions of competing and mutually exclusive hypotheses for the origin of eukaryotes, we identified from a sample of 27 sequenced eukaryotic and 994 sequenced prokaryotic genomes 571 genes that were present in the eukaryote common ancestor and that have homologues among eubacterial and archaebacterial genomes. Maximum-likelihood trees identified the prokaryotic genomes that most frequently contained genes branching as the sister to the eukaryotic nuclear homologues. Among the archaebacteria, euryarchaeote genomes most frequently harbored the sister to the eukaryotic nuclear gene, whereas among eubacteria, the α-proteobacteria were most frequently represented within the sister group. Only 3 genes out of 571 gave a 3-domain tree. Homologues from α-proteobacterial genomes that branched as the sister to nuclear genes were found more frequently in genomes of facultatively anaerobic members of the rhiozobiales and rhodospirilliales than in obligate intracellular ricketttsial parasites. Following α-proteobacteria, the most frequent eubacterial sister lineages were γ-proteobacteria, δ-proteobacteria, and firmicutes, which were also the prokaryote genomes least frequently found as monophyletic groups in our trees. Although all 22 higher prokaryotic taxa sampled (crenarchaeotes, γ-proteobacteria, spirochaetes, chlamydias, etc.) harbor genes that branch as the sister to homologues present in the eukaryotic common ancestor, that is not evidence of 22 different prokaryotic cells participating at eukaryote origins because prokaryotic "lineages" have laterally acquired genes for more than 1.5 billion years since eukaryote origins. The data underscore the archaebacterial (host) nature of the eukaryotic informational genes and the eubacterial (mitochondrial) nature of eukaryotic energy metabolism. The network linking genes of the eukaryote ancestor to contemporary homologues distributed across prokaryotic genomes elucidates eukaryote gene origins in a dialect cognizant of gene transfer in nature.}, } @article {pmid22079833, year = {2011}, author = {Schneider, RE and Brown, MT and Shiflett, AM and Dyall, SD and Hayes, RD and Xie, Y and Loo, JA and Johnson, PJ}, title = {The Trichomonas vaginalis hydrogenosome proteome is highly reduced relative to mitochondria, yet complex compared with mitosomes.}, journal = {International journal for parasitology}, volume = {41}, number = {13-14}, pages = {1421-1434}, pmid = {22079833}, issn = {1879-0135}, support = {T32 AI007323/AI/NIAID NIH HHS/United States ; 2-T32-AI-007323/AI/NIAID NIH HHS/United States ; F32 AI080084/AI/NIAID NIH HHS/United States ; R37 AI027857/AI/NIAID NIH HHS/United States ; R37 AI027587/AI/NIAID NIH HHS/United States ; F32-AI080084/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Mass Spectrometry ; Mitochondria/chemistry/genetics/*metabolism ; Organelles/chemistry/genetics/*metabolism ; Phylogeny ; Proteome/chemistry/genetics/*metabolism ; Proteomics ; Protozoan Proteins/chemistry/genetics/*metabolism ; Trichomonas vaginalis/chemistry/classification/genetics/*metabolism ; }, abstract = {The human pathogen Trichomonas vaginalis lacks conventional mitochondria and instead contains divergent mitochondrial-related organelles. These double-membrane bound organelles, called hydrogenosomes, produce molecular hydrogen. Phylogenetic and biochemical analyses of hydrogenosomes indicate a common origin with mitochondria; however identification of hydrogenosomal proteins and studies on its metabolism have been limited. Here we provide a detailed proteomic analysis of the T. vaginalis hydrogenosome. The proteome of purified hydrogenosomes consists of 569 proteins, a number substantially lower than the 1,000-1,500 proteins reported for fungal and animal mitochondrial proteomes, yet considerably higher than proteins assigned to mitosomes. Pathways common to and distinct from both mitochondria and mitosomes were revealed by the hydrogenosome proteome. Proteins known to function in amino acid and energy metabolism, Fe-S cluster assembly, flavin-mediated catalysis, oxygen stress response, membrane translocation, chaperonin functions, proteolytic processing and ATP hydrolysis account for ∼30% of the hydrogenosome proteome. Of the 569 proteins in the hydrogenosome proteome, many appear to be associated with the external surface of hydrogenosomes, including large numbers of GTPases and ribosomal proteins. Glycolytic proteins were also found to be associated with the hydrogenosome proteome, similar to that previously observed for mitochondrial proteomes. Approximately 18% of the hydrogenosomal proteome is composed of hypothetical proteins of unknown function, predictive of multiple activities and properties yet to be uncovered for these highly adapted organelles.}, } @article {pmid22016847, year = {2011}, author = {Hampl, V and Stairs, CW and Roger, AJ}, title = {The tangled past of eukaryotic enzymes involved in anaerobic metabolism.}, journal = {Mobile genetic elements}, volume = {1}, number = {1}, pages = {71-74}, pmid = {22016847}, issn = {2159-2543}, abstract = {There is little doubt that genes can spread across unrelated prokaryotes, eukaryotes and even between these domains. It is expected that organisms inhabiting a common niche may exchange their genes even more often due to their physical proximity and similar demands. One such niche is anaerobic or microaerophilic environments in some sediments and intestines of animals. Indeed, enzymes advantageous for metabolism in these environments often exhibit an evolutionary history incoherent with the history of their hosts indicating potential transfers. The evolutionary paths of some very basic enzymes for energy metabolism of anaerobic eukaryotes (pyruvate formate lyase, pyruvate:ferredoxin oxidoreductase, [FeFe]hydrogenase and arginine deiminase) seems to be particularly intriguing and although their histories are not identical they share several unexpected features in common. Every enzyme mentioned above is present in groups of eukaryotes that are unrelated to each other. Although the enzyme phylogenies are not always robustly supported, they always suggest that the eukaryotic homologues form one or two clades, in which the relationships are not congruent with the eukaryotic phylogeny. Finally, these eukaryotic enzymes are never specifically related to homologues from α-proteobacteria, ancestors of mitochondria. The most plausible explanation for evolution of this pattern expects one or two interdomain transfers to one or two eukaryotes from prokaryotes, who were not the mitochondrial endosymbiont. Once the genes were introduced into the eukaryotic domain they have spread to other eukaryotic groups exclusively via eukaryote-to-eukaryote transfers. Currently, eukaryote-to-eukaryote gene transfers have been regarded as less common than prokaryote-to-eukaryote transfers. The fact that eukaryotes accepted genes for these enzymes solely from other eukaryotes and not prokaryotes present in the same environment is surprising.}, } @article {pmid21982590, year = {2011}, author = {Wone, B and Donovan, ER and Hayes, JP}, title = {Metabolomics of aerobic metabolism in mice selected for increased maximal metabolic rate.}, journal = {Comparative biochemistry and physiology. Part D, Genomics & proteomics}, volume = {6}, number = {4}, pages = {399-405}, pmid = {21982590}, issn = {1878-0407}, support = {P20 RR016464/RR/NCRR NIH HHS/United States ; P20 RR-016464/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; *Basal Metabolism ; Fatty Acids/*metabolism ; Gas Chromatography-Mass Spectrometry ; Liver/metabolism ; Male ; *Metabolome ; Metabolomics ; Mice/*metabolism ; Muscle, Skeletal/metabolism ; }, abstract = {Maximal aerobic metabolic rate (MMR) is an important physiological and ecological variable that sets an upper limit to sustained, vigorous activity. How the oxygen cascade from the external environment to the mitochondria may affect MMR has been the subject of much interest, but little is known about the metabolic profiles that underpin variation in MMR. We tested how seven generations of artificial selection for high mass-independent MMR affected metabolite profiles of two skeletal muscles (gastrocnemius and plantaris) and the liver. MMR was 12.3% higher in mass selected for high MMR than in controls. Basal metabolic rate was 3.5% higher in selected mice than in controls. Artificial selection did not lead to detectable changes in the metabolic profiles from plantaris muscle, but in the liver amino acids and tricarboxylic acid cycle (TCA cycle) metabolites were lower in high-MMR mice than in controls. In gastrocnemius, amino acids and TCA cycle metabolites were higher in high-MMR mice than in controls, indicating elevated amino acid and energy metabolism. Moreover, in gastrocnemius free fatty acids and triacylglycerol fatty acids were lower in high-MMR mice than in controls. Because selection for high MMR was associated with changes in the resting metabolic profile of both liver and gastrocnemius, the result suggests a possible mechanistic link between resting metabolism and MMR. In addition, it is well established that diet and exercise affect the composition of fatty acids in muscle. The differences that we found between control lines and lines selected for high MMR demonstrate that the composition of fatty acids in muscle is also affected by genetic factors.}, } @article {pmid21969854, year = {2011}, author = {Garvin, MR and Bielawski, JP and Gharrett, AJ}, title = {Positive Darwinian selection in the piston that powers proton pumps in complex I of the mitochondria of Pacific salmon.}, journal = {PloS one}, volume = {6}, number = {9}, pages = {e24127}, pmid = {21969854}, issn = {1932-6203}, mesh = {Adenosine Triphosphate/chemistry ; Amino Acid Sequence ; Animals ; Bayes Theorem ; Biological Evolution ; Evolution, Molecular ; Genomics ; Mitochondria/*metabolism ; Molecular Conformation ; Molecular Sequence Data ; Oxygen/chemistry ; Phosphorylation ; Phylogeny ; Proton Pumps/*physiology ; Salmon ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; }, abstract = {The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm.}, } @article {pmid21937710, year = {2011}, author = {Hardie, DG}, title = {AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function.}, journal = {Genes & development}, volume = {25}, number = {18}, pages = {1895-1908}, pmid = {21937710}, issn = {1549-5477}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; Cell Polarity ; Cell Proliferation ; Cells/cytology/*enzymology ; *Energy Metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Mitochondria/enzymology ; Neoplasms/enzymology ; Virus Diseases/enzymology ; }, abstract = {AMP-activated protein kinase (AMPK) is a sensor of energy status that maintains cellular energy homeostasis. It arose very early during eukaryotic evolution, and its ancestral role may have been in the response to starvation. Recent work shows that the kinase is activated by increases not only in AMP, but also in ADP. Although best known for its effects on metabolism, AMPK has many other functions, including regulation of mitochondrial biogenesis and disposal, autophagy, cell polarity, and cell growth and proliferation. Both tumor cells and viruses establish mechanisms to down-regulate AMPK, allowing them to escape its restraining influences on growth.}, } @article {pmid21922504, year = {2011}, author = {Lane, N}, title = {Mitonuclear match: optimizing fitness and fertility over generations drives ageing within generations.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {33}, number = {11}, pages = {860-869}, doi = {10.1002/bies.201100051}, pmid = {21922504}, issn = {1521-1878}, mesh = {Adenosine Triphosphate/metabolism ; Aging/genetics/metabolism/*physiology ; Animals ; Apoptosis ; Cell Nucleus/genetics/metabolism/*physiology ; Cell Respiration ; DNA, Mitochondrial/genetics/metabolism ; Electron Transport ; Female ; *Fertility ; Free Radicals/metabolism ; *Genetic Fitness ; Genetic Speciation ; Humans ; Male ; Mammals ; Membrane Potential, Mitochondrial ; Mitochondria/genetics/metabolism/*physiology ; Selection, Genetic ; Signal Transduction ; }, abstract = {Many conserved eukaryotic traits, including apoptosis, two sexes, speciation and ageing, can be causally linked to a bioenergetic requirement for mitochondrial genes. Mitochondrial genes encode proteins involved in cell respiration, which interact closely with proteins encoded by nuclear genes. Functional respiration requires the coadaptation of mitochondrial and nuclear genes, despite divergent tempi and modes of evolution. Free-radical signals emerge directly from the biophysics of mosaic respiratory chains encoded by two genomes prone to mismatch, with apoptosis being the default penalty for compromised respiration. Selection for genomic matching is facilitated by two sexes, and optimizes fitness, adaptability and fertility in youth. Mismatches cause infertility, low fitness, hybrid breakdown, and potentially speciation. The dynamics of selection for mitonuclear function optimize fitness over generations, but the same selective processes also operate within generations, driving ageing and age-related diseases. This coherent view of eukaryotic energetics offers striking insights into infertility and age-related diseases.}, } @article {pmid21830829, year = {2011}, author = {García-Cañaveras, JC and Donato, MT and Castell, JV and Lahoz, A}, title = {A comprehensive untargeted metabonomic analysis of human steatotic liver tissue by RP and HILIC chromatography coupled to mass spectrometry reveals important metabolic alterations.}, journal = {Journal of proteome research}, volume = {10}, number = {10}, pages = {4825-4834}, doi = {10.1021/pr200629p}, pmid = {21830829}, issn = {1535-3907}, mesh = {Adult ; Aged ; Antioxidants/metabolism ; Bile Acids and Salts/chemistry ; Biomarkers/metabolism ; Chromatography, Liquid/methods ; Fatty Liver/*metabolism ; Female ; *Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Lipid Metabolism ; Liver/metabolism ; Male ; Mass Spectrometry/methods ; Metabolomics/*methods ; Middle Aged ; Mitochondria/metabolism ; Phospholipids/chemistry ; Solvents ; }, abstract = {Steatosis, or excessive accumulation of lipids in the liver, is a generally accepted previous step to the development of more severe conditions like nonalcoholic steatohepatitis, fibrosis, and cirrhosis. We aimed to characterize the metabolic profile that defines simple steatosis in human tissue and to identify potential disturbances in the hepatic metabolism that could favor the switch to progressive liver damage. A total of 46 samples, 23 from steatotic and 23 from nonsteatotic human livers, were analyzed following a holistic LC-MS-based metabonomic analysis that combines RP and HILIC chromatographic separations. Multivariate statistical data analysis satisfactorily classified samples and revealed steatosis-associated biomarkers. Increased levels of bile acids and phospholipid degradation products, and decreased levels of antioxidant species, were found in steatotic livers, indicating disturbances in lipid and bile acid homeostasis and mitochondrial dysfunction. Changes in hypoxanthine, creatinine, glutamate, glutamine, or γ-glutamyl-dipeptides concentrations, suggestive of alterations in energy metabolism and amino acid metabolism and transport, were also found. The results show that the proposed analytical strategy is suitable to achieve a comprehensive metabolic profile of steatotic human liver tissue and provide new insights into the metabolic alterations occurring in fatty liver that could contribute to its predisposition to damage evolution.}, } @article {pmid21723951, year = {2011}, author = {Tomasco, IH and Lessa, EP}, title = {The evolution of mitochondrial genomes in subterranean caviomorph rodents: adaptation against a background of purifying selection.}, journal = {Molecular phylogenetics and evolution}, volume = {61}, number = {1}, pages = {64-70}, doi = {10.1016/j.ympev.2011.06.014}, pmid = {21723951}, issn = {1095-9513}, mesh = {*Adaptation, Physiological ; Anaerobiosis ; Animals ; Biological Evolution ; DNA, Mitochondrial/*genetics ; *Evolution, Molecular ; Genetic Variation ; *Genome, Mitochondrial ; Mitochondria/genetics ; Phylogeny ; Proteins/*genetics ; Rodentia/*classification/*genetics/physiology ; *Selection, Genetic ; }, abstract = {South American tuco-tucos (Ctenomys) and the related coruro (Spalacopus) are two rodent lineages that have independently colonised the subterranean niche. The energetically demanding lifestyles of these species, coupled with the hypoxic atmospheres characteristic of subterranean environments, may have altered the selective regimes on genes encoding proteins related to cellular respiration. Here, we examined the molecular evolution of 13 protein-coding genes in the mitochondrial genome of seven caviomorph rodents, including these two subterranean genera and their above-ground relatives. Using maximum-likelihood and Bayesian approaches, we estimated rates of synonymous (dS) and nonsynonymous (dN) substitutions. We found a significantly higher ω ratio (dN/dS) in subterranean groups as compared to their non-subterranean counterparts in 11 of 13 genes, although no ω ratio was larger than 1. Additionally, we applied a method based on quantitative physicochemical properties to test for positive selection. Amino acid changes implicated in radical structural or functional shifts in the protein property were found to be ubiquitous across the phylogeny, but concentrated in the subterranean lineages. Convergent changes were also found between the subterranean genera used in this study and other mammals adapted to hypoxia. The results of this study suggest a link between niche shifts and weak directional (or episodic) selection at the molecular level against a background of purifying selection.}, } @article {pmid21714942, year = {2011}, author = {Martin, WF}, title = {Early evolution without a tree of life.}, journal = {Biology direct}, volume = {6}, number = {}, pages = {36}, pmid = {21714942}, issn = {1745-6150}, mesh = {Adenosine Triphosphate/metabolism ; *Biological Evolution ; *Energy Metabolism ; Environment ; Eukaryotic Cells/chemistry/cytology ; Genes ; Hydrogen/chemistry ; Mitochondria/chemistry/genetics ; Origin of Life ; Oxygen/chemistry ; Phagocytosis ; Phylogeny ; Prokaryotic Cells/chemistry/cytology ; Symbiosis ; }, abstract = {Life is a chemical reaction. Three major transitions in early evolution are considered without recourse to a tree of life. The origin of prokaryotes required a steady supply of energy and electrons, probably in the form of molecular hydrogen stemming from serpentinization. Microbial genome evolution is not a treelike process because of lateral gene transfer and the endosymbiotic origins of organelles. The lack of true intermediates in the prokaryote-to-eukaryote transition has a bioenergetic cause.}, } @article {pmid21714941, year = {2011}, author = {Lane, N}, title = {Energetics and genetics across the prokaryote-eukaryote divide.}, journal = {Biology direct}, volume = {6}, number = {}, pages = {35}, pmid = {21714941}, issn = {1745-6150}, mesh = {Adenosine Triphosphate/metabolism ; *Biological Evolution ; Cell Cycle ; Cell Membrane/physiology ; Cell Nucleus/genetics ; Cytoplasm/genetics/physiology ; *Energy Metabolism ; Eukaryotic Cells/*cytology/physiology ; Gene Transfer, Horizontal ; Genes, Mitochondrial ; Introns ; Mitochondria/genetics/physiology ; Mutation ; Oxidative Phosphorylation ; Phylogeny ; Prokaryotic Cells/*cytology/physiology ; Selection, Genetic ; *Symbiosis ; }, abstract = {BACKGROUND: All complex life on Earth is eukaryotic. All eukaryotic cells share a common ancestor that arose just once in four billion years of evolution. Prokaryotes show no tendency to evolve greater morphological complexity, despite their metabolic virtuosity. Here I argue that the eukaryotic cell originated in a unique prokaryotic endosymbiosis, a singular event that transformed the selection pressures acting on both host and endosymbiont.

RESULTS: The reductive evolution and specialisation of endosymbionts to mitochondria resulted in an extreme genomic asymmetry, in which the residual mitochondrial genomes enabled the expansion of bioenergetic membranes over several orders of magnitude, overcoming the energetic constraints on prokaryotic genome size, and permitting the host cell genome to expand (in principle) over 200,000-fold. This energetic transformation was permissive, not prescriptive; I suggest that the actual increase in early eukaryotic genome size was driven by a heavy early bombardment of genes and introns from the endosymbiont to the host cell, producing a high mutation rate. Unlike prokaryotes, with lower mutation rates and heavy selection pressure to lose genes, early eukaryotes without genome-size limitations could mask mutations by cell fusion and genome duplication, as in allopolyploidy, giving rise to a proto-sexual cell cycle. The side effect was that a large number of shared eukaryotic basal traits accumulated in the same population, a sexual eukaryotic common ancestor, radically different to any known prokaryote.

CONCLUSIONS: The combination of massive bioenergetic expansion, release from genome-size constraints, and high mutation rate favoured a protosexual cell cycle and the accumulation of eukaryotic traits. These factors explain the unique origin of eukaryotes, the absence of true evolutionary intermediates, and the evolution of sex in eukaryotes but not prokaryotes.

REVIEWERS: This article was reviewed by: Eugene Koonin, William Martin, Ford Doolittle and Mark van der Giezen. For complete reports see the Reviewers' Comments section.}, } @article {pmid21687738, year = {2011}, author = {García-Giménez, JL and Gimeno, A and Gonzalez-Cabo, P and Dasí, F and Bolinches-Amorós, A and Mollá, B and Palau, F and Pallardó, FV}, title = {Differential expression of PGC-1α and metabolic sensors suggest age-dependent induction of mitochondrial biogenesis in Friedreich ataxia fibroblasts.}, journal = {PloS one}, volume = {6}, number = {6}, pages = {e20666}, pmid = {21687738}, issn = {1932-6203}, mesh = {AMP-Activated Protein Kinases/metabolism ; Adenosine Triphosphate/metabolism ; Adolescent ; Adult ; Aging/*genetics/*metabolism ; Alleles ; Antioxidants/pharmacology ; Catalase/metabolism ; Child ; DNA-Binding Proteins/metabolism ; Disease Progression ; Energy Metabolism/drug effects ; Female ; Fibroblasts/drug effects/enzymology/*pathology ; Friedreich Ataxia/genetics/metabolism/*pathology ; *Gene Expression Regulation/drug effects ; Glutathione Peroxidase/metabolism ; Heat-Shock Proteins/*genetics ; Humans ; Male ; Middle Aged ; Mitochondria/drug effects/enzymology/*metabolism/pathology ; Mitochondrial Proteins/metabolism ; Oxidative Stress/drug effects ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; Transcription Factors/*genetics/metabolism ; Trinucleotide Repeats/genetics ; Ubiquinone/analogs & derivatives/pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND: Friedreich's ataxia (FRDA) is a mitochondrial rare disease, which molecular origin is associated with defect in the expression of frataxin. The pathological consequences are degeneration of nervous system structures and cardiomyopathy with necrosis and fibrosis, among others.

PRINCIPAL FINDINGS: Using FRDA fibroblasts we have characterized the oxidative stress status and mitochondrial biogenesis. We observed deficiency of MnSOD, increased ROS levels and low levels of ATP. Expression of PGC-1α and mtTFA was increased and the active form of the upstream signals p38 MAPK and AMPK in fibroblasts from two patients. Interestingly, the expression of energetic factors correlated with the natural history of disease of the patients, the age when skin biopsy was performed and the size of the GAA expanded alleles. Furthermore, idebenone inhibit mitochondriogenic responses in FRDA cells.

CONCLUSIONS: The induction of mitochondrial biogenesis in FRDA may be a consequence of the mitochondrial impairment associated with disease evolution. The increase of ROS and the involvement of the oxidative phosphorylation may be an early event in the cell pathophysiology of frataxin deficiency, whereas increase of mitochondriogenic response might be a later phenomenon associated to the individual age and natural history of the disease, being more evident as the patient age increases and disease evolves. This is a possible explanation of heart disease in FRDA.}, } @article {pmid21618648, year = {2011}, author = {Goizet, C and Depienne, C and Benard, G and Boukhris, A and Mundwiller, E and Solé, G and Coupry, I and Pilliod, J and Martin-Négrier, ML and Fedirko, E and Forlani, S and Cazeneuve, C and Hannequin, D and Charles, P and Feki, I and Pinel, JF and Ouvrard-Hernandez, AM and Lyonnet, S and Ollagnon-Roman, E and Yaouanq, J and Toutain, A and Dussert, C and Fontaine, B and Leguern, E and Lacombe, D and Durr, A and Rossignol, R and Brice, A and Stevanin, G}, title = {REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.}, journal = {Human mutation}, volume = {32}, number = {10}, pages = {1118-1127}, doi = {10.1002/humu.21542}, pmid = {21618648}, issn = {1098-1004}, mesh = {Adolescent ; Adult ; Aged ; Base Sequence ; Child ; Child, Preschool ; Energy Metabolism ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Membrane Transport Proteins/*genetics ; Middle Aged ; Mitochondria/*metabolism ; Muscle, Skeletal/metabolism/pathology ; *Mutation ; Mutation Rate ; Pedigree ; Phenotype ; Sequence Deletion ; Spastic Paraplegia, Hereditary/*genetics/metabolism ; Young Adult ; }, abstract = {Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with a pure dominant HSP, SPG31. We sequenced all exons of REEP1 and searched for rearrangements by multiplex ligation-dependent probe amplification (MLPA) in a large panel of 175 unrelated HSP index patients from kindreds with dominant inheritance (AD-HSP), with either pure (n = 102) or complicated (n = 73) forms of the disease, after exclusion of other known HSP genes. We identified 12 different heterozygous mutations, including two exon deletions, associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but nine had a complex phenotype associating axonal peripheral neuropathy (= 5/11 patients) including a Silver-like syndrome in one patient, and less frequently cerebellar ataxia, tremor, dementia. Interestingly, we evidenced abnormal mitochondrial network organization in fibroblasts of one patient in addition to defective mitochondrial energy production in both fibroblasts and muscle, but whether these anomalies are directly or indirectly related to the mutations remains uncertain.}, } @article {pmid21566257, year = {2011}, author = {Valerio, A and D'Antona, G and Nisoli, E}, title = {Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective.}, journal = {Aging}, volume = {3}, number = {5}, pages = {464-478}, pmid = {21566257}, issn = {1945-4589}, mesh = {Amino Acids, Branched-Chain/*metabolism ; Animals ; *Biological Evolution ; Caloric Restriction ; Diet ; Dietary Supplements ; Energy Metabolism ; Humans ; Longevity/*physiology ; Mitochondria/*metabolism ; Nutritional Status ; }, abstract = {Malnutrition is common among older persons, with important consequences increasing frailty and morbidity and reducing health expectancy. On the contrary, calorie restriction (CR, a low-calorie dietary regimen with adequate nutrition) slows the progression of age-related diseases and extends the lifespan of many species. Identification of strategies mimicking key CR mechanisms - increased mitochondrial respiration and reduced production of oxygen radicals - is a hot topic in gerontology. Dietary supplementation with essential and/or branched chain amino acids (BCAAs) exerts a variety of beneficial effects in experimental animals and humans and has been recently demonstrated to support cardiac and skeletal muscle mitochondrial biogenesis, prevent oxidative damage, and enhance physical endurance in middle-aged mice, resulting in prolonged survival. Here we review recent studies addressing the possible role of BCAAs in energy metabolism and in the longevity of species ranging from unicellular organisms to mammals. We also summarize observations from human studies supporting the exciting hypothesis that dietary BCAA enriched mixture supplementation might be a health-promoting strategy in aged patients at risk.}, } @article {pmid21292038, year = {2011}, author = {Yu, L and Wang, X and Ting, N and Zhang, Y}, title = {Mitogenomic analysis of Chinese snub-nosed monkeys: Evidence of positive selection in NADH dehydrogenase genes in high-altitude adaptation.}, journal = {Mitochondrion}, volume = {11}, number = {3}, pages = {497-503}, doi = {10.1016/j.mito.2011.01.004}, pmid = {21292038}, issn = {1872-8278}, mesh = {*Adaptation, Biological ; Altitude ; Animals ; China ; Cold Temperature ; Colobinae/genetics/*physiology ; DNA, Mitochondrial/chemistry/genetics ; Energy Metabolism ; *Genome, Mitochondrial ; Hypoxia ; Mitochondria/genetics/*physiology ; Mitochondrial Proteins/genetics ; Molecular Sequence Data ; Oxidative Phosphorylation ; Sequence Analysis, DNA ; }, abstract = {Chinese snub-nosed monkeys belong to the genus Rhinopithecus and are limited in distribution to six isolated mountainous areas in the temperate regions of Central and Southwest China. Compared to the other members of the subfamily Colobinae (or leaf-eating monkeys), these endangered primates are unique in being adapted to a high altitude environment and display a remarkable ability to tolerate low temperatures and hypoxia. They thus offer an interesting organismal model of adaptation to extreme environmental stress. Mitochondria generate energy by oxidative phosphorylation (OXPHOS) and play important roles in oxygen usage and energy metabolism. We analyzed the mitochondrial genomes of two Chinese snub-nosed monkey species and eight other colobines in the first attempt to understand the genetic basis of high altitude adaptation in non-human primates. We found significant evidence of positive selection in one Chinese snub-nosed monkey, Rhinopithecus roxellana, which is suggestive of adaptive change related to high altitude and cold weather stress. In addition, our study identified two potentially important adaptive amino acid residues (533 and 3307) in the NADH2 and NADH6 genes, respectively. Surprisingly, no evidence for positive selection was found in Rhinopithecus bieti (the other Chinese snub-nosed monkey analyzed). This finding is intriguing, especially considering that R. bieti inhabits a higher altitudinal distribution than R. roxellana. We hypothesize that a different adaptive genetic basis to high altitude survival exists in R. bieti from those seen in other mammals, and that positive selection and functionally associated mutations in this species may be detected in nuclear genes related to energy and oxygen metabolism. More information on the structure, function, and evolution of mitochondrial and nuclear genomes in Chinese snub-nosed monkeys is required to reveal the molecular mechanisms that underlie adaptations to high altitude survival in non-human primates.}, } @article {pmid21289219, year = {2011}, author = {Roth, J and Szulc, AL and Danoff, A}, title = {Energy, evolution, and human diseases: an overview.}, journal = {The American journal of clinical nutrition}, volume = {93}, number = {4}, pages = {875S-83}, doi = {10.3945/ajcn.110.001909}, pmid = {21289219}, issn = {1938-3207}, mesh = {Adipose Tissue/physiology ; *Biological Evolution ; *Energy Metabolism ; Humans ; *Immunity ; *Infections ; Life Expectancy ; *Obesity ; Reproduction/physiology ; }, abstract = {In the symposium entitled "Transcriptional controls of energy sensing," the authors presented recent advances on 1) AMP kinase, an intracellular energy sensor; 2) PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α), a transcriptional co-activator that has powerful effects on mitochondria; 3) methylation and demethylation in response to metabolic fluctuations; and 4) FGF21 (fibroblast growth factor 21) as an emerging hormone-like intercellular metabolic coordinator. This introduction places these advances within a broad overview of energy sensing and energy balance, with a focus on human evolution and disease. Four key elements of human biology are analyzed: 1) elevated body temperature; 2) complex prolonged reproductive pathways; 3) emergence of 4 large, well-defined fat depots, each with its own functional role; and 4) an immune system that is often up-regulated by nutrition-related signals, independent of the actual presence of a pathogen. We propose that an overactive immune system, including the "metabolic syndrome," was adopted evolutionarily in the distant past to help hold out against unconquerable infections such as tuberculosis, malaria, and trypanosomiasis. This immune activation is advantageous in the absence of other disease management methods, especially under conditions in which life expectancy is short. The inflammation has become a major agent of pathology in wealthy populations in whom the pathogens are a minor threat and life expectancy is long. The "Conclusions" section sketches cautiously how understanding the molecules involved in energy sensing and energy balance may lead to specific therapies for obesity and diabetes and for their complications.}, } @article {pmid21244359, year = {2011}, author = {Acuña Castroviejo, D and López, LC and Escames, G and López, A and García, JA and Reiter, RJ}, title = {Melatonin-mitochondria interplay in health and disease.}, journal = {Current topics in medicinal chemistry}, volume = {11}, number = {2}, pages = {221-240}, doi = {10.2174/156802611794863517}, pmid = {21244359}, issn = {1873-4294}, mesh = {Aging ; Animals ; Antioxidants/*metabolism ; Apoptosis ; Biological Evolution ; DNA, Mitochondrial/metabolism ; Energy Metabolism/physiology ; Humans ; Hydrogen/metabolism ; Melatonin/metabolism/*pharmacology/therapeutic use ; Mice ; Mitochondria/*metabolism ; Mitochondrial Diseases/physiopathology/prevention & control/therapy ; Oxidation-Reduction ; Oxidative Stress ; Oxygen/metabolism ; Rats ; Reactive Nitrogen Species/*metabolism ; Reactive Oxygen Species/*metabolism ; Symbiosis ; }, abstract = {Although two main hypotheses of mitochondrial origin have been proposed, i.e., the autogenous and the endosymbiotic, only the second is being seriously considered currently. The 'hydrogen hypothesis' invokes metabolic symbiosis as the driving force for a symbiotic association between an anaerobic, strictly hydrogen-dependent (the host) and an eubacterium (the symbiont) that was able to respire, but which generated molecular hydrogen as an end product of anaerobic metabolism. The resulting proto-eukaryotic cell would have acquired the essentials of eukaryotic energy metabolism, evolving not only aerobic respiration, but also the physiological cost of the oxygen consumption, i.e., generation of reactive oxygen species (ROS) and the associated oxidative damage. This is not the only price to pay for respiring oxygen: mitochondria possess nitric oxide (NO·) for regulatory purposes but, in some instances it may react with superoxide anion radical to produce the toxic reactive nitrogen species (RNS), i.e. peroxynitrite anion, and the subsequent nitrosative damage. New mitochondria contain their own genome with a modified genetic code that is highly conserved among mammals. The transcription of certain mitochondrial genes may depend on the redox potential of the mitochondrial membrane. Mitochondria are related to the life and death of cells. They are involved in energy production and conservation, having an uncoupling mechanism to produce heat instead of ATP, but they are also involved in programmed cell death. Increasing evidence suggest the participation of mitochondria in neurodegenerative and neuromuscular diseases involving alterations in both nuclear (nDNA) and mitochondrial (mtDNA) DNA. Melatonin is a known powerful antioxidant and anti-inflammatory and increasing experimental and clinical evidence shows its beneficial effects against oxidative/nitrosative stress status, including that involving mitochondrial dysfunction. This review summarizes the data and mechanisms of action of melatonin in relation to mitochondrial pathologies.}, } @article {pmid21177938, year = {2011}, author = {Suarez, RK and Herrera M, LG and Welch, KC}, title = {The sugar oxidation cascade: aerial refueling in hummingbirds and nectar bats.}, journal = {The Journal of experimental biology}, volume = {214}, number = {Pt 2}, pages = {172-178}, doi = {10.1242/jeb.047936}, pmid = {21177938}, issn = {1477-9145}, mesh = {Animals ; Biological Evolution ; Birds/*metabolism ; Body Temperature Regulation ; *Carbohydrate Metabolism ; Chiroptera/*metabolism ; Energy Metabolism ; Feeding Behavior ; Oxidation-Reduction ; }, abstract = {Most hummingbirds and some species of nectar bats hover while feeding on floral nectar. While doing so, they achieve some of the highest mass-specific V(O(2)) values among vertebrates. This is made possible by enhanced functional capacities of various elements of the 'O(2) transport cascade', the pathway of O(2) from the external environment to muscle mitochondria. Fasted hummingbirds and nectar bats fly with respiratory quotients (RQs; V(CO(2))/V(O(2))) of ~0.7, indicating that fat fuels flight in the fasted state. During repeated hover-feeding on dietary sugar, RQ values progressively climb to ~1.0, indicating a shift from fat to carbohydrate oxidation. Stable carbon isotope experiments reveal that recently ingested sugar directly fuels ~80 and 95% of energy metabolism in hover-feeding nectar bats and hummingbirds, respectively. We name the pathway of carbon flux from flowers, through digestive and cardiovascular systems, muscle membranes and into mitochondria the 'sugar oxidation cascade'. O(2) and sugar oxidation cascades operate in parallel and converge in muscle mitochondria. Foraging behavior that favours the oxidation of dietary sugar avoids the inefficiency of synthesizing fat from sugar and breaking down fat to fuel foraging. Sugar oxidation yields a higher P/O ratio (ATP made per O atom consumed) than fat oxidation, thus requiring lower hovering V(O(2)) per unit mass. We propose that dietary sugar is a premium fuel for flight in nectarivorous, flying animals.}, } @article {pmid21164222, year = {2010}, author = {Artal-Sanz, M and Tavernarakis, N}, title = {Opposing function of mitochondrial prohibitin in aging.}, journal = {Aging}, volume = {2}, number = {12}, pages = {1004-1011}, pmid = {21164222}, issn = {1945-4589}, mesh = {Aging/*metabolism ; Animals ; Cellular Senescence ; Energy Metabolism ; Evolution, Molecular ; Humans ; Longevity ; Mitochondria/*metabolism ; Oxidative Stress ; Prohibitins ; Repressor Proteins/*metabolism ; *Signal Transduction ; }, abstract = {While specific signalling cascades involved in aging, such as the insulin/IGF-1 pathway, are well-described, the actual metabolic changes they elicit to prolong lifespan remain obscure. Nevertheless, the tuning of cellular metabolism towards maximal survival is the molecular basis of longevity. The eukaryotic mitochondrial prohibitin complex is a macromolecular structure at the inner mitochondrial membrane, implicated in several important cellular processes such as mitochondrial biogenesis and function, molecular signalling, replicative senescence, and cell death. Recent studies inC. elegans have revealed that prohibitin differentially influences aging by moderating fat metabolism and energy production, in response to both intrinsic signalling events and extrinsic cues. These findings indicate that prohibitin is a context-dependent modulator of longevity. The tight evolutionary conservation and ubiquitous expression of prohibitin proteins suggest a similar role for the mitochondrial prohibitin complex during aging in other organisms.}, } @article {pmid21087461, year = {2010}, author = {Martínez-Fernández, M and Bernatchez, L and Rolán-Alvarez, E and Quesada, H}, title = {Insights into the role of differential gene expression on the ecological adaptation of the snail Littorina saxatilis.}, journal = {BMC evolutionary biology}, volume = {10}, number = {}, pages = {356}, pmid = {21087461}, issn = {1471-2148}, mesh = {Adaptation, Physiological/*genetics ; Amplified Fragment Length Polymorphism Analysis ; Animals ; DNA, Complementary/genetics ; DNA, Mitochondrial/genetics ; Ecology ; Electron Transport Complex IV/genetics ; Female ; *Gene Expression Profiling ; Gene Flow ; *Genetic Speciation ; Male ; Sequence Analysis, DNA ; Snails/*genetics ; }, abstract = {BACKGROUND: In the past 40 years, there has been increasing acceptance that variation in levels of gene expression represents a major source of evolutionary novelty. Gene expression divergence is therefore likely to be involved in the emergence of incipient species, namely, in a context of adaptive radiation. In this study, a genome-wide expression profiling approach (cDNA-AFLP), validated by quantitative real-time polymerase chain reaction (qPCR) were used to get insights into the role of differential gene expression on the ecological adaptation of the marine snail Littorina saxatilis. This gastropod displays two sympatric ecotypes (RB and SU) which are becoming one of the best studied systems for ecological speciation.

RESULTS: Among the 99 transcripts shared between ecotypes, 12.12% showed significant differential expression. At least 4% of these transcripts still displayed significant differences after correction for multiple tests, highlighting that gene expression can differ considerably between subpopulations adapted to alternative habitats in the face of gene flow. One of the transcripts identified was Cytochrome c Oxidase subunit I (COI). In addition, 6 possible reference genes were validated to normalize and confirm this result using qPCR. α-Tubulin and histone H3.3 showed the more stable expression levels, being therefore chosen as the best option for normalization. The qPCR analysis confirmed a higher COI expression in SU individuals.

CONCLUSIONS: At least 4% of the transcriptome studied is being differentially expressed between ecotypes living in alternative habitats, even when gene flow is still substantial between ecotypes. We could identify a candidate transcript of such ecotype differentiation: Cytochrome c Oxidase Subunit I (COI), a mitochondrial gene involved in energy metabolism. Quantitative PCR was used to confirm the differences found in COI and its over-expression in the SU ecotype. Interestingly, COI is involved in the oxidative phosphorylation, suggesting an enhanced mitochondrial gene expression (or increased number of mitochondria) to improve energy supply in the ecotype subjected to the strongest wave action.}, } @article {pmid21064038, year = {2011}, author = {Shi, LZ and Nascimento, J and Botvinick, E and Durrant, B and Berns, MW}, title = {An interdisciplinary systems approach to study sperm physiology and evolution.}, journal = {Wiley interdisciplinary reviews. Systems biology and medicine}, volume = {3}, number = {1}, pages = {36-47}, doi = {10.1002/wsbm.106}, pmid = {21064038}, issn = {1939-005X}, mesh = {Algorithms ; Biological Evolution ; Glycolysis/physiology ; Humans ; Male ; Oxidative Phosphorylation ; Sperm Motility ; Spermatozoa/*physiology ; }, abstract = {Optical trapping is a noninvasive biophotonic tool that has been developed to study the physiological and biomechanical properties of cells. The custom-designed optical system is built to direct near-infrared laser light into an inverted microscope to create a single-point three-dimensional gradient laser trap at the microscope focal point. A real-time automated tracking and trapping system (RATTS) is described that provides a remote user-friendly robotic interface. The combination of laser tweezers, fluorescent imaging, and RATTS can measure sperm swimming speed and swimming force simultaneously with mitochondrial membrane potential (MMP). The roles of two sources of adenosine triphosphate in sperm motility/energetics are studied: oxidative phosphorylation, which occurs in the mitochondria located in the sperm midpiece, and glycolysis, which occurs along the length of the sperm tail (flagellum). The effects of glucose, oxidative phosphorylation inhibitors, and glycolytic inhibitors on human sperm motility are studied. This combination of photonic physical and engineering tools has been used to examine the evolutionary effect of sperm competition in primates. The results demonstrate a correlation between mating type and sperm motility: sperm from polygamous (multi-partner) primate species swim faster and with greater force than sperm from polygynous (single partner) primate species. In summary, engineering and biological systems are combined to provide a powerful interdisciplinary approach to study the complex biological systems that drive the sperm toward the egg.}, } @article {pmid21037180, year = {2010}, author = {Barberà, MJ and Ruiz-Trillo, I and Tufts, JY and Bery, A and Silberman, JD and Roger, AJ}, title = {Sawyeria marylandensis (Heterolobosea) has a hydrogenosome with novel metabolic properties.}, journal = {Eukaryotic cell}, volume = {9}, number = {12}, pages = {1913-1924}, pmid = {21037180}, issn = {1535-9786}, mesh = {Amino Acid Sequence ; Eukaryota/classification/*enzymology/metabolism/ultrastructure ; Hydrogenase/chemistry/genetics/*metabolism ; Mitochondria/chemistry/*enzymology/genetics ; Molecular Sequence Data ; Phylogeny ; Pyruvate Synthase/chemistry/genetics/*metabolism ; Sequence Alignment ; }, abstract = {Protists that live under low-oxygen conditions often lack conventional mitochondria and instead possess mitochondrion-related organelles (MROs) with distinct biochemical functions. Studies of mostly parasitic organisms have suggested that these organelles could be classified into two general types: hydrogenosomes and mitosomes. Hydrogenosomes, found in parabasalids, anaerobic chytrid fungi, and ciliates, metabolize pyruvate anaerobically to generate ATP, acetate, CO(2), and hydrogen gas, employing enzymes not typically associated with mitochondria. Mitosomes that have been studied have no apparent role in energy metabolism. Recent investigations of free-living anaerobic protists have revealed a diversity of MROs with a wider array of metabolic properties that defy a simple functional classification. Here we describe an expressed sequence tag (EST) survey and ultrastructural investigation of the anaerobic heteroloboseid amoeba Sawyeria marylandensis aimed at understanding the properties of its MROs. This organism expresses typical anaerobic energy metabolic enzymes, such as pyruvate:ferredoxin oxidoreductase, [FeFe]-hydrogenase, and associated hydrogenase maturases with apparent organelle-targeting peptides, indicating that its MRO likely functions as a hydrogenosome. We also identified 38 genes encoding canonical mitochondrial proteins in S. marylandensis, many of which possess putative targeting peptides and are phylogenetically related to putative mitochondrial proteins of its heteroloboseid relative Naegleria gruberi. Several of these proteins, such as a branched-chain alpha keto acid dehydrogenase, likely function in pathways that have not been previously associated with the well-studied hydrogenosomes of parabasalids. Finally, morphological reconstructions based on transmission electron microscopy indicate that the S. marylandensis MROs form novel cup-like structures within the cells. Overall, these data suggest that Sawyeria marylandensis possesses a hydrogenosome of mitochondrial origin with a novel combination of biochemical and structural properties.}, } @article {pmid20962839, year = {2010}, author = {Lane, N and Martin, W}, title = {The energetics of genome complexity.}, journal = {Nature}, volume = {467}, number = {7318}, pages = {929-934}, pmid = {20962839}, issn = {1476-4687}, mesh = {Aerobiosis ; Anaerobiosis ; Animals ; Cell Nucleus/genetics ; Cell Size ; *Energy Metabolism ; Eukaryotic Cells/*cytology/*metabolism/ultrastructure ; Gene Expression ; Genes, Mitochondrial/genetics ; Genome/*genetics ; Humans ; Mitochondria/metabolism ; *Models, Biological ; Prokaryotic Cells/*cytology/*metabolism/ultrastructure ; Symbiosis/genetics/physiology ; }, abstract = {All complex life is composed of eukaryotic (nucleated) cells. The eukaryotic cell arose from prokaryotes just once in four billion years, and otherwise prokaryotes show no tendency to evolve greater complexity. Why not? Prokaryotic genome size is constrained by bioenergetics. The endosymbiosis that gave rise to mitochondria restructured the distribution of DNA in relation to bioenergetic membranes, permitting a remarkable 200,000-fold expansion in the number of genes expressed. This vast leap in genomic capacity was strictly dependent on mitochondrial power, and prerequisite to eukaryote complexity: the key innovation en route to multicellular life.}, } @article {pmid20924083, year = {2011}, author = {Sun, YB and Shen, YY and Irwin, DM and Zhang, YP}, title = {Evaluating the roles of energetic functional constraints on teleost mitochondrial-encoded protein evolution.}, journal = {Molecular biology and evolution}, volume = {28}, number = {1}, pages = {39-44}, doi = {10.1093/molbev/msq256}, pmid = {20924083}, issn = {1537-1719}, mesh = {Animals ; Body Temperature Regulation/genetics ; Energy Metabolism/genetics ; *Evolution, Molecular ; Fishes/*genetics/*metabolism ; Genome, Mitochondrial ; Mitochondria/*genetics/*metabolism ; Mitochondrial Proteins/*genetics ; }, abstract = {Mitochondria are the power plant of cells, which play critical roles not only in energy metabolism but also in thermoregulation. These two roles have been individually suggested to influence mitochondrial DNA (mtDNA) evolution, however their relative importance is still rarely considered. Here, we conduct a comparative genomic analysis of 401 teleost complete mitochondrial genomes and test the roles of these dual functional constraints on mitochondria to provide a more complete view of mtDNA evolution. We found that mitochondrial protein-coding genes of migratory fishes have significantly smaller Ka/Ks than nonmigratory fishes. The same data set showed that the genes of fishes living in cold climates have significantly smaller Ka/Ks than tropical fishes. In contrast, these trends were not observed for two nuclear genes that are not involved in energy metabolism. The differences in selection patterns observed between mitochondrial and nuclear genes suggest that the functional constraints acting on mitochondria, due to energy metabolism and/or thermoregulation, influence the evolution of mitochondrial-encoded proteins in teleosts.}, } @article {pmid20874734, year = {2010}, author = {Arnqvist, G and Dowling, DK and Eady, P and Gay, L and Tregenza, T and Tuda, M and Hosken, DJ}, title = {Genetic architecture of metabolic rate: environment specific epistasis between mitochondrial and nuclear genes in an insect.}, journal = {Evolution; international journal of organic evolution}, volume = {64}, number = {12}, pages = {3354-3363}, doi = {10.1111/j.1558-5646.2010.01135.x}, pmid = {20874734}, issn = {1558-5646}, mesh = {Animals ; Cell Nucleus/*genetics ; Coleoptera/*genetics/*metabolism ; Crosses, Genetic ; Energy Metabolism ; *Epistasis, Genetic ; Evolution, Molecular ; Female ; *Genes, Mitochondrial ; Genome, Insect ; Genotype ; Male ; Polymorphism, Genetic ; Temperature ; }, abstract = {The extent to which mitochondrial DNA (mtDNA) variation is involved in adaptive evolutionary change is currently being reevaluated. In particular, emerging evidence suggests that mtDNA genes coevolve with the nuclear genes with which they interact to form the energy producing enzyme complexes in the mitochondria. This suggests that intergenomic epistasis between mitochondrial and nuclear genes may affect whole-organism metabolic phenotypes. Here, we use crossed combinations of mitochondrial and nuclear lineages of the seed beetle Callosobruchus maculatus and assay metabolic rate under two different temperature regimes. Metabolic rate was affected by an interaction between the mitochondrial and nuclear lineages and the temperature regime. Sequence data suggests that mitochondrial genetic variation has a role in determining the outcome of this interaction. Our genetic dissection of metabolic rate reveals a high level of complexity, encompassing genetic interactions over two genomes, and genotype × genotype × environment interactions. The evolutionary implications of these results are twofold. First, because metabolic rate is at the root of life histories, our results provide insights into the complexity of life-history evolution in general, and thermal adaptation in particular. Second, our results suggest a mechanism that could contribute to the maintenance of nonneutral mtDNA polymorphism.}, } @article {pmid20868295, year = {2011}, author = {Sevrioukova, IF}, title = {Apoptosis-inducing factor: structure, function, and redox regulation.}, journal = {Antioxidants & redox signaling}, volume = {14}, number = {12}, pages = {2545-2579}, pmid = {20868295}, issn = {1557-7716}, mesh = {Amino Acid Sequence ; Animals ; Apoptosis/physiology ; Apoptosis Inducing Factor/*chemistry/classification/genetics/*metabolism ; Catalytic Domain ; Electron Transport/physiology ; Gene Expression Regulation ; Humans ; Mitochondria/metabolism/ultrastructure ; Models, Molecular ; Molecular Sequence Data ; Oxidation-Reduction ; Phylogeny ; *Protein Conformation ; Protein Folding ; Protein Isoforms/*chemistry/genetics/*metabolism ; Sequence Alignment ; Signal Transduction/physiology ; }, abstract = {Apoptosis-inducing factor (AIF) is a flavin adenine dinucleotide-containing, NADH-dependent oxidoreductase residing in the mitochondrial intermembrane space whose specific enzymatic activity remains unknown. Upon an apoptotic insult, AIF undergoes proteolysis and translocates to the nucleus, where it triggers chromatin condensation and large-scale DNA degradation in a caspase-independent manner. Besides playing a key role in execution of caspase-independent cell death, AIF has emerged as a protein critical for cell survival. Analysis of in vivo phenotypes associated with AIF deficiency and defects, and identification of its mitochondrial, cytoplasmic, and nuclear partners revealed the complexity and multilevel regulation of AIF-mediated signal transduction and suggested an important role of AIF in the maintenance of mitochondrial morphology and energy metabolism. The redox activity of AIF is essential for optimal oxidative phosphorylation. Additionally, the protein is proposed to regulate the respiratory chain indirectly, through assembly and/or stabilization of complexes I and III. This review discusses accumulated data with respect to the AIF structure and outlines evidence that supports the prevalent mechanistic view on the apoptogenic actions of the flavoprotein, as well as the emerging concept of AIF as a redox sensor capable of linking NAD(H)-dependent metabolic pathways to apoptosis.}, } @article {pmid20816580, year = {2010}, author = {Rubinstein, WS}, title = {Endocrine cancer predisposition syndromes: hereditary paraganglioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, and hereditary thyroid cancer.}, journal = {Hematology/oncology clinics of North America}, volume = {24}, number = {5}, pages = {907-937}, doi = {10.1016/j.hoc.2010.06.008}, pmid = {20816580}, issn = {1558-1977}, mesh = {Diagnosis, Differential ; *Genetic Predisposition to Disease ; Genetic Testing ; Genomic Imprinting ; Humans ; Multiple Endocrine Neoplasia Type 1/*genetics/therapy ; Multiple Endocrine Neoplasia Type 2a/*genetics/therapy ; Thyroid Neoplasms/*genetics/therapy ; }, abstract = {The hereditary paraganglioma, MEN1, MEN2, and hereditary thyroid cancer syndromes are clinically discernable and genetically distinct. The first 3 syndromes have been well characterized in the past 10 to 15 years. Recognizing these 3 syndromes and using a multidisciplinary team approach creates valuable opportunities for early diagnosis, reduction of morbidity and mortality, and avoidance of surgical misadventures. Hereditary paraganglioma has parent-of-origin effects and gene-environment interactions that indicate its evolution, and the syndrome sheds light on the role of mitochondria and energy metabolism in cancer. This article delineates the clinical presentation and practical management issues and summarizes the history, gene discovery, and molecular insights for each syndrome.}, } @article {pmid20704490, year = {2010}, author = {Pörtner, HO and Schulte, PM and Wood, CM and Schiemer, F}, title = {Niche dimensions in fishes: an integrative view.}, journal = {Physiological and biochemical zoology : PBZ}, volume = {83}, number = {5}, pages = {808-826}, doi = {10.1086/655977}, pmid = {20704490}, issn = {1537-5293}, mesh = {Adaptation, Biological/*physiology ; Animals ; *Biological Evolution ; Climate Change ; Ecology ; *Ecosystem ; Energy Metabolism/*physiology ; Fishes/*physiology ; Genetic Fitness/*physiology ; Mitochondria/*physiology ; Models, Theoretical ; Physiology, Comparative ; Species Specificity ; }, abstract = {Current shifts in ecosystem composition and function emphasize the need for an understanding of the links between environmental factors and organism fitness and tolerance. The examples discussed here illustrate how recent progress in the field of comparative physiology may provide a better mechanistic understanding of the ecological concepts of the fundamental and realized niches and thus provide insights into the impacts of anthropogenic disturbance. Here we argue that, as a link between physiological and ecological indicators of organismal performance, the mechanisms shaping aerobic scope and passive tolerance set the dimensions of an animal's niche, here defined as its capacity to survive, grow, behave, and interact with other species. We demonstrate how comparative studies of cod or killifish populations in a latitudinal cline have unraveled mitochondrial mechanisms involved in establishing a species' niche, performance, and energy budget. Riverine fish exemplify how the performance windows of various developmental stages follow the dynamic regimes of both seasonal temperatures and river hydrodynamics, as synergistic challenges. Finally, studies of species in extreme environments, such as the tilapia of Lake Magadi, illustrate how on evolutionary timescales functional and morphological shifts can occur, associated with new specializations. We conclude that research on the processes and time course of adaptations suitable to overcome current niche limits is urgently needed to assess the resilience of species and ecosystems to human impact, including the challenges of global climate change.}, } @article {pmid20685719, year = {2011}, author = {Scott, GR and Schulte, PM and Egginton, S and Scott, AL and Richards, JG and Milsom, WK}, title = {Molecular evolution of cytochrome C oxidase underlies high-altitude adaptation in the bar-headed goose.}, journal = {Molecular biology and evolution}, volume = {28}, number = {1}, pages = {351-363}, doi = {10.1093/molbev/msq205}, pmid = {20685719}, issn = {1537-1719}, mesh = {Adaptation, Physiological/*genetics ; *Altitude ; Animals ; Biological Evolution ; Coronary Vessels/metabolism ; Electron Transport Complex IV/chemistry/*genetics/metabolism ; Energy Metabolism/genetics ; *Evolution, Molecular ; Flight, Animal/physiology ; Geese/anatomy & histology/classification/*genetics/*physiology ; Hypoxia/genetics ; Isoenzymes/*genetics ; Mitochondria/genetics/metabolism ; Models, Molecular ; Myocardium/cytology/enzymology ; Oxygen Consumption/physiology ; Phylogeny ; Protein Conformation ; Protein Subunits/genetics/metabolism ; }, abstract = {Bar-headed geese (Anser indicus) fly at up to 9,000 m elevation during their migration over the Himalayas, sustaining high metabolic rates in the severe hypoxia at these altitudes. We investigated the evolution of cardiac energy metabolism and O(2) transport in this species to better understand the molecular and physiological mechanisms of high-altitude adaptation. Compared with low-altitude geese (pink-footed geese and barnacle geese), bar-headed geese had larger lungs and higher capillary densities in the left ventricle of the heart, both of which should improve O(2) diffusion during hypoxia. Although myoglobin abundance and the activities of many metabolic enzymes (carnitine palmitoyltransferase, citrate synthase, 3-hydroxyacyl-coA dehydrogenase, lactate dehydrogenase, and pyruvate kinase) showed only minor variation between species, bar-headed geese had a striking alteration in the kinetics of cytochrome c oxidase (COX), the heteromeric enzyme that catalyzes O(2) reduction in oxidative phosphorylation. This was reflected by a lower maximum catalytic activity and a higher affinity for reduced cytochrome c. There were small differences between species in messenger RNA and protein expression of COX subunits 3 and 4, but these were inconsistent with the divergence in enzyme kinetics. However, the COX3 gene of bar-headed geese contained a nonsynonymous substitution at a site that is otherwise conserved across vertebrates and resulted in a major functional change of amino acid class (Trp-116 → Arg). This mutation was predicted by structural modeling to alter the interaction between COX3 and COX1. Adaptations in mitochondrial enzyme kinetics and O(2) transport capacity may therefore contribute to the exceptional ability of bar-headed geese to fly high.}, } @article {pmid20680393, year = {2010}, author = {Bao, J and Sack, MN}, title = {Protein deacetylation by sirtuins: delineating a post-translational regulatory program responsive to nutrient and redox stressors.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {67}, number = {18}, pages = {3073-3087}, pmid = {20680393}, issn = {1420-9071}, support = {ZIA HL006047-02/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylation ; Humans ; Mitochondria/enzymology ; Neoplasms/enzymology ; Neurons/enzymology ; Oxidation-Reduction ; Phylogeny ; *Protein Processing, Post-Translational ; Proteins/*metabolism ; Sirtuins/classification/*metabolism ; }, abstract = {Lysine acetylation/deacetylation is increasingly being recognized as common post-translational modification that appears to be broadly operational throughout the cell. The functional roles of these modifications, outside of the nucleus, have not been extensively studied. Moreover, as acetyl-CoA donates the acetyl group for acetylation, nutrient availability and energetic status may be pivotal in this modification. Similarly, nutrient limitation is associated with the deacetylation reaction. This modification is orchestrated by a novel family of sirtuin deacetylases that function in a nutrient and redox dependent manner and targets non-histone protein deacetylation. In compartment-specific locations, candidate target proteins undergoing lysine-residue deacetylation are being identified. Through these investigations, the functional role of this post-translational modification is being delineated. We review the sirtuin family proteins, discuss their functional effects on target proteins, and postulate on potential biological programs and disease processes that may be modified by sirtuin-mediated deacetylation of target proteins.}, } @article {pmid20637123, year = {2010}, author = {Janz, D and Behnke, K and Schnitzler, JP and Kanawati, B and Schmitt-Kopplin, P and Polle, A}, title = {Pathway analysis of the transcriptome and metabolome of salt sensitive and tolerant poplar species reveals evolutionary adaption of stress tolerance mechanisms.}, journal = {BMC plant biology}, volume = {10}, number = {}, pages = {150}, pmid = {20637123}, issn = {1471-2229}, mesh = {*Adaptation, Physiological ; *Biological Evolution ; Energy Metabolism ; *Gene Expression Profiling ; Gene Expression Regulation, Plant ; *Metabolome ; Plant Leaves/chemistry/metabolism ; Populus/genetics/metabolism/*physiology ; Protein Transport ; Reproducibility of Results ; Sequence Homology, Nucleic Acid ; Sodium Chloride/*metabolism ; Starch/metabolism ; Stress, Physiological ; Sucrose/metabolism ; }, abstract = {BACKGROUND: Populus euphratica is a salt tolerant and Populus x canescens a salt sensitive poplar species. Because of low transcriptional responsiveness of P. euphratica to salinity we hypothesized that this species exhibits an innate activation of stress protective genes compared with salt sensitive poplars. To test this hypothesis, the transcriptome and metabolome of mature unstressed leaves of P. euphratica and P. x canescens were compared by whole genome microarray analyses and FT-ICR-MS metabolite profiling.

RESULTS: Direct cross-species comparison of the transcriptomes of the two poplar species from phylogenetically different sections required filtering of the data set. Genes assigned to the GO slim categories 'mitochondria', 'cell wall', 'transport', 'energy metabolism' and 'secondary metabolism' were significantly enriched, whereas genes in the categories 'nucleus', 'RNA or DNA binding', 'kinase activity' and 'transcription factor activity' were significantly depleted in P. euphratica compared with P. x canescens. Evidence for a general activation of stress relevant genes in P. euphratica was not detected. Pathway analyses of metabolome and transcriptome data indicated stronger accumulation of primary sugars, activation of pathways for sugar alcohol production, and faster consumption of secondary metabolites in P. euphratica compared to P. x canescens. Physiological measurements showing higher respiration, higher tannin and soluble phenolic contents as well as enrichment of glucose and fructose in P. euphratica compared to P. x canescens corroborated the results of pathway analyses.

CONCLUSION: P. euphratica does not rely on general over-expression of stress pathways to tolerate salt stress. Instead, it exhibits permanent activation of control mechanisms for osmotic adjustment (sugar and sugar alcohols), ion compartmentalization (sodium, potassium and other metabolite transporters) and detoxification of reactive oxygen species (phenolic compounds). The evolutionary adaptation of P. euphratica to saline environments is apparently linked with higher energy requirement of cellular metabolism and a loss of transcriptional regulation.}, } @article {pmid20625286, year = {2010}, author = {Cioffi, F and Lanni, A and Goglia, F}, title = {Thyroid hormones, mitochondrial bioenergetics and lipid handling.}, journal = {Current opinion in endocrinology, diabetes, and obesity}, volume = {17}, number = {5}, pages = {402-407}, doi = {10.1097/MED.0b013e32833cf354}, pmid = {20625286}, issn = {1752-2978}, mesh = {Acetates/pharmacology/therapeutic use ; Adiposity/drug effects ; Anilides/pharmacology/therapeutic use ; Animals ; Atherosclerosis/drug therapy ; Cardiovascular Diseases/drug therapy ; Clinical Trials as Topic ; Diiodothyronines/pharmacology/therapeutic use ; Dyslipidemias/drug therapy ; Energy Metabolism/drug effects ; Fatty Liver/drug therapy ; Humans ; *Lipid Metabolism ; Mice ; Mitochondria/*metabolism ; Obesity/drug therapy ; Phenols/pharmacology/therapeutic use ; Rats ; Thyroid Hormones/*metabolism/pharmacology ; }, abstract = {PURPOSE OF REVIEW: The article is principally intended to describe the recent evolutions in the field of research concerned with the metabolic actions of thyroid hormones and those of some of their metabolites or derivatives. Mitochondria, as a result of their functions, represent the principal objective of scientists investigating the mechanisms underlying the effects of thyroid hormones or their metabolites/derivatives.

RECENT FINDINGS: Indeed, some important recent findings concern these organelles, and in particular mitochondrial uncoupling and its modulation by effectors. Traditionally, thyroxine (T4) and tri-iodo-L-thyronine (T3) were the only thyroid hormones considered to have metabolic effects, and they alone were considered for potential as agents that might counteract some important abnormalities such as dyslipidaemias and obesity. Several observations, however, led to a reconsideration of this idea. In recent years, studies dealing with the biological activities of some natural metabolites or structural analogues of thyroid hormones have revealed abilities to ameliorate some major worldwide medical problems, such as artherosclerosis, obesity and cardiovascular diseases. Among natural metabolites, 3,5-diiodothyronine (T2) has been shown to powerfully reduce adiposity and dyslipidaemia and to reverse hepatic steatosis without unfavourable side-effects usually observed when T3 or T4 is used. Examples of synthetic analogues are GC-1 (or sobetirome) and KB2115 (or eprotirome) which show ipolipidaemic and antiaterogenic capacities. Clinical trials are in progress for these last agents.

SUMMARY: In view of the above-mentioned actions, some of these compounds are now undergoing clinical trials and may have important implications for clinical practice or researches in the field of both endocrinology and metabolic-related abnormalities such as diabetes and dyslipidaemias.}, } @article {pmid20568109, year = {2010}, author = {Monticone, M and Panfoli, I and Ravera, S and Puglisi, R and Jiang, MM and Morello, R and Candiani, S and Tonachini, L and Biticchi, R and Fabiano, A and Cancedda, R and Boitani, C and Castagnola, P}, title = {The nuclear genes Mtfr1 and Dufd1 regulate mitochondrial dynamic and cellular respiration.}, journal = {Journal of cellular physiology}, volume = {225}, number = {3}, pages = {767-776}, doi = {10.1002/jcp.22279}, pmid = {20568109}, issn = {1097-4652}, mesh = {Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Animals ; *Cell Respiration/genetics ; *Energy Metabolism/genetics ; Gene Expression Regulation, Developmental ; HeLa Cells ; Humans ; In Situ Hybridization ; Leydig Cells/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/*metabolism ; Mitochondrial Proteins/deficiency/genetics/*metabolism ; Molecular Sequence Data ; Oxygen Consumption ; Phylogeny ; Polymerase Chain Reaction ; RNA Interference ; RNA, Messenger/metabolism ; Sertoli Cells/metabolism ; Spermatids/metabolism ; Spermatocytes/metabolism ; Testis/cytology/*metabolism ; Transfection ; }, abstract = {Dufd1 (DUF729 domain containing 1) is related to Mtfr1 (mitochondrial fission regulator 1), a gene involved in the regulation of antioxidant activity in the mouse testis. The present study was undertaken to better understand their role in regulating mitochondrial architecture and function in the mouse. We show that Dufd1 is expressed as a 2 kb mRNA and has a more specific tissue pattern compared to Mtfr1, with highest level of expression in testes, lower level in spleen, and negligible levels in other organs and/or tissues. In the male gonad, Dufd1 mRNA expression increases during postnatal development, similarly to Mtfr1. In situ hybridization and real-time PCR analyses show that Dufd1 is expressed in the seminiferous tubules by middle-late pachytene spermatocytes and spermatids. In transfected cells, the Dufd1-tagged protein is located in mitochondria, associated with the tips of mitochondrial tubules and to tubules constrictions, and induces mitochondrial fission although with a lesser efficiency than Mtfr1. We also found that both endogenous Dufd1 and Mtfr1 proteins are associated with membrane-enriched subcellular fractions, including mitochondria. Inhibition of Mtfr1 and/or Dufd1 expression, in a testicular germ cells line, severely impairs O(2) consumption and indicates that both genes are required for mitochondrial respiration. Accordingly, analysis of testes mitochondria from Mtfr1-deficient mice reveals severely reduced O(2) consumption and ATP synthesis compared to wt animals. These data show that, in murine testis, Dufd1 and Mtfr1 have redundant functions related to mitochondrial physiology and represent genes with a potential role in testicular function.}, } @article {pmid20445102, year = {2010}, author = {Wallace, DC}, title = {Colloquium paper: bioenergetics, the origins of complexity, and the ascent of man.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107 Suppl 2}, number = {Suppl 2}, pages = {8947-8953}, pmid = {20445102}, issn = {1091-6490}, support = {NS21328/NS/NINDS NIH HHS/United States ; R01 AG024373-05/AG/NIA NIH HHS/United States ; AG16573/AG/NIA NIH HHS/United States ; R01 NS021328-24/NS/NINDS NIH HHS/United States ; R01 DK073691-04/DK/NIDDK NIH HHS/United States ; DK73691/DK/NIDDK NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; R01 AG013154-11/AG/NIA NIH HHS/United States ; AG24373/AG/NIA NIH HHS/United States ; R01 AG024373/AG/NIA NIH HHS/United States ; R01 DK073691/DK/NIDDK NIH HHS/United States ; R01 NS021328/NS/NINDS NIH HHS/United States ; R01 AG013154/AG/NIA NIH HHS/United States ; AG13154/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Biological Evolution ; Cell Nucleus/metabolism ; DNA/metabolism ; Electrochemistry/methods ; *Energy Metabolism ; Humans ; Membrane Potentials ; Mitochondria/metabolism ; Mutation ; Selection, Genetic ; }, abstract = {Complex structures are generated and maintained through energy flux. Structures embody information, and biological information is stored in nucleic acids. The progressive increase in biological complexity over geologic time is thus the consequence of the information-generating power of energy flow plus the information-accumulating capacity of DNA, winnowed by natural selection. Consequently, the most important component of the biological environment is energy flow: the availability of calories and their use for growth, survival, and reproduction. Animals can exploit and adapt to available energy resources at three levels. They can evolve different anatomical forms through nuclear DNA (nDNA) mutations permitting exploitation of alternative energy reservoirs, resulting in new species. They can evolve modified bioenergetic physiologies within a species, primarily through the high mutation rate of mitochondrial DNA (mtDNA)-encoded bioenergetic genes, permitting adjustment to regional energetic environments. They can alter the epigenomic regulation of the thousands of dispersed bioenergetic genes via mitochondrially generated high-energy intermediates permitting individual accommodation to short-term environmental energetic fluctuations. Because medicine pertains to a single species, Homo sapiens, functional human variation often involves sequence changes in bioenergetic genes, most commonly mtDNA mutations, plus changes in the expression of bioenergetic genes mediated by the epigenome. Consequently, common nDNA polymorphisms in anatomical genes may represent only a fraction of the genetic variation associated with the common "complex" diseases, and the ascent of man has been the product of 3.5 billion years of information generation by energy flow, accumulated and preserved in DNA and edited by natural selection.}, } @article {pmid20433942, year = {2010}, author = {Mogi, T and Kita, K}, title = {Diversity in mitochondrial metabolic pathways in parasitic protists Plasmodium and Cryptosporidium.}, journal = {Parasitology international}, volume = {59}, number = {3}, pages = {305-312}, doi = {10.1016/j.parint.2010.04.005}, pmid = {20433942}, issn = {1873-0329}, mesh = {Animals ; Cryptosporidiosis/parasitology ; Cryptosporidium/enzymology/genetics/*metabolism ; DNA, Mitochondrial/genetics/metabolism ; Humans ; Malaria/parasitology ; *Metabolic Networks and Pathways ; Mitochondria/enzymology/genetics/*metabolism ; Plasmodium/enzymology/genetics/*metabolism ; }, abstract = {Apicomplexans are obligate intracellular parasites and occupy diverse niches. They have remodeled mitochondrial carbon and energy metabolism through reductive evolution. Plasmodium lacks mitochondrial pyruvate dehydrogenase and H(+)-translocating NADH dehydrogenase (Complex I, NDH1). The mitochondorion contains a minimal mtDNA (approximately 6kb) and carries out oxidative phosphorylation in the insect vector stages, by using 2-oxoglutarate as an alternative means of entry into the TCA cycle and a single-subunit flavoprotein as an alternative NADH dehydrogenase (NDH2). In the blood stages of mammalian hosts, mitochondrial enzymes are down-regulated and parasite energy metabolism relies mainly on glycolysis. Mitosomes of Cryptosporidium parvum and Cryptosporidium hominis (human intestine parasites) lack mtDNA, pyruvate dehydrogenase, TCA cycle enzymes except malate-quinone oxidoreductase (MQO), and ATP synthase subunits except alpha and beta. In contrast, mitosomes of Cryptosporidium muris (a rodent gastric parasite) retain all TCA cycle enzymes and functional ATP synthase and carry out oxidative phosphorylation with pyruvate-NADP(+) oxidoreductase (PNO) and a simple and unique respiratory chain consisting of NDH2 and alternative oxidase (AOX). Cryptosporidium and Perkinsus are early branching groups of chromoalveolates (apicomplexa and dinoflagellates, respectively), and both Cryptosporidium mitosome and Perkinsus mitochondrion use PNO, MQO, and AOX. All apicomplexan parasites and dinoflagellates share MQO, which has been acquired from epsilon-proteobacteria via lateral gene transfer. By genome data mining on Plasmodium, Cryptosporidium and Perkinsus, here we summarized their mitochondrial metabolic pathways, which are varied largely from those of mammalian hosts. We hope that our findings will help in understanding the apicomplexan metabolism and development of new chemotherapeutics with novel targets.}, } @article {pmid20421465, year = {2010}, author = {Shen, YY and Liang, L and Zhu, ZH and Zhou, WP and Irwin, DM and Zhang, YP}, title = {Adaptive evolution of energy metabolism genes and the origin of flight in bats.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107}, number = {19}, pages = {8666-8671}, pmid = {20421465}, issn = {1091-6490}, mesh = {Adaptation, Physiological/*genetics ; Animals ; Chiroptera/*genetics/*physiology ; Energy Metabolism/*genetics ; *Evolution, Molecular ; Flight, Animal/*physiology ; Humans ; Molecular Sequence Data ; Phylogeny ; Rodentia/genetics ; Selection, Genetic ; }, abstract = {Bat flight poses intriguing questions about how flight independently developed in mammals. Flight is among the most energy-consuming activities. Thus, we deduced that changes in energy metabolism must be a primary factor in the origin of flight in bats. The respiratory chain of the mitochondrial produces 95% of the adenosine triphosphate (ATP) needed for locomotion. Because the respiratory chain has a dual genetic foundation, with genes encoded by both the mitochondrial and nuclear genomes, we examined both genomes to gain insights into the evolution of flight within mammals. Evidence for positive selection was detected in 23.08% of the mitochondrial-encoded and 4.90% of nuclear-encoded oxidative phosphorylation (OXPHOS) genes, but in only 2.25% of the nuclear-encoded nonrespiratory genes that function in mitochondria or 1.005% of other nuclear genes in bats. To address the caveat that the two available bat genomes are of only draft quality, we resequenced 77 OXPHOS genes from four species of bats. The analysis of the resequenced gene data are in agreement with our conclusion that a significantly higher proportion of genes involved in energy metabolism, compared with background genes, show evidence of adaptive evolution specific on the common ancestral bat lineage. Both mitochondrial and nuclear-encoded OXPHOS genes display evidence of adaptive evolution along the common ancestral branch of bats, supporting our hypothesis that genes involved in energy metabolism were targets of natural selection and allowed adaptation to the huge change in energy demand that were required during the origin of flight.}, } @article {pmid20345689, year = {2010}, author = {Ballard, JW and Melvin, RG}, title = {Linking the mitochondrial genotype to the organismal phenotype.}, journal = {Molecular ecology}, volume = {19}, number = {8}, pages = {1523-1539}, doi = {10.1111/j.1365-294X.2010.04594.x}, pmid = {20345689}, issn = {1365-294X}, mesh = {Adaptation, Biological/genetics ; Cell Nucleus/genetics ; DNA, Mitochondrial/genetics ; Energy Metabolism ; *Evolution, Molecular ; Genes, Mitochondrial ; Genetic Variation ; *Genotype ; Mitochondria/*genetics ; Models, Molecular ; Mutation ; Oxidative Phosphorylation ; *Phenotype ; Protein Structure, Quaternary ; }, abstract = {One of the grand challenges of the postgenomics era is to mechanistically link the genotype with the phenotype. Here, we consider the link between the mitochondrial genotype and the organismal phenotype that is provided by bioenergetic studies of the electron transport chain. That linkage is pertinent for the fields of molecular ecology and phylogeography as it tests if, and potentially how, natural selection can influence the evolutionary and demographic past of both populations and species. We introduce the mitochondrial genotype in terms of mitochondrial-encoded genes, nuclear-encoded genes that produce structural proteins imported into the mitochondria, and mitochondrial DNA-nuclear interactions. We then review the potential for quaternary structure modelling to predict the functional consequence of specific naturally occurring mutations. We discuss how the energy-producing reactions of oxidative phosphorylation can be used to provide a mechanistic biochemical link between genotype and phenotype. Experimental manipulations can then be used to test the functional consequences of specific mutations in multiple genetic backgrounds. Finally, we examine how mitochondria can influence the organismal mitochondrial phenotype using the examples of lifespan, fertility and starvation resistance and discuss how mitochondria may be involved in establishing both the upper and lower thermal limits of organisms. We conclude that mitochondrial DNA mutations can be important in determining aspects of organism life history. The question that remains to be resolved is how common are these adaptive mutations?}, } @article {pmid20334646, year = {2010}, author = {Li, D and Guo, Y and Shao, H and Tellier, LC and Wang, J and Xiang, Z and Xia, Q}, title = {Genetic diversity, molecular phylogeny and selection evidence of the silkworm mitochondria implicated by complete resequencing of 41 genomes.}, journal = {BMC evolutionary biology}, volume = {10}, number = {}, pages = {81}, pmid = {20334646}, issn = {1471-2148}, mesh = {Animals ; Bombyx/classification/*genetics ; Comparative Genomic Hybridization ; Cytochromes b/genetics ; DNA, Mitochondrial/genetics ; *Evolution, Molecular ; Genes, Insect ; *Genome, Insect ; *Genome, Mitochondrial ; Linkage Disequilibrium ; *Phylogeny ; Polymorphism, Single Nucleotide ; Population Density ; Selection, Genetic ; Sequence Alignment ; Sequence Analysis, DNA ; }, abstract = {BACKGROUND: Mitochondria are a valuable resource for studying the evolutionary process and deducing phylogeny. A few mitochondria genomes have been sequenced, but a comprehensive picture of the domestication event for silkworm mitochondria remains to be established. In this study, we integrate the extant data, and perform a whole genome resequencing of Japanese wild silkworm to obtain breakthrough results in silkworm mitochondrial (mt) population, and finally use these to deduce a more comprehensive phylogeny of the Bombycidae.

RESULTS: We identified 347 single nucleotide polymorphisms (SNPs) in the mt genome, but found no past recombination event to have occurred in the silkworm progenitor. A phylogeny inferred from these whole genome SNPs resulted in a well-classified tree, confirming that the domesticated silkworm, Bombyx mori, most recently diverged from the Chinese wild silkworm, rather than from the Japanese wild silkworm. We showed that the population sizes of the domesticated and Chinese wild silkworms both experience neither expansion nor contraction. We also discovered that one mt gene, named cytochrome b, shows a strong signal of positive selection in the domesticated clade. This gene is related to energy metabolism, and may have played an important role during silkworm domestication.

CONCLUSIONS: We present a comparative analysis on 41 mt genomes of B. mori and B. mandarina from China and Japan. With these, we obtain a much clearer picture of the evolution history of the silkworm. The data and analyses presented here aid our understanding of the silkworm in general, and provide a crucial insight into silkworm phylogeny.}, } @article {pmid20198570, year = {2010}, author = {Ning, T and Xiao, H and Li, J and Hua, S and Zhang, YP}, title = {Adaptive evolution of the mitochondrial ND6 gene in the domestic horse.}, journal = {Genetics and molecular research : GMR}, volume = {9}, number = {1}, pages = {144-150}, doi = {10.4238/vol9-1gmr705}, pmid = {20198570}, issn = {1676-5680}, mesh = {Altitude ; Animals ; China ; *Evolution, Molecular ; Genes, Mitochondrial/*genetics ; Genetic Variation ; Horses/*genetics ; Likelihood Functions ; NADH Dehydrogenase/*genetics ; Phylogeny ; Selection, Genetic ; }, abstract = {Mitochondria play a crucial role in energy metabolism through oxidative phosphorylation. Organisms living at high altitudes are potentially influenced by oxygen deficits and cold temperatures. The severe environmental conditions can impact on metabolism and direct selection of mitochondrial DNA. As a wide-ranging animal, the domestic horse (Equus caballus) has developed various morphological and physiological characteristics for adapting to different altitudes. Thus, this is a good species for studying adaption to high altitudes at a molecular level. We sequenced the complete NADH dehydrogenase 6 gene (ND6) of 509 horses from 24 sampling locations. By comparative analysis of three horse populations living at different altitudes (>2200 m, 1200-1700 m, and <900 m), we found that the high-altitude population had the lowest genetic diversity and significant negative Tajima's D; both values declined with increasing elevation. Moreover, non-directional selection was identified for the ND6 gene by a tree-based relative ratio test (P = 0.007); the highest proportion of high-altitude horses was found distributed on the selected branches. We conclude that the high-altitude environment has directed adaptive evolution of the mitochondrial ND6 gene in the plateau horse.}, } @article {pmid20157523, year = {2009}, author = {Blagosklonny, MV and Hall, MN}, title = {Growth and aging: a common molecular mechanism.}, journal = {Aging}, volume = {1}, number = {4}, pages = {357-362}, pmid = {20157523}, issn = {1945-4589}, mesh = {Aging/*physiology ; Animals ; *Biological Evolution ; Energy Metabolism ; Humans ; Signal Transduction/*genetics/*physiology ; }, abstract = {It is commonly assumed that growth and aging are somehow linked, but the nature of this link has been elusive. Here we review the aging process as a continuation of TOR-driven growth. TOR is absolutely essential for developmental growth, but upon completion of development it causes aging and age-related diseases. Thus, the nutrient-sensing and growth-promoting TOR signaling pathway may provide a molecular link between growth and aging that is universal from yeast to human.}, } @article {pmid20105154, year = {2010}, author = {Clarke, A and Pörtner, HO}, title = {Temperature, metabolic power and the evolution of endothermy.}, journal = {Biological reviews of the Cambridge Philosophical Society}, volume = {85}, number = {4}, pages = {703-727}, doi = {10.1111/j.1469-185X.2010.00122.x}, pmid = {20105154}, issn = {1469-185X}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; *Biological Evolution ; Biometry ; *Body Temperature Regulation ; *Energy Metabolism ; Humans ; Mitochondria/metabolism ; Models, Biological ; Muscles/metabolism ; Oxygen Consumption ; Thermogenesis ; }, abstract = {Endothermy has evolved at least twice, in the precursors to modern mammals and birds. The most widely accepted explanation for the evolution of endothermy has been selection for enhanced aerobic capacity. We review this hypothesis in the light of advances in our understanding of ATP generation by mitochondria and muscle performance. Together with the development of isotope-based techniques for the measurement of metabolic rate in free-ranging vertebrates these have confirmed the importance of aerobic scope in the evolution of endothermy: absolute aerobic scope, ATP generation by mitochondria and muscle power output are all strongly temperature-dependent, indicating that there would have been significant improvement in whole-organism locomotor ability with a warmer body. New data on mitochondrial ATP generation and proton leak suggest that the thermal physiology of mitochondria may differ between organisms of contrasting ecology and thermal flexibility. Together with recent biophysical modelling, this strengthens the long-held view that endothermy originated in smaller, active eurythermal ectotherms living in a cool but variable thermal environment. We propose that rather than being a secondary consequence of the evolution of an enhanced aerobic scope, a warmer body was the means by which that enhanced aerobic scope was achieved. This modified hypothesis requires that the rise in metabolic rate and the insulation necessary to retain metabolic heat arose early in the lineages leading to birds and mammals. Large dinosaurs were warm, but were not endotherms, and the metabolic status of pterosaurs remains unresolved.}, } @article {pmid20050804, year = {2010}, author = {Robert, KA and Bronikowski, AM}, title = {Evolution of senescence in nature: physiological evolution in populations of garter snake with divergent life histories.}, journal = {The American naturalist}, volume = {175}, number = {2}, pages = {147-159}, doi = {10.1086/649595}, pmid = {20050804}, issn = {1537-5323}, mesh = {Aging/*genetics/*physiology ; Animals ; Animals, Newborn ; *Biological Evolution ; Corticosterone ; DNA Damage ; DNA Repair ; Energy Metabolism ; Free Radicals/metabolism ; Mitochondria/physiology ; Oxidative Stress ; Snakes/classification/*genetics/*physiology ; }, abstract = {Evolutionary theories of aging are linked to life-history theory in that age-specific schedules of reproduction and survival determine the trajectory of age-specific mutation/selection balances across the life span and thus the rate of senescence. This is predicted to manifest at the organismal level in the evolution of energy allocation strategies of investing in somatic maintenance and robust stress responses in less hazardous environments in exchange for energy spent on growth and reproduction. Here we report experiments from long-studied populations of western terrestrial garter snakes (Thamnophis elegans) that reside in low and high extrinsic mortality environments, with evolved long and short life spans, respectively. Laboratory common-environment colonies of these two ecotypes were tested for a suite of physiological traits after control and stressed gestations. In offspring derived from control and corticosterone-treated dams, we measured resting metabolism; mitochondrial oxygen consumption, ATP and free radical production rates; and erythrocyte DNA damage and repair ability. We evaluated whether these aging biomarkers mirrored the evolution of life span and whether they were sensitive to stress. Neonates from the long-lived ecotype (1) were smaller, (2) consumed equal amounts of oxygen when corrected for body mass, (3) had DNA that damaged more readily but repaired more efficiently, and (4) had more efficient mitochondria and more efficient cellular antioxidant defenses than short-lived snakes. Many ecotype differences were enhanced in offspring derived from stress-treated dams, which supports the conclusion that nongenetic maternal effects may further impact the cellular stress defenses of offspring. Our findings reveal that physiological evolution underpins reptilian life histories and sheds light on the connectedness between stress response and aging pathways in wild-dwelling organisms.}, } @article {pmid20042463, year = {2010}, author = {Dallabona, C and Marsano, RM and Arzuffi, P and Ghezzi, D and Mancini, P and Zeviani, M and Ferrero, I and Donnini, C}, title = {Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator.}, journal = {Human molecular genetics}, volume = {19}, number = {6}, pages = {1098-1107}, doi = {10.1093/hmg/ddp581}, pmid = {20042463}, issn = {1460-2083}, support = {GGP07019/TI_/Telethon/Italy ; }, mesh = {Alleles ; Blotting, Northern ; Blotting, Western ; Citric Acid Cycle/genetics ; *Energy Metabolism ; Gene Dosage/genetics ; Gene Expression Regulation, Fungal ; Genes, Suppressor ; Genetic Complementation Test ; Humans ; Membrane Proteins/*chemistry/genetics/*metabolism ; Mitochondria/enzymology/*metabolism/ultrastructure ; Mitochondrial Proteins/*chemistry/genetics/*metabolism ; *Morphogenesis ; Mutation/genetics ; Oxidation-Reduction ; Phenotype ; Promoter Regions, Genetic/genetics ; Saccharomyces cerevisiae/cytology/growth & development/ultrastructure ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism ; *Sequence Homology, Amino Acid ; *Stress, Physiological ; Transcription, Genetic ; }, abstract = {A peculiar form of hepatocerebral mtDNA depletion syndrome is caused by mutations in the MPV17 gene, which encodes a small hydrophobic protein of unknown function located in the mitochondrial inner membrane. In order to define the molecular basis of MPV17 variants associated with the human disorder, we have previously taken advantage of S. cerevisiae as a model system thanks to the presence of an MPV17 ortholog gene, SYM1. We demonstrate here that the SYM1 gene product is essential to maintain OXPHOS, glycogen storage, mitochondrial morphology and mtDNA stability in stressing conditions such as high temperature and ethanol-dependent growth. To gain insight into the molecular basis of the Sym1-less phenotype, we identified and characterized multicopy suppressor genes and metabolic suppressor compounds. Our results suggest that (i) metabolic impairment and mtDNA instability occur independently from each other as a consequence of SYM1 ablation; (ii) ablation of Sym1 causes depletion of glycogen storage, possibly due to defective anaplerotic flux of tricarboxylic acid (TCA) cycle intermediates to the cytosol; (iii) flattening of mitochondrial cristae in Sym1-defective organelles suggests a role for Sym1 in the structural preservation of the inner mitochondrial membrane, which could in turn control mtDNA maintenance and stability.}, } @article {pmid19955254, year = {2009}, author = {Wallace, DC}, title = {Mitochondria, bioenergetics, and the epigenome in eukaryotic and human evolution.}, journal = {Cold Spring Harbor symposia on quantitative biology}, volume = {74}, number = {}, pages = {383-393}, pmid = {19955254}, issn = {1943-4456}, support = {NS21328/NS/NINDS NIH HHS/United States ; R01 AG024373-05/AG/NIA NIH HHS/United States ; AG16573/AG/NIA NIH HHS/United States ; R01 NS021328-24/NS/NINDS NIH HHS/United States ; R01 DK073691-04/DK/NIDDK NIH HHS/United States ; DK73691/DK/NIDDK NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; R01 AG013154-11/AG/NIA NIH HHS/United States ; AG24373/AG/NIA NIH HHS/United States ; R01 AG024373/AG/NIA NIH HHS/United States ; R01 DK073691/DK/NIDDK NIH HHS/United States ; R01 NS021328/NS/NINDS NIH HHS/United States ; R01 AG013154/AG/NIA NIH HHS/United States ; AG13154/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; DNA, Mitochondrial/genetics ; Disease/genetics ; Energy Metabolism/*genetics ; *Epigenesis, Genetic ; Eukaryota ; *Evolution, Molecular ; Genetic Speciation ; Humans ; Mitochondria/*genetics/*metabolism ; Models, Genetic ; Mutation ; }, abstract = {Studies on the origin of species have focused largely on anatomy, yet animal populations are generally limited by energy. Animals can adapt to available energy resources at three levels: (1) evolution of different anatomical forms between groups of animals through nuclear DNA (nDNA) mutations, permitting exploitation of alternative energy reservoirs and resulting in new species with novel niches, (2) evolution of different physiologies within intraspecific populations through mutations in mitochondrial DNA (mtDNA) and nDNA bioenergetic genes, permitting adjustment to energetic variation within a species' niche, and (3) epigenomic regulation of dispersed bioenergetic genes within an individual via mitochondrially generated high-energy intermediates, permitting individual adjustment to environmental fluctuations. Because medicine focuses on changes within our species, clinically relevant variation is more likely to involve changes in bioenergetics than anatomy. This may explain why mitochondrial diseases and epigenomic diseases frequently have similar phenotypes and why epigenomic diseases are being found to involve mitochondrial dysfunction. Therefore, common complex diseases may be the result of changes in any of a large number of mtDNA and nDNA bioenergetic genes or to altered epigenomic regulation of these bioenergetic genes. All of these changes result in similar bioenergetic failure and consequently related phenotypes.}, } @article {pmid19946245, year = {2009}, author = {Kream, RM and Stefano, GB}, title = {Endogenous morphine and nitric oxide coupled regulation of mitochondrial processes.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {15}, number = {12}, pages = {RA263-8}, pmid = {19946245}, issn = {1643-3750}, mesh = {Animals ; Biological Evolution ; Cardiovascular System/metabolism ; Catecholamines/metabolism ; Humans ; Mitochondria/*metabolism ; Models, Biological ; Morphine/*metabolism ; Nitric Oxide/*metabolism ; Receptors, Opioid, mu/chemistry/metabolism ; Signal Transduction ; }, abstract = {The widespread expression of morphine by plants, invertebrate and vertebrate cells/organ systems strongly indicates a high level of evolutionary conservation of morphine and related morphinan alkaloids as essential chemical factors required for normal growth and development. The prototype catecholamine dopamine (DA) serves as an essential chemical intermediate in morphine biosynthesis both in plants and animals. We surmise primordial, multi-potential cell types, before the emergence of specialized plant and animal cells/organ systems, required selective mechanisms to limit their responsiveness to environmental noise. Accordingly, cellular systems that emerged with the potential for recruitment of the free radical gas nitric oxide (NO) as a multi-faceted autocrine/paracrine signaling molecule were provided with extremely positive evolutionary advantages. Endogenous "morphinergic" in concert with NO-coupled signaling systems have evolved as autocrine/paracrine regulators of metabolic homeostasis, energy metabolism, mitochondrial respiration and energy production. Basic physiological processes involving "morphinergic"/NO-coupled regulation of mitochondrial function, with special emphasis on the cardiovascular system, are critical to all organismic survival. Critical to this concept may be the phenomenon of mitochondrial enslavement in eukaryotic evolution via morphine.}, } @article {pmid19768753, year = {2009}, author = {Jaroszewska, M and Dabrowski, K}, title = {The nature of exocytosis in the yolk trophoblastic layer of silver arowana (Osteoglossum bicirrhosum) juvenile, the representative of ancient teleost fishes.}, journal = {Anatomical record (Hoboken, N.J. : 2007)}, volume = {292}, number = {11}, pages = {1745-1755}, doi = {10.1002/ar.20996}, pmid = {19768753}, issn = {1932-8494}, mesh = {Animals ; Biological Evolution ; Bodily Secretions/physiology ; Embryo, Nonmammalian/cytology/*physiology ; Embryonic Development/physiology ; Energy Metabolism/physiology ; Exocytosis/*physiology ; Fishes/*embryology/physiology ; Hydrolysis ; Lipoproteins/metabolism ; Microvilli/physiology/ultrastructure ; Mitochondria/physiology/ultrastructure ; Phylogeny ; Species Specificity ; Trophoblasts/cytology/*metabolism ; Yolk Sac/cytology/*metabolism ; }, abstract = {We have chosen the silver arowana (Osteoglossum bicirrhosum), a representative of the most ancient teleost family Osteoglossidae, to address the question of yolk nutrients utilization. Silver arowana have particularly large eggs (1-1.5 cm of diameter) and a unique morphology of the yolk. We present evidence that the yolk cytoplasmic zone (ycz) in the "yolksac juveniles" is a very complex structure involved in sequential processes of yolk hydrolysis, lipoprotein particles synthesis, their transport, and exocytosis. Vacuoles filled with yolk granules in different stages of digestion move from the vitellolysis zone through the ycz to be emptied into the microvillar interspace in the process of exocytosis. The area of the ycz with the abundance of the mitochondria must play an important role in providing energy for both the transport of vacuoles and the release of their contents. Therefore, we postulate that the function of yolk syncytial layer (ysl) as the "early embryonic patterning center" transforms in fish larvae or yolksac juveniles into a predominantly specialized role as the yolk trophoblastic layer (ytl) involved in yolk nutrients utilization. In addition to discovering the mechanism of transformation of the ysl function into ytl function, we suggest that the machinery involved in nutrient mobilization and exocytosis in yolk of arowana yolksac juveniles can be very attractive system for studies of regulatory processes in almost all secretory pathways in animal cells.}, } @article {pmid19657102, year = {2009}, author = {Scott, GR and Richards, JG and Milsom, WK}, title = {Control of respiration in flight muscle from the high-altitude bar-headed goose and low-altitude birds.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {297}, number = {4}, pages = {R1066-74}, doi = {10.1152/ajpregu.00241.2009}, pmid = {19657102}, issn = {1522-1490}, mesh = {Acclimatization ; Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; *Altitude ; *Animal Migration ; Animals ; Biological Evolution ; Cell Respiration ; Creatine/metabolism ; Creatine Kinase, Mitochondrial Form/metabolism ; Ducks/*physiology ; Electron Transport Complex IV/metabolism ; *Energy Metabolism ; *Flight, Animal ; Geese/*physiology ; Glycolysis ; Kinetics ; Mitochondria, Muscle/metabolism ; *Muscle Contraction ; Oxidative Phosphorylation ; Pectoralis Muscles/enzymology/*metabolism ; Succinic Acid/metabolism ; }, abstract = {Bar-headed geese fly at altitudes of up to 9,000 m on their biannual migration over the Himalayas. To determine whether the flight muscle of this species has evolved to facilitate exercise at high altitude, we compared the respiratory properties of permeabilized muscle fibers from bar-headed geese and several low-altitude waterfowl species. Respiratory capacities were assessed for maximal ADP stimulation (with single or multiple inputs to the electron transport system) and cytochrome oxidase excess capacity (with an exogenous electron donor) and were generally 20-40% higher in bar-headed geese when creatine was present. When respiration rates were extrapolated to the entire pectoral muscle mass, bar-headed geese had a higher mass-specific aerobic capacity. This may represent a surplus capacity that counteracts the depressive effects of hypoxia on mitochondrial respiration. However, there were no differences in activity for mitochondrial or glycolytic enzymes measured in homogenized muscle. The [ADP] leading to half-maximal stimulation (K(m)) was approximately twofold higher in bar-headed geese (10 vs. 4-6 microM), and, while creatine reduced K(m) by 30% in this species, it had no effect on K(m) in low-altitude birds. Mitochondrial creatine kinase may therefore contribute to the regulation of oxidative phosphorylation in flight muscle of bar-headed geese, which could promote efficient coupling of ATP supply and demand. However, this was not based on differences in creatine kinase activity in isolated mitochondria or homogenized muscle. The unique differences in bar-headed geese existed without prior exercise or hypoxia exposure and were not a result of phylogenetic history, and may, therefore, be important evolutionary specializations for high-altitude flight.}, } @article {pmid19617425, year = {2009}, author = {Walter, I and Seebacher, F}, title = {Endothermy in birds: underlying molecular mechanisms.}, journal = {The Journal of experimental biology}, volume = {212}, number = {Pt 15}, pages = {2328-2336}, doi = {10.1242/jeb.029009}, pmid = {19617425}, issn = {0022-0949}, mesh = {Animals ; Body Temperature Regulation/*physiology ; Cell Respiration ; Chick Embryo ; Chickens/growth & development/metabolism/*physiology ; Energy Metabolism ; Mitochondria/metabolism ; Oxidation-Reduction ; Thyroid Hormones/physiology ; }, abstract = {Endothermy is significant in vertebrate evolution because it changes the relations between animals and their environment. How endothermy has evolved in archosaurs (birds, crocodiles and dinosaurs) is controversial especially because birds do not possess brown adipose tissue, the specialized endothermic tissue of mammals. Internal heat production is facilitated by increased oxidative metabolic capacity, accompanied by the uncoupling of aerobic metabolism from energy (ATP) production. Here we show that the transition from an ectothermic to an endothermic metabolic state in developing chicken embryos occurs by the interaction between increased basal ATP demand (Na(+)/K(+)-ATPase activity and gene expression), increased oxidative capacity and increased uncoupling of mitochondria; this process is controlled by thyroid hormone via its effect on PGC1alpha and adenine nucleotide translocase (ANT) gene expression. Mitochondria become more uncoupled during development, but unlike in mammals, avian uncoupling protein (avUCP) does not uncouple electron transport from oxidative phosphorylation and therefore plays no role in heat production. Instead, ANT is the principal uncoupling protein in birds. The relationship between oxidative capacity and uncoupling indicates that there is a continuum of phenotypes that fall between the extremes of selection for increased heat production and increased aerobic activity, whereas increased cellular ATP demand is a prerequisite for increased oxidative capacity.}, } @article {pmid19496327, year = {2009}, author = {Savina, MV and Emel'yanova, LV and Korotkov, SM and Brailovskaya, IV and Nadeev, AD}, title = {Bioenergetics of mitochondria of the liver with biliary atresia during prolonged starvation.}, journal = {Doklady. Biochemistry and biophysics}, volume = {425}, number = {}, pages = {80-83}, pmid = {19496327}, issn = {1607-6729}, mesh = {Animals ; Biliary Atresia/*metabolism/*pathology ; *Energy Metabolism ; Female ; Fluorescence ; Humans ; Lampreys/metabolism ; Liver/metabolism/*pathology ; Male ; Mitochondria/*metabolism/pathology ; Mitochondrial Swelling/drug effects ; Phenazines/metabolism ; Rats ; Seasons ; Starvation/*metabolism/*pathology ; Time Factors ; Voltage-Dependent Anion Channels/antagonists & inhibitors ; }, } @article {pmid19408245, year = {2009}, author = {Gershoni, M and Templeton, AR and Mishmar, D}, title = {Mitochondrial bioenergetics as a major motive force of speciation.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {31}, number = {6}, pages = {642-650}, doi = {10.1002/bies.200800139}, pmid = {19408245}, issn = {1521-1878}, mesh = {Animals ; Biological Evolution ; DNA/genetics/metabolism ; *DNA, Mitochondrial/genetics/metabolism ; Energy Metabolism/*genetics ; Environment ; *Genetic Speciation ; Genetic Variation ; Humans ; *Mitochondria/genetics/metabolism ; Oxidative Phosphorylation ; }, abstract = {Mitochondrial bioenergetics plays a key role in multiple basic cellular processes, such as energy production, nucleotide biosynthesis, and iron metabolism. It is an essential system for animals' life and death (apoptosis) and it is required for embryo development. This, in conjunction with its being subjected to adaptive processes in multiple species and its gene products being involved in the formation of reproductive barriers in animals, raises the possibility that mitochondrial bioenergetics could be a candidate genetic mechanism of speciation. Here, we discuss genetic and biochemical evidence for the possible involvement of this unique system, encoded by two genomes (the mitochondrial and nuclear genomes), that differ by an order of magnitude in their mutation rates in processes leading to speciation events.}, } @article {pmid19325118, year = {2009}, author = {Takeuchi, K and Nakano, Y and Kato, U and Kaneda, M and Aizu, M and Awano, W and Yonemura, S and Kiyonaka, S and Mori, Y and Yamamoto, D and Umeda, M}, title = {Changes in temperature preferences and energy homeostasis in dystroglycan mutants.}, journal = {Science (New York, N.Y.)}, volume = {323}, number = {5922}, pages = {1740-1743}, doi = {10.1126/science.1165712}, pmid = {19325118}, issn = {1095-9203}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Animals, Genetically Modified ; Body Temperature Regulation ; Calcium/metabolism ; *Cold Temperature ; Drosophila Proteins/genetics/*physiology ; Drosophila melanogaster/genetics/*physiology ; Dystroglycans/genetics/*physiology ; *Energy Metabolism ; Homeostasis ; Mitochondria/metabolism ; Mutant Proteins ; Mutation ; Oxygen Consumption ; Phenotype ; Pyruvate Dehydrogenase Complex/metabolism ; Temperature ; }, abstract = {Temperature affects the physiology, behavior, and evolution of organisms. We conducted mutagenesis and screens for mutants with altered temperature preference in Drosophila melanogaster and identified a cryophilic (cold-seeking) mutant, named atsugari (atu). Reduced expression of the Drosophila ortholog of dystroglycan (DmDG) induced tolerance to cold as well as preference for the low temperature. A sustained increase in mitochondrial oxidative metabolism caused by the reduced expression of DmDG accounted for the cryophilic phenotype of the atu mutant. Although most ectothermic animals do not use metabolically produced heat to regulate body temperature, our results indicate that their thermoregulatory behavior is closely linked to rates of mitochondrial oxidative metabolism and that a mutation in a single gene can induce a sustained change in energy homeostasis and the thermal responses.}, } @article {pmid19324832, year = {2009}, author = {Tieleman, BI and Versteegh, MA and Fries, A and Helm, B and Dingemanse, NJ and Gibbs, HL and Williams, JB}, title = {Genetic modulation of energy metabolism in birds through mitochondrial function.}, journal = {Proceedings. Biological sciences}, volume = {276}, number = {1662}, pages = {1685-1693}, pmid = {19324832}, issn = {0962-8452}, mesh = {Animals ; Basal Metabolism/*genetics ; Body Size ; DNA, Mitochondrial ; Female ; *Genetic Variation ; Hybridization, Genetic ; Male ; Mitochondria/genetics/*physiology ; Songbirds/*genetics/metabolism ; }, abstract = {Despite their central importance for the evolution of physiological variation, the genetic mechanisms that determine energy expenditure in animals have largely remained unstudied. We used quantitative genetics to confirm that both mass-specific and whole-organism basal metabolic rate (BMR) were heritable in a captive-bred population of stonechats (Saxicola torquata spp.) founded on birds from three wild populations (Europe, Africa and Asia) that differed in BMR. This argues that BMR is at least partially under genetic control by multiple unknown nuclear loci each with a limited effect on the phenotype. We then tested for a genetic effect on BMR based on mitochondrial-nuclear coadaptation using hybrids between ancestral populations with high and low BMR (Europe-Africa and Asia-Europe), with different parental configurations (female(high)-male(low) or female(low)-male(high)) within each combination of populations. Hybrids with different parental configurations have on average identical mixtures of nuclear DNA, but differ in mitochondrial DNA because it is inherited only from the mother. Mass-specific BMR differed between hybrids with different parental configurations, implying that the combination of mitochondrial and nuclear DNA affected metabolic rate. Therefore, our findings implicate mitochondrial function as an important regulator of energy metabolism. In combination with the substantial heritabilities of metabolic rate, and corroborated by genetic differences in the mitochondrial genome, these results set the stage for further investigations of a genetic control mechanism involving both mitochondrial and nuclear genes determining metabolic rate at the whole-organism level.}, } @article {pmid19306035, year = {2009}, author = {Bouteloup, C and Desport, JC and Clavelou, P and Guy, N and Derumeaux-Burel, H and Ferrier, A and Couratier, P}, title = {Hypermetabolism in ALS patients: an early and persistent phenomenon.}, journal = {Journal of neurology}, volume = {256}, number = {8}, pages = {1236-1242}, pmid = {19306035}, issn = {1432-1459}, mesh = {Age Distribution ; Aged ; Aging/metabolism ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/physiopathology ; Basal Metabolism/*physiology ; Biomarkers/analysis/metabolism ; Dietary Proteins/metabolism ; Disease Progression ; Eating/physiology ; Energy Metabolism/*physiology ; Female ; Humans ; Male ; Metabolic Diseases/genetics/*metabolism/physiopathology ; Middle Aged ; Mitochondrial Diseases/genetics/metabolism/physiopathology ; Predictive Value of Tests ; Prognosis ; Serum Albumin/analysis/metabolism ; Time Factors ; }, abstract = {The malnutrition common among patients with ALS can be attributed in some cases to increased resting energy expenditure (REE). However, the origins and evolution of this hypermetabolism have yet to be fully elucidated. The aim of the present study was to monitor REE over time in patients with ALS and to identify factors that may explain any variation observed. ALS patients underwent nutritional, neurological and respiratory assessment every 6 months for 2 years (or until they died or became physically incapable of being examined). Sixty-one patients were studied. At inclusion, 47.5% exhibited hypermetabolism, with a mean measured REE (mREE) 19.7 +/- 6.4% higher than the mean calculated REE (cREE) (P < 0.0001). The hypermetabolism persisted when mREE was normalized for fat free mass (FFM): 35.1 +/- 4.2 versus 32.3 +/- 4.7 kcal/kg day(-1) (P = 0.02) in hypermetabolic and normometabolic patients, respectively. In univariate analysis, mREE was negatively correlated with age and positively correlated with BMI, FFM, energy and protein intakes, and albumin level. No correlation was found with neurological scores, disease characteristics, respiratory function and survival. Multivariate analysis revealed no significant factors. Only 10 of 45 patients in whom REE was measured at least twice changed their metabolic status. Neither mREE nor mREE/cREE varied significantly over time, despite deteriorating neurological, nutritional and respiratory parameters (P < 0.0001), and an increase in mREE/FFM (P = 0.01). This study confirms that about 50% of ALS patients are hypermetabolic, and 80% show no change in metabolic status over time. Thus, metabolic status (a clinically useful indicator of the need for nutritional support) can be determined early in the evolution of the disease. The origin of hypermetabolism in this context remains unknown, but growing evidence points to mitochondria as having an important role.}, } @article {pmid19067526, year = {2008}, author = {McGill, AT}, title = {Malnutritive obesity ('malnubesity'): is it driven by human brain evolution?.}, journal = {Metabolic syndrome and related disorders}, volume = {6}, number = {4}, pages = {241-246}, doi = {10.1089/met.2008.0031}, pmid = {19067526}, issn = {1557-8518}, mesh = {Animals ; Antioxidants/metabolism ; Biological Evolution ; Brain/*physiology ; Diet ; Energy Metabolism ; Humans ; Immune System ; Malnutrition/*diagnosis/genetics ; *Metabolism ; Nutritional Sciences ; Obesity/*diagnosis/genetics/prevention & control ; Phenotype ; Public Health ; }, abstract = {Abstract Health messages on low-energy diets for healthy weight loss are muddled and not working, and obesity rates are rising. Are there missing links? Accumulating evidence shows that humans have well developed 'self-addictive' appetite pathways to enhance the uptake of highly energy-dense food. Humans synthesize fewer co-factors and vitamins than other mammals and must ingest them. Both processes probably arose to maximize available energy for the developing, large association cortex of the human brain. The default phenotype resulting from consuming an 'addictive', westernized, highly refined, energy-dense, hypomicronutrient diet is 'malnutritive obesity' or 'malnubesity'. A relative lack of antioxidant (and other) co-factors contributes to inefficiently oxidized energy. This 'stress' leads to central fat deposition, disordered energy use by cell mitochondria, especially in muscle and liver, and malfunctioning immune, coagulation, endothelial, and other systems. The resultant problems appear to range from epigenetic reprogramming in utero to end organ damage of the metabolic syndrome and the immune failure of cancer. Treatment of 'malnubesity' may require: (1) understanding the drivers and mechanisms of addictions, (2) reprioritizing satiating, micronutrient-dense whole foods, (3) nonjudgmental general, psychological, and medical support for those at risk or affected by obesity; and (4) practical incentives/regulation for healthy food production and distribution.}, } @article {pmid19033201, year = {2008}, author = {Rostovtseva, TK and Sheldon, KL and Hassanzadeh, E and Monge, C and Saks, V and Bezrukov, SM and Sackett, DL}, title = {Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {105}, number = {48}, pages = {18746-18751}, pmid = {19033201}, issn = {1091-6490}, support = {//Intramural NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Cell Respiration/*physiology ; Electrophysiology ; Evolution, Molecular ; Humans ; Ion Channel Gating ; Lipid Bilayers/chemistry ; Mitochondria/*metabolism ; Models, Molecular ; Molecular Sequence Data ; Oxidative Phosphorylation ; Peptides/chemistry/genetics/metabolism ; Protein Binding ; Protein Conformation ; Rats ; Sequence Alignment ; Tubulin/chemistry/genetics/*metabolism ; Voltage-Dependent Anion Channels/genetics/*metabolism ; }, abstract = {Regulation of mitochondrial outer membrane (MOM) permeability has dual importance: in normal metabolite and energy exchange between mitochondria and cytoplasm and thus in control of respiration, and in apoptosis by release of apoptogenic factors into the cytosol. However, the mechanism of this regulation, dependent on the voltage-dependent anion channel (VDAC), the major channel of MOM, remains controversial. A long-standing puzzle is that in permeabilized cells, adenine nucleotide translocase (ANT) is less accessible to cytosolic ADP than in isolated mitochondria. We solve this puzzle by finding a missing player in the regulation of MOM permeability: the cytoskeletal protein tubulin. We show that nanomolar concentrations of dimeric tubulin induce voltage-sensitive reversible closure of VDAC reconstituted into planar phospholipid membranes. Tubulin strikingly increases VDAC voltage sensitivity and at physiological salt conditions could induce VDAC closure at <10 mV transmembrane potentials. Experiments with isolated mitochondria confirm these findings. Tubulin added to isolated mitochondria decreases ADP availability to ANT, partially restoring the low MOM permeability (high apparent K(m) for ADP) found in permeabilized cells. Our findings suggest a previously unknown mechanism of regulation of mitochondrial energetics, governed by VDAC and tubulin at the mitochondria-cytosol interface. This tubulin-VDAC interaction requires tubulin anionic C-terminal tail (CTT) peptides. The significance of this interaction may be reflected in the evolutionary conservation of length and anionic charge in CTT throughout eukaryotes, despite wide changes in the exact sequence. Additionally, tubulins that have lost significant length or anionic character are only found in cells that do not have mitochondria.}, } @article {pmid18979193, year = {2008}, author = {Trézéguet, V and Pélosi, L and Lauquin, GJ and Brandolin, G}, title = {The mitochondrial ADP/ATP carrier: functional and structural studies in the route of elucidating pathophysiological aspects.}, journal = {Journal of bioenergetics and biomembranes}, volume = {40}, number = {5}, pages = {435-443}, pmid = {18979193}, issn = {0145-479X}, mesh = {Animals ; Conserved Sequence ; Evolution, Molecular ; Humans ; Mitochondria/enzymology/genetics ; Mitochondrial ADP, ATP Translocases/*chemistry/deficiency/genetics/*physiology ; Mitochondrial Diseases/enzymology/genetics ; Models, Molecular ; Mutation ; Oxidative Phosphorylation ; Protein Structure, Quaternary ; }, abstract = {The mitochondrial ADP/ATP carrier plays a central role in aerobic cell energetics by providing to the cytosol the ATP generated by oxidative phosphorylation. Though discovered around 40 years ago owing to the existence of unique inhibitors and in spite of numerous experimental approaches, this carrier, which stands as a model of the mitochondrial solute carriers keeps some long-standing mystery. There are still open challenging questions among them the precise ADP/ATP transport mechanism, the functional oligomeric state of the carrier and relationships between human ADP/ATP carrier dysfunctioning and pathologies. Deciphering the 3D structure of this carrier afforded a considerable progress of the knowledge but requires now additional data focused on molecular dynamics from this static picture. State of the art in this topic is reviewed and debated in this paper in view of better comprehending origin of the discrepancies in these questions and, finally, the multiple physiological roles of this carrier in eukaryotic cell economy.}, } @article {pmid18688271, year = {2008}, author = {Rosso, L and Marques, AC and Reichert, AS and Kaessmann, H}, title = {Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydrogenase driven by positive Darwinian selection.}, journal = {PLoS genetics}, volume = {4}, number = {8}, pages = {e1000150}, pmid = {18688271}, issn = {1553-7404}, mesh = {Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; Cell Line ; Chlorocebus aethiops ; Evolution, Molecular ; Gene Duplication ; Glutamate Dehydrogenase/chemistry/genetics/*physiology ; Glutamate Dehydrogenase (NADP+)/chemistry/genetics/*metabolism ; Hominidae/*genetics/metabolism ; Humans ; Hylobates ; Mice ; Mitochondria/chemistry/*enzymology/genetics ; Molecular Sequence Data ; Phylogeny ; Protein Sorting Signals ; Protein Transport ; *Selection, Genetic ; Sequence Alignment ; Species Specificity ; }, abstract = {Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor approximately 18-25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions.}, } @article {pmid18637481, year = {2008}, author = {Chen, JQ and Brown, TR and Yager, JD}, title = {Mechanisms of hormone carcinogenesis: evolution of views, role of mitochondria.}, journal = {Advances in experimental medicine and biology}, volume = {630}, number = {}, pages = {1-18}, pmid = {18637481}, issn = {0065-2598}, mesh = {*Concept Formation ; Energy Metabolism/physiology ; Estrogens/pharmacology ; Hormones/*physiology ; Humans ; Mitochondria/metabolism/*physiology ; Models, Biological ; Neoplasms/chemically induced/*etiology/metabolism ; Neoplasms, Hormone-Dependent/metabolism ; Receptors, Estrogen/physiology ; Signal Transduction/physiology ; }, abstract = {CumuIative and excessive exposure to estrogens is associated with increased breast cancer risk. The traditional mechanism explaining this association is that estrogens affect the rate of cell division and apoptosis and thus manifest their effect on the risk of breast cancer by affecting the growth of breast epithelial tissues. Highly proliferative cells are susceptible to genetic errors during DNA replication. The action of estrogen metabolites offers a complementary genotoxic pathway mediated by the generation of reactive estrogen quinone metabolites that can form adducts with DNA and generate reactive oxygen species through redox cycling. In this chapter, we discussed a novel mitochondrial pathway mediated by estrogens and their cognate estrogen receptors (ERs) and its potential implications in estrogen-dependent carcinogenesis. Several lines of evidence are presented to show: (1) mitochondrial localization of ERs in human breast cancer cells and other cell types; (2) a functional role for the mitochondrial ERs in regulation of the mitochondrial respiratory chain (MRC) proteins and (3) potential implications of the mitochondrial ER-mediated pathway in stimulation of cell proliferation, inhibition of apoptosis and oxidative damage to mitochondrial DNA. The possible involvement of estrogens and ERs in deregulation of mitochondrial bioenergetics, an important hallmark of cancer cells, is also described. An evolutionary view is presented to suggest that persistent stimulation by estrogens through ER signaling pathways of MRC proteins and energy metabolic pathways leads to the alterations in mitochondrial bioenergetics and contributes to the development of estrogen-related cancers.}, } @article {pmid18619978, year = {2008}, author = {Locke, BR and Kinsey, ST}, title = {Diffusional constraints on energy metabolism in skeletal muscle.}, journal = {Journal of theoretical biology}, volume = {254}, number = {2}, pages = {417-429}, doi = {10.1016/j.jtbi.2008.06.008}, pmid = {18619978}, issn = {1095-8541}, support = {R15-AR052708/AR/NIAMS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Animals ; *Computer Simulation ; Diffusion ; Energy Metabolism/*physiology ; Models, Biological ; *Models, Statistical ; Muscle Contraction/physiology ; Muscle, Skeletal/*metabolism ; }, abstract = {Aerobic metabolic flux depends on the diffusion of high-energy phosphate molecules (e.g., ATP and phosphocreatine) from the mitochondria to cellular ATPases, as well as the diffusion of other molecules (e.g., ADP, Pi) back to the mitochondria. Here, we develop an approach for evaluating the influence of intracellular metabolite diffusion on skeletal muscle aerobic metabolism through the application of the effectiveness factor (eta). This parameter provides an intuitive and informative means of quantifying the extent to which diffusion limits metabolic flux. We start with the classical approach assuming an infinite supply of substrate at the fiber boundary, and we expand this model to ultimately include nonlinear boundary and homogeneous reactions. Comparison of the model with experimental data from a wide range of skeletal muscle types reveals that most muscle fibers are not substantially limited by diffusion (eta close to unity), but many are on the brink of rather substantial diffusion limitation. This implies that intracellular metabolite diffusion does not dramatically limit aerobic metabolic flux in most fibers, but it likely plays a role in limiting the evolution of muscle fiber design and function.}, } @article {pmid18579651, year = {2008}, author = {Richards, JG and Sardella, BA and Schulte, PM}, title = {Regulation of pyruvate dehydrogenase in the common killifish, Fundulus heteroclitus, during hypoxia exposure.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {295}, number = {3}, pages = {R979-90}, doi = {10.1152/ajpregu.00192.2008}, pmid = {18579651}, issn = {0363-6119}, mesh = {Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Cytosol/metabolism ; Energy Metabolism/physiology ; Fundulidae/genetics/*metabolism ; Hypoxia/*metabolism/*physiopathology ; Isoenzymes/genetics/metabolism ; Mitochondria/metabolism ; Muscle, Skeletal/enzymology ; NAD/metabolism ; Oxygen/metabolism ; Phylogeny ; Protein Serine-Threonine Kinases/genetics/metabolism ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase ; Pyruvate Dehydrogenase Complex/*metabolism ; Pyruvic Acid/metabolism ; }, abstract = {We examined the metabolic responses of the hypoxia-tolerant killifish (Fundulus heteroclitus) to 15 h of severe hypoxia and recovery with emphasis on muscle substrate usage and the regulation of the mitochondrial protein pyruvate dehydrogenase (PDH), which controls carbohydrate oxidation. Hypoxia survival involved a transient activation of substrate-level phosphorylation in muscle (decreases in [creatine phospate] and increases in [lactate]) during which time mechanisms to reduce overall ATP consumption were initiated. This metabolic transition did not affect total cellular [ATP], but had an impact on cellular energy status as indicated by large decreases in [ATP]/[ADP(free)] and [ATP]/[AMP(free)] and a significant loss of phosphorylation potential and Gibbs free energy of ATP hydrolysis (DeltafG'). The activity of PDH was rapidly (within 3 h) decreased by approximately 50% upon hypoxia exposure and remained depressed relative to normoxic samples throughout. Inactivation of PDH was primarily mediated via posttranslational modification following the accumulation of acetyl-CoA and subsequent activation of pyruvate dehydrogenase kinase (PDK). Estimated changes in cytoplasmic and mitochondrial [NAD(+)]/[NADH] did not parallel one another, suggesting the mitochondrial NADH shuttles do not function during hypoxia exposure. Large increases in the expression of PDK (PDK isoform 2) were consistent with decreased PDH activity; however, these changes in mRNA were not associated with changes in total PDK-2 protein content assessed using mammalian antibodies. No other changes in the expression of other known hypoxia-responsive genes (e.g., lactate dehydrogenase-A or -B) were observed in either muscle or liver.}, } @article {pmid18524881, year = {2008}, author = {Cosson, J and Groison, AL and Suquet, M and Fauvel, C and Dreanno, C and Billard, R}, title = {Marine fish spermatozoa: racing ephemeral swimmers.}, journal = {Reproduction (Cambridge, England)}, volume = {136}, number = {3}, pages = {277-294}, doi = {10.1530/REP-07-0522}, pmid = {18524881}, issn = {1741-7899}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Axoneme/metabolism ; Energy Metabolism ; Fishes/metabolism/*physiology ; Male ; Models, Biological ; Seawater ; Sperm Motility/*physiology ; Sperm Tail/metabolism/physiology ; Spermatozoa/metabolism/*physiology ; }, abstract = {After a long period of spermatogenesis (several weeks to months), marine fish spermatozoa are delivered at male spawning in seawater (SW) at the same time as ova. In some fish species, as the ova micropyle closes quickly after release, these minute unicells, the spermatozoa, have to accomplish their task of reaching the micropyle within a very brief period (several seconds to minutes), for delivery of the haploid male genetic information to the ova. To achieve this goal, their high-performance motile equipment, the flagellum, must fully activate immediately on contact with the SW and then propel the sperm cell at an unusually high initial velocity. The cost of such 'hyperactivity' is a very rapid consumption of intracellular ATP that outstrips the supply. The spermatozoa become rapidly exhausted because mitochondria cannot compensate for this very fast flagellar energy consumption. Therefore, any spermatozoon ends up with two possibilities: either becoming exhausted and immotile or reaching the egg micropyle within its very short period of forward motility (in the range of tens of seconds) before micropyle closure in relation to both contact of SW and cortical reaction. The aim of the present review is to present step by step the successive events occurring in marine fish spermatozoa from activation until their full arrest of motility. The present knowledge of activation mechanisms is summarized, as well as a description of the motility parameters characterizing the motility period. As a complement, in vitro results on axonemal motility obtained after demembranation of flagella bring further understanding. The description of the sperm energetic content (ATP and other high energy compounds) and its evolution during the swimming period is also discussed. A general model aiming to explain all the successive cellular events occurring immediately after the activation is presented. This model is proposed as a guideline for understanding the events governing the sperm lifespan in the marine fish species that reproduce through external fertilization.}, } @article {pmid18515712, year = {2008}, author = {Hand, SC and Menze, MA}, title = {Mitochondria in energy-limited states: mechanisms that blunt the signaling of cell death.}, journal = {The Journal of experimental biology}, volume = {211}, number = {Pt 12}, pages = {1829-1840}, doi = {10.1242/jeb.000299}, pmid = {18515712}, issn = {0022-0949}, support = {1-R01-GM071345-01/GM/NIGMS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Artemia/*physiology ; Cell Death/*physiology ; Cell Hypoxia/physiology ; Energy Metabolism/*physiology ; Mitochondria/*physiology ; Mitochondrial Membranes/metabolism ; *Models, Biological ; Permeability ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Signal Transduction/*physiology ; }, abstract = {Cellular conditions experienced during energy-limited states--elevated calcium, shifts in cellular adenylate status, compromised mitochondrial membrane potential--are precisely those that trigger, at least in mammals, the mitochondrion to initiate opening of the permeability transition pore, to assemble additional protein release channels, and to release pro-apoptotic factors. These pro-apototic factors in turn activate initiator and executer caspases. How is activation of mitochondria-based pathways for the signaling of apoptotic and necrotic cell death avoided under conditions of hypoxia, anoxia, diapause, estivation and anhydrobiosis? Functional trade-offs in environmental tolerance may have occurred in parallel with the evolution of diversified pathways for the signaling of cell death in eukaryotic organisms. Embryos of the brine shrimp, Artemia franciscana, survive extended periods of anoxia and diapause, and evidence indicates that opening of the mitochondrial permeability transition pore and release of cytochrome c (cyt-c) do not occur. Further, caspase activation in this crustacean is not dependent on cyt-c. Its caspases display regulation by nucleotides that is consistent with ;applying the brakes' to cell death during energy limitation. Unraveling the mechanisms by which organisms in extreme environments avoid cell death may suggest possible interventions during disease states and biostabilization of mammalian cells.}, } @article {pmid18468979, year = {2008}, author = {Mentel, M and Martin, W}, title = {Energy metabolism among eukaryotic anaerobes in light of Proterozoic ocean chemistry.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {363}, number = {1504}, pages = {2717-2729}, pmid = {18468979}, issn = {0962-8436}, mesh = {Anaerobiosis ; Animals ; *Biological Evolution ; *Energy Metabolism ; Eukaryotic Cells ; Fungi/metabolism ; Mitochondria/metabolism ; Oceans and Seas ; Organelles/metabolism ; Sulfides/metabolism ; Symbiosis ; Trichomonas/metabolism ; }, abstract = {Recent years have witnessed major upheavals in views about early eukaryotic evolution. One very significant finding was that mitochondria, including hydrogenosomes and the newly discovered mitosomes, are just as ubiquitous and defining among eukaryotes as the nucleus itself. A second important advance concerns the readjustment, still in progress, about phylogenetic relationships among eukaryotic groups and the roughly six new eukaryotic supergroups that are currently at the focus of much attention. From the standpoint of energy metabolism (the biochemical means through which eukaryotes gain their ATP, thereby enabling any and all evolution of other traits), understanding of mitochondria among eukaryotic anaerobes has improved. The mainstream formulations of endosymbiotic theory did not predict the ubiquity of mitochondria among anaerobic eukaryotes, while an alternative hypothesis that specifically addressed the evolutionary origin of energy metabolism among eukaryotic anaerobes did. Those developments in biology have been paralleled by a similar upheaval in the Earth sciences regarding views about the prevalence of oxygen in the oceans during the Proterozoic (the time from ca 2.5 to 0.6 Ga ago). The new model of Proterozoic ocean chemistry indicates that the oceans were anoxic and sulphidic during most of the Proterozoic. Its proponents suggest the underlying geochemical mechanism to entail the weathering of continental sulphides by atmospheric oxygen to sulphate, which was carried into the oceans as sulphate, fueling marine sulphate reducers (anaerobic, hydrogen sulphide-producing prokaryotes) on a global scale. Taken together, these two mutually compatible developments in biology and geology underscore the evolutionary significance of oxygen-independent ATP-generating pathways in mitochondria, including those of various metazoan groups, as a watermark of the environments within which eukaryotes arose and diversified into their major lineages.}, } @article {pmid18452512, year = {2008}, author = {Hamblin, K and Standley, DM and Rogers, MB and Stechmann, A and Roger, AJ and Maytum, R and van der Giezen, M}, title = {Localization and nucleotide specificity of Blastocystis succinyl-CoA synthetase.}, journal = {Molecular microbiology}, volume = {68}, number = {6}, pages = {1395-1405}, pmid = {18452512}, issn = {1365-2958}, support = {078566/WT_/Wellcome Trust/United Kingdom ; 078566/A/05/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Base Sequence ; Blastocystis/chemistry/*cytology/*enzymology/genetics ; Blastocystis Infections/parasitology ; Cytoplasmic Structures/chemistry/enzymology/genetics ; Humans ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Phylogeny ; Protein Subunits/chemistry/genetics/metabolism ; Protozoan Proteins/chemistry/genetics/metabolism ; Purine Nucleotides/*metabolism ; Sequence Alignment ; Substrate Specificity ; Succinate-CoA Ligases/*chemistry/genetics/metabolism ; Swine/genetics ; }, abstract = {The anaerobic lifestyle of the intestinal parasite Blastocystis raises questions about the biochemistry and function of its mitochondria-like organelles. We have characterized the Blastocystis succinyl-CoA synthetase (SCS), a tricarboxylic acid cycle enzyme that conserves energy by substrate-level phosphorylation. We show that SCS localizes to the enigmatic Blastocystis organelles, indicating that these organelles might play a similar role in energy metabolism as classic mitochondria. Although analysis of residues inside the nucleotide-binding site suggests that Blastocystis SCS is GTP-specific, we demonstrate that it is ATP-specific. Homology modelling, followed by flexible docking and molecular dynamics simulations, indicates that while both ATP and GTP fit into the Blastocystis SCS active site, GTP is destabilized by electrostatic dipole interactions with Lys 42 and Lys 110, the side-chains of which lie outside the nucleotide-binding cavity. It has been proposed that residues in direct contact with the substrate determine nucleotide specificity in SCS. However, our results indicate that, in Blastocystis, an electrostatic gatekeeper controls which ligands can enter the binding site.}, } @article {pmid18403202, year = {2008}, author = {Stechmann, A and Hamblin, K and Pérez-Brocal, V and Gaston, D and Richmond, GS and van der Giezen, M and Clark, CG and Roger, AJ}, title = {Organelles in Blastocystis that blur the distinction between mitochondria and hydrogenosomes.}, journal = {Current biology : CB}, volume = {18}, number = {8}, pages = {580-585}, pmid = {18403202}, issn = {0960-9822}, support = {078566/WT_/Wellcome Trust/United Kingdom ; 078566/A/05/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Aerobiosis/physiology ; Anaerobiosis/physiology ; Animals ; Biological Evolution ; Blastocystis/genetics/*metabolism ; Energy Metabolism/physiology ; Expressed Sequence Tags ; Genome, Mitochondrial ; Mitochondria/genetics/*metabolism ; Molecular Sequence Data ; }, abstract = {Blastocystis is a unicellular stramenopile of controversial pathogenicity in humans. Although it is a strict anaerobe, Blastocystis has mitochondrion-like organelles with cristae, a transmembrane potential and DNA. An apparent lack of several typical mitochondrial pathways has led some to suggest that these organelles might be hydrogenosomes, anaerobic organelles related to mitochondria. We generated 12,767 expressed sequence tags (ESTs) from Blastocystis and identified 115 clusters that encode putative mitochondrial and hydrogenosomal proteins. Among these is the canonical hydrogenosomal protein iron-only [FeFe] hydrogenase that we show localizes to the organelles. The organelles also have mitochondrial characteristics, including pathways for amino acid metabolism, iron-sulfur cluster biogenesis, and an incomplete tricarboxylic acid cycle as well as a mitochondrial genome. Although complexes I and II of the electron transport chain (ETC) are present, we found no evidence for complexes III and IV or F1Fo ATPases. The Blastocystis organelles have metabolic properties of aerobic and anaerobic mitochondria and of hydrogenosomes. They are convergently similar to organelles recently described in the unrelated ciliate Nyctotherus ovalis. These findings blur the boundaries between mitochondria, hydrogenosomes, and mitosomes, as currently defined, underscoring the disparate selective forces that shape these organelles in eukaryotes.}, } @article {pmid18380897, year = {2008}, author = {Mulkidjanian, AY and Galperin, MY and Makarova, KS and Wolf, YI and Koonin, EV}, title = {Evolutionary primacy of sodium bioenergetics.}, journal = {Biology direct}, volume = {3}, number = {}, pages = {13}, pmid = {18380897}, issn = {1745-6150}, support = {Z99 LM999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/chemistry/genetics/*metabolism ; Bacteria/enzymology ; Cation Transport Proteins/chemistry/genetics/*metabolism ; Energy Metabolism/*physiology ; *Evolution, Molecular ; Phylogeny ; Protein Subunits/chemistry/genetics/*metabolism ; Sodium/*metabolism ; Sodium-Potassium-Exchanging ATPase/chemistry/genetics/*metabolism ; Structure-Activity Relationship ; Vacuolar Proton-Translocating ATPases/chemistry/genetics/*metabolism ; }, abstract = {BACKGROUND: The F- and V-type ATPases are rotary molecular machines that couple translocation of protons or sodium ions across the membrane to the synthesis or hydrolysis of ATP. Both the F-type (found in most bacteria and eukaryotic mitochondria and chloroplasts) and V-type (found in archaea, some bacteria, and eukaryotic vacuoles) ATPases can translocate either protons or sodium ions. The prevalent proton-dependent ATPases are generally viewed as the primary form of the enzyme whereas the sodium-translocating ATPases of some prokaryotes are usually construed as an exotic adaptation to survival in extreme environments.

RESULTS: We combine structural and phylogenetic analyses to clarify the evolutionary relation between the proton- and sodium-translocating ATPases. A comparison of the structures of the membrane-embedded oligomeric proteolipid rings of sodium-dependent F- and V-ATPases reveals nearly identical sets of amino acids involved in sodium binding. We show that the sodium-dependent ATPases are scattered among proton-dependent ATPases in both the F- and the V-branches of the phylogenetic tree.

CONCLUSION: Barring convergent emergence of the same set of ligands in several lineages, these findings indicate that the use of sodium gradient for ATP synthesis is the ancestral modality of membrane bioenergetics. Thus, a primitive, sodium-impermeable but proton-permeable cell membrane that harboured a set of sodium-transporting enzymes appears to have been the evolutionary predecessor of the more structurally demanding proton-tight membranes. The use of proton as the coupling ion appears to be a later innovation that emerged on several independent occasions.}, } @article {pmid18262354, year = {2008}, author = {De Simoni, S and Goemaere, J and Knoops, B}, title = {Silencing of peroxiredoxin 3 and peroxiredoxin 5 reveals the role of mitochondrial peroxiredoxins in the protection of human neuroblastoma SH-SY5Y cells toward MPP+.}, journal = {Neuroscience letters}, volume = {433}, number = {3}, pages = {219-224}, doi = {10.1016/j.neulet.2007.12.068}, pmid = {18262354}, issn = {0304-3940}, mesh = {1-Methyl-4-phenylpyridinium/toxicity ; Apoptosis/drug effects/genetics ; Cell Survival/drug effects/genetics ; Cytoprotection/drug effects/*genetics ; Down-Regulation/genetics ; Electron Transport Chain Complex Proteins/drug effects/genetics/metabolism ; Energy Metabolism/drug effects/genetics ; Gene Silencing/physiology ; Humans ; Mitochondria/drug effects/*metabolism ; Neuroblastoma ; Neurons/drug effects/*metabolism ; Neurotoxins/toxicity ; Oxidative Stress/drug effects/genetics ; Peroxiredoxin III ; Peroxiredoxins/drug effects/genetics/*metabolism ; RNA, Small Interfering/genetics ; Substantia Nigra/drug effects/*metabolism/physiopathology ; Tumor Cells, Cultured ; }, abstract = {Peroxiredoxins (PRDXs) are a family of peroxidases well conserved throughout evolution. Human PRDX3 and PRDX5, two mitochondrial PRDXs, have been implicated in several pathologies associated with oxidative stress. However, the individual role of PRDX3 and PRDX5 in cellular antioxidant defense has never been well established due to their overlapping peroxidatic activities. We investigated the expression and function of mitochondrial PRDXs in human neuroblastoma SH-SY5Y cells. Our results show that PRDX3 and PRDX5 are expressed constitutively in these neuronal cells. To examine further the function of mitochondrial PRDXs, we silenced the expression of PRDX3 and/or PRDX5 using small hairpin RNAs. Our results show that mitochondrial PRDX-depleted cells are more prone to oxidative damages and apoptosis induced by MPP(+), a complex I inhibitor which provides an experimental paradigm of Parkinson's disease.}, } @article {pmid18197981, year = {2008}, author = {Uddin, M and Opazo, JC and Wildman, DE and Sherwood, CC and Hof, PR and Goodman, M and Grossman, LI}, title = {Molecular evolution of the cytochrome c oxidase subunit 5A gene in primates.}, journal = {BMC evolutionary biology}, volume = {8}, number = {}, pages = {8}, pmid = {18197981}, issn = {1471-2148}, support = {AG14308/AG/NIA NIH HHS/United States ; P30 AG13854/AG/NIA NIH HHS/United States ; R01 DK56927/DK/NIDDK NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Base Sequence ; Electron Transport Complex IV/*genetics ; *Evolution, Molecular ; Gene Expression Regulation, Enzymologic ; Humans ; Immunohistochemistry ; Mitochondria/enzymology ; Neocortex/enzymology ; Open Reading Frames ; Prefrontal Cortex/enzymology ; Primates/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Species Specificity ; Tissue Distribution ; }, abstract = {BACKGROUND: Many electron transport chain (ETC) genes show accelerated rates of nonsynonymous nucleotide substitutions in anthropoid primate lineages, yet in non-anthropoid lineages the ETC proteins are typically highly conserved. Here, we test the hypothesis that COX5A, the ETC gene that encodes cytochrome c oxidase subunit 5A, shows a pattern of anthropoid-specific adaptive evolution, and investigate the distribution of this protein in catarrhine brains.

RESULTS: In a dataset comprising 29 vertebrate taxa, including representatives from all major groups of primates, there is nearly 100% conservation of the COX5A amino acid sequence among extant, non-anthropoid placental mammals. The most recent common ancestor of these species lived about 100 million years (MY) ago. In contrast, anthropoid primates show markedly elevated rates of nonsynonymous evolution. In particular, branch site tests identify five positively selected codons in anthropoids, and ancestral reconstructions infer that substitutions in these codons occurred predominantly on stem lineages (anthropoid, ape and New World monkey) and on the human terminal branch. Examination of catarrhine brain samples by immunohistochemistry characterizes for the first time COX5A protein distribution in the primate neocortex, and suggests that the protein is most abundant in the mitochondria of large-size projection neurons. Real time quantitative PCR supports previous microarray results showing COX5A is expressed in cerebral cortical tissue at a higher level in human than in chimpanzee or gorilla.

CONCLUSION: Taken together, these results suggest that both protein structural and gene regulatory changes contributed to COX5A evolution during humankind's ancestry. Furthermore, these findings are consistent with the hypothesis that adaptations in ETC genes contributed to the emergence of the energetically expensive anthropoid neocortex.}, } @article {pmid18167542, year = {2008}, author = {Hampl, V and Silberman, JD and Stechmann, A and Diaz-Triviño, S and Johnson, PJ and Roger, AJ}, title = {Genetic evidence for a mitochondriate ancestry in the 'amitochondriate' flagellate Trimastix pyriformis.}, journal = {PloS one}, volume = {3}, number = {1}, pages = {e1383}, pmid = {18167542}, issn = {1932-6203}, mesh = {Amino Acid Sequence ; Amino Acids/metabolism ; Animals ; DNA, Mitochondrial/*genetics ; Energy Metabolism ; Eukaryota/classification/*genetics/metabolism ; Expressed Sequence Tags ; Molecular Sequence Data ; Phylogeny ; Protein Transport ; Sequence Homology, Amino Acid ; }, abstract = {Most modern eukaryotes diverged from a common ancestor that contained the alpha-proteobacterial endosymbiont that gave rise to mitochondria. The 'amitochondriate' anaerobic protist parasites that have been studied to date, such as Giardia and Trichomonas harbor mitochondrion-related organelles, such as mitosomes or hydrogenosomes. Yet there is one remaining group of mitochondrion-lacking flagellates known as the Preaxostyla that could represent a primitive 'pre-mitochondrial' lineage of eukaryotes. To test this hypothesis, we conducted an expressed sequence tag (EST) survey on the preaxostylid flagellate Trimastix pyriformis, a poorly-studied free-living anaerobe. Among the ESTs we detected 19 proteins that, in other eukaryotes, typically function in mitochondria, hydrogenosomes or mitosomes, 12 of which are found exclusively within these organelles. Interestingly, one of the proteins, aconitase, functions in the tricarboxylic acid cycle typical of aerobic mitochondria, whereas others, such as pyruvate:ferredoxin oxidoreductase and [FeFe] hydrogenase, are characteristic of anaerobic hydrogenosomes. Since Trimastix retains genetic evidence of a mitochondriate ancestry, we can now say definitively that all known living eukaryote lineages descend from a common ancestor that had mitochondria.}, } @article {pmid17921152, year = {2007}, author = {Kinsey, ST and Hardy, KM and Locke, BR}, title = {The long and winding road: influences of intracellular metabolite diffusion on cellular organization and metabolism in skeletal muscle.}, journal = {The Journal of experimental biology}, volume = {210}, number = {Pt 20}, pages = {3505-3512}, doi = {10.1242/jeb.000331}, pmid = {17921152}, issn = {0022-0949}, support = {R15-AR052708/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; Cell Size ; Diffusion ; Energy Metabolism ; Humans ; Muscle Fibers, Skeletal/cytology/metabolism ; Muscle, Skeletal/*cytology/*metabolism ; }, abstract = {A fundamental principle of physiology is that cells are small in order to minimize diffusion distances for O(2) and intracellular metabolites. In skeletal muscle, it has long been recognized that aerobic fibers that are used for steady state locomotion tend to be smaller than anaerobic fibers that are used for burst movements. This tendency reflects the interaction between diffusion distances and aerobic ATP turnover rates, since maximal intracellular diffusion distances are ultimately limited by fiber size. The effect of diffusion distance on O(2) flux in muscle has been the subject of quantitative analyses for a century, but the influence of ATP diffusion from mitochondria to cellular ATPases on aerobic metabolism has received much less attention. The application of reaction-diffusion mathematical models to experimental measurements of aerobic metabolic processes has revealed that the extreme diffusion distances between mitochondria found in some muscle fibers do not necessarily limit the rates of aerobic processes per se, as long as the metabolic process is sufficiently slow. However, skeletal muscle fibers from a variety of animals appear to have intracellular diffusion distances and/or fiber sizes that put them on the brink of diffusion limitation. Thus, intracellular metabolite diffusion likely influences the evolution of muscle design and places limits on muscle function.}, } @article {pmid17880942, year = {2008}, author = {Aguilera, P and Barry, T and Tovar, J}, title = {Entamoeba histolytica mitosomes: organelles in search of a function.}, journal = {Experimental parasitology}, volume = {118}, number = {1}, pages = {10-16}, doi = {10.1016/j.exppara.2007.08.004}, pmid = {17880942}, issn = {0014-4894}, support = {BB/C507145/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Aerobiosis ; Anaerobiosis ; Animals ; Entamoeba histolytica/classification/physiology/*ultrastructure ; Entamoebiasis/parasitology ; Genome, Protozoan ; Humans ; Intestine, Large/parasitology ; Iron-Sulfur Proteins/biosynthesis/physiology ; Mitochondria/physiology ; Organelles/genetics/*physiology/ultrastructure ; Oxygen Consumption ; Phylogeny ; Protozoan Proteins/metabolism ; Pyruvic Acid/metabolism ; Symbiosis ; }, abstract = {It has been more than eight years since the discovery of mitosomes (mitochondrial remnant organelles) in the intestinal human pathogen Entamoeba histolytica. Despite detailed knowledge about the biochemistry of this parasite and the completion of the E. histolytica genome sequencing project no physiological function has yet been unequivocally assigned to these organelles. Entamoeba mitosomes seem to be the most degenerate of all endosymbiosis-derived organelles studied to date. They do not appear to participate in energy metabolism and may have dispensed completely with the proteins required for iron-sulphur cluster biosynthesis. However, the large number of mitosomes found in E. histolytica trophozoites hints at a significant biological role for these organelles in their natural environment. Identifying the protein complement of mitosomes will provide answers as to their biological significance and the reason(s) for their retention in this parasite.}, } @article {pmid17786631, year = {2007}, author = {Orrenius, S}, title = {Reactive oxygen species in mitochondria-mediated cell death.}, journal = {Drug metabolism reviews}, volume = {39}, number = {2-3}, pages = {443-455}, doi = {10.1080/03602530701468516}, pmid = {17786631}, issn = {0360-2532}, mesh = {Animals ; Antioxidants/metabolism ; Apoptosis/physiology ; Cardiolipins/metabolism ; Cell Death/*physiology ; Cytochromes c/metabolism ; Humans ; Mitochondria/*physiology ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; }, abstract = {In addition to the well-established role of the mitochondria in energy metabolism, regulation of cell death has recently emerged as a second major function of these organelles. This, in turn, seems to be intimately linked to their role as the major intracellular source of reactive oxygen species (ROS) which are mainly, generated at Complex I and III of the respiratory chain. Excessive ROS production can lead to oxidation of macromolecules and has been implicated in mtDNA mutations, ageing, and cell death. Although mitochondrial dysfunction can cause ATP depletion and necrosis, these organelles are also involved in the regulation of apoptotic cell death by mechanisms, which have been conserved through evolution. Thus, many lethal agents target the mitochondria and cause release of cytochrome c and other pro-apoptotic proteins, which can trigger caspase activation and apoptosis. Taken together, these findings have placed the mitochondria in the focus of current cell death research.}, } @article {pmid17567455, year = {2007}, author = {Sato, N}, title = {Central role of mitochondria in metabolic regulation of liver pathophysiology.}, journal = {Journal of gastroenterology and hepatology}, volume = {22 Suppl 1}, number = {}, pages = {S1-6}, doi = {10.1111/j.1440-1746.2007.04963.x}, pmid = {17567455}, issn = {0815-9319}, mesh = {Animals ; Biological Evolution ; Cytochromes/physiology ; Electron Transport ; Energy Metabolism/*physiology ; Humans ; Liver Diseases/metabolism/*physiopathology ; Mitochondria, Liver/*physiology ; Oxidative Phosphorylation ; Reactive Oxygen Species ; }, abstract = {Mitochondria play a central role in cellular energy metabolism. Oxidative phosphorylation occurs in the electron transport system of the inner mitochondrial membrane. Cytochrome aa3, b and c1 are encoded by mitochondrial DNA whereas cytochrome c is encoded by the nuclear gene, and these mitochondrial-DNA dependent cytochromes are decreased and electron transport at complex II, III and IV is disturbed in liver carcinomas and during carcinogenesis. The more the decreased cytochrome and oxidase activity are seen, the more significant is the increase in reactive oxygen species (ROS) production. ROS produced in mitochondria may be the main cause of nuclear-gene mutation in carcinogenesis. The mitochondrial dysfunction and overproduction of ROS plays a key role in progression of chronic hepatitis C and ethanol-induced liver injury. Ethanol also causes bacterial translocation in the intestine and the resulting lipopolysaccharides (LPS) activates Kupffer cells to produce pro-inflammatory cytokines. We suspect that non-alcoholic steatohepatitis (NASH) also is the result of increased ROS production in Kupffer cells and hepatocytes.}, } @article {pmid17635416, year = {2007}, author = {Lambert, AJ and Brand, MD}, title = {Research on mitochondria and aging, 2006-2007.}, journal = {Aging cell}, volume = {6}, number = {4}, pages = {417-420}, doi = {10.1111/j.1474-9726.2007.00316.x}, pmid = {17635416}, issn = {1474-9718}, support = {MC_U105663137/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aging/*physiology ; Animals ; DNA Damage ; DNA, Mitochondrial/genetics/metabolism ; Electron Transport Complex I/*metabolism ; Energy Metabolism ; Humans ; Longevity/physiology ; Mice ; Mitochondria/*physiology ; Oxidation-Reduction ; Oxidative Stress/physiology ; Reactive Oxygen Species/*metabolism ; }, abstract = {This review focuses on some of the 'hot topics' that fall under the general heading 'mitochondria and aging'. For each selected topic, we highlight recent publications that have either addressed specific problems within the field or presented novel findings of interest regarding the links between mitochondria and aging. These include studies on the structure of complex I and the mechanisms of superoxide production by this complex; work showing a novel site of hydrogen peroxide production within mitochondria that is modulated by caloric restriction; explorations of the relationship between the rate of evolution of mitochondrial DNA and lifespan; a demonstration that mitochondrial DNA mutations do not limit lifespan in mice; and investigations of the effects of mitochondrial fission on aging. We also list other relevant articles of interest and suggest some key challenges for the field in the near future.}, } @article {pmid17625545, year = {2007}, author = {Davidov, Y and Jurkevitch, E}, title = {How incompatibilities may have led to eukaryotic cell.}, journal = {Nature}, volume = {448}, number = {7150}, pages = {130}, doi = {10.1038/448130a}, pmid = {17625545}, issn = {1476-4687}, mesh = {Archaea/*genetics/metabolism ; Bacteria/*genetics/metabolism ; *Biological Evolution ; Energy Metabolism ; Eukaryotic Cells/*cytology/metabolism ; Mitochondria ; }, } @article {pmid17600515, year = {2007}, author = {Sullivan, PG and Krishnamurthy, S and Patel, SP and Pandya, JD and Rabchevsky, AG}, title = {Temporal characterization of mitochondrial bioenergetics after spinal cord injury.}, journal = {Journal of neurotrauma}, volume = {24}, number = {6}, pages = {991-999}, doi = {10.1089/neu.2006.0242}, pmid = {17600515}, issn = {0897-7151}, support = {NS 048191/NS/NINDS NIH HHS/United States ; }, mesh = {Aldehydes/analysis/metabolism ; Animals ; Disease Models, Animal ; Disease Progression ; Energy Metabolism/*physiology ; Female ; Free Radicals/analysis/metabolism ; Lipid Peroxidation/physiology ; Mitochondria/*metabolism ; Oxidative Stress/physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/analysis/metabolism ; Spinal Cord/*metabolism/*physiopathology ; Spinal Cord Injuries/drug therapy/*metabolism/*physiopathology ; Time Factors ; Tyrosine/analogs & derivatives/analysis/metabolism ; }, abstract = {Mitochondrial dysfunction following spinal cord injury (SCI) may be critical for the development of secondary pathophysiology and neuronal cell death. Previous studies have demonstrated a loss of mitochondrial bioenergetics at 24 h following SCI. To begin to understand the evolution and study the contribution of mitochondrial dysfunction in pathophysiology of SCI, we investigated mitochondrial bioenergetics in the mid-thoracic region at 6, 12, and 24 h following contusion SCI. It is widely accepted that increased free radical generation plays a critical role in neuronal damage after SCI. Hence, to ascertain the role of free radicals in SCI-induced mitochondrial dysfunction, markers for oxidative damage, including nitrotyrosine (3-NT), lipid peroxidation byproduct (4-hydroxynonenal [HNE]), and protein oxidation (protein carbonyls) were quantified in the same samples of isolated mitochondria during the 24-h time course. The results demonstrate that a significant decline in mitochondrial function begins to occur 12 h post-injury and persists for a least 24 h following SCI. Furthermore, there was a progressive increase in mitochondrial oxidative damage that preceded the loss of mitochondrial bioenergetics, suggesting that free radical damage may be a major mitochondrial secondary injury process. Based on the present results, the temporal profile of mitochondrial dysfunction indicates that interventions targeting mitochondrial oxidative damage and dysfunction may serve as a beneficial pharmacological treatment for acute SCI.}, } @article {pmid17562131, year = {2007}, author = {Kakkar, P and Singh, BK}, title = {Mitochondria: a hub of redox activities and cellular distress control.}, journal = {Molecular and cellular biochemistry}, volume = {305}, number = {1-2}, pages = {235-253}, pmid = {17562131}, issn = {0300-8177}, mesh = {Aging/physiology ; Animals ; Antioxidants/metabolism/physiology ; Biological Evolution ; Calcium Signaling/physiology ; Cell Death/physiology ; Drug Delivery Systems ; Energy Metabolism/physiology ; Humans ; Ion Channels/physiology ; Mitochondria/drug effects/*metabolism/*physiology ; Mitochondrial Diseases/etiology ; Mitochondrial Proteins/physiology ; Models, Biological ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Uncoupling Protein 1 ; }, abstract = {In their reductionist approach in unraveling phenomena inside the cell, scientists in recent times have focused attention to mitochondria. An organelle with peculiar evolutionary history and organization, it is turning out to be an important cell survival switch. Besides controlling bioenergetics of a cell it also has its own genetic machinery which codes 37 genes. It is a major source of generation of reactive oxygen species, acts as a safety device against toxic increases of cytosolic Ca2+ and its membrane permeability transition is a critical control point in cell death. Redox status of mitochondria is important in combating oxidative stress and maintaining membrane permeability. Importance of mitochondria in deciding the response of cell to multiplicity of physiological and genetic stresses, inter-organelle communication, and ultimate cell survival is constantly being unraveled and discussed in this review. Mitochondrial events involved in apoptosis and necrotic cell death, such as activation of Bcl-2 family proteins, formation of permeability transition pore, release of cytochrome c and apoptosis inducing factors, activation of caspase cascade, and ultimate cell death is the focus of attention not only for cell biologists, but also for toxicologists in unraveling stress responses. Mutations caused by ROS to mitochondrial DNA, its inability to repair it completely and creation of a vicious cycle of mutations along with role of Bcl-2 family genes and proteins has been implicated in many diseases where mitochondrial dysfunctions play a key role. New therapeutic approaches toward targeting low molecular weight compounds to mitochondria, including antioxidants is a step toward nipping the stress in the bud.}, } @article {pmid17156084, year = {2007}, author = {Harper, JM and Salmon, AB and Leiser, SF and Galecki, AT and Miller, RA}, title = {Skin-derived fibroblasts from long-lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor rotenone.}, journal = {Aging cell}, volume = {6}, number = {1}, pages = {1-13}, pmid = {17156084}, issn = {1474-9718}, support = {T32 AG000114/AG/NIA NIH HHS/United States ; U19 AG023122/AG/NIA NIH HHS/United States ; AG023122/AG/NIA NIH HHS/United States ; P30 AG024824-019003/AG/NIA NIH HHS/United States ; P30 AG024824/AG/NIA NIH HHS/United States ; AG024824/AG/NIA NIH HHS/United States ; GM07315/GM/NIGMS NIH HHS/United States ; Z01 AG000114/ImNIH/Intramural NIH HHS/United States ; T32 GM007315/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Cadmium/toxicity ; Cells, Cultured ; Cellular Senescence/drug effects/*physiology/radiation effects ; Chiroptera ; Energy Metabolism/drug effects/physiology ; Fibroblasts/drug effects/*metabolism/radiation effects ; Glucose/metabolism ; Heat Stress Disorders/metabolism/physiopathology ; Hydrogen Peroxide/toxicity ; Immunity, Innate/drug effects/physiology ; Linear Models ; Longevity/*physiology ; Mice ; Mitochondria/drug effects/*metabolism ; Oxidative Stress/physiology ; Rodentia ; Rotenone/*toxicity ; Skin/*cytology ; Species Specificity ; Ultraviolet Rays ; Uncoupling Agents/toxicity ; }, abstract = {Fibroblast cell lines were developed from skin biopsies of eight species of wild-trapped rodents, one species of bat, and a group of genetically heterogeneous laboratory mice. Each cell line was tested in vitro for their resistance to six varieties of lethal stress, as well as for resistance to the nonlethal metabolic effects of the mitochondrial inhibitor rotenone and of culture at very low glucose levels. Standard linear regression of species-specific lifespan against each species mean stress resistance showed that longevity was associated with resistance to death induced by cadmium and hydrogen peroxide, as well as with resistance to rotenone inhibition. A multilevel regression method supported these associations, and suggested a similar association for resistance to heat stress. Regressions for resistance to cadmium, peroxide, heat, and rotenone remained significant after various statistical adjustments for body weight. In contrast, cells from longer-lived species did not show significantly greater resistance to ultraviolet light, paraquat, or the DNA alkylating agent methylmethanesulfonate. There was a strong correlation between species longevity and resistance to the metabolic effects of low-glucose medium among the rodent cell lines, but this test did not distinguish mice and rats from the much longer-lived little brown bat. These results are consistent with the idea that evolution of long-lived species may require development of cellular resistance to several forms of lethal injury, and provide justification for evaluation of similar properties in a much wider range of mammals and bird species.}, } @article {pmid17029566, year = {2007}, author = {Orrenius, S and Gogvadze, V and Zhivotovsky, B}, title = {Mitochondrial oxidative stress: implications for cell death.}, journal = {Annual review of pharmacology and toxicology}, volume = {47}, number = {}, pages = {143-183}, doi = {10.1146/annurev.pharmtox.47.120505.105122}, pmid = {17029566}, issn = {0362-1642}, mesh = {Apoptosis/*physiology ; Cardiolipins/physiology ; Mitochondria/*physiology ; Necrosis ; Oxidative Stress/*physiology ; *Reactive Oxygen Species ; }, abstract = {In addition to the established role of the mitochondria in energy metabolism, regulation of cell death has emerged as a second major function of these organelles. This seems to be intimately linked to their generation of reactive oxygen species (ROS), which have been implicated in mtDNA mutations, aging, and cell death. Mitochondrial regulation of apoptosis occurs by mechanisms, which have been conserved through evolution. Thus, many lethal agents target the mitochondria and cause release of cytochrome c and other pro-apoptotic proteins into the cytoplasm. Cytochrome c release is initiated by the dissociation of the hemoprotein from its binding to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and increases the level of soluble cytochrome c in the intermembrane space. Subsequent release of the hemoprotein occurs by pore formation mediated by pro-apoptotic Bcl-2 family proteins, or by Ca(2+) and ROS-triggered mitochondrial permeability transition, although the latter pathway might be more closely associated with necrosis. Taken together, these findings have placed the mitochondria in the focus of current cell death research.}, } @article {pmid16948501, year = {2006}, author = {Morel, F and Renoux, M and Alziari, S}, title = {Mitochondrial biochemical activities and heteroplasmy evolution in established D. subobscura cell line.}, journal = {In vitro cellular & developmental biology. Animal}, volume = {42}, number = {7}, pages = {201-207}, pmid = {16948501}, issn = {1071-2690}, mesh = {Animals ; Cell Culture Techniques ; *Cell Line ; Culture Media ; Drosophila/*cytology/genetics/metabolism ; Energy Metabolism/physiology ; *Evolution, Molecular ; Gene Deletion ; Genes, Mitochondrial ; Genome, Insect ; Glycolysis ; Mitochondria/genetics/*metabolism ; }, abstract = {A mutant strain of drosophila (D. subobscura) has two types of mitochondrial genomes: a small population (20%) identical to that of the wild strain (15.9 kb) and a predominant population (80%) which has undergone a 5-kb deletion affecting more than 30% of the coding zone. Two cell lines were established from homogenates of embryos from mutant and wild strains. The activities of the respiratory complexes measured in the different cell lines are much lower than in the flies, indicating a glycolytic metabolism. Various modifications of the medium composition did not change this metabolic pathway. The mutant cell line has two types of populations of mitochondrial genomes and the heteroplasmy is equivalent to that measured in the mutant strain. However, the biochemical characteristics differ from those observed in the flies (i.e., the decrease of complex I and III activities), and the various systems of compensation for the consequences of the deletion that are showed in the mutant strain are no longer observed. Furthermore, in contrast with observations made on mutant flies, the heteroplasmy appears unstable in the mutant cell lines: after 60 or so generations, it progressively decreases until it disappears completely. The limited importance of mitochondrial energy metabolism in cells may explain the low impact of the mutation on the established cell line, in contrast to what is seen in the mutant strain.}, } @article {pmid16937356, year = {2006}, author = {Das, J}, title = {The role of mitochondrial respiration in physiological and evolutionary adaptation.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {28}, number = {9}, pages = {890-901}, doi = {10.1002/bies.20463}, pmid = {16937356}, issn = {0265-9247}, mesh = {*Adaptation, Physiological ; Animals ; *Biological Evolution ; Cell Respiration/*physiology ; Energy Metabolism ; Mitochondria/*metabolism ; Selection, Genetic ; }, abstract = {Aerobic mitochondria serve as the power sources of eukaryotes by producing ATP through oxidative phosphorylation (OXPHOS). The enzymes involved in OXPHOS are multisubunit complexes encoded by both nuclear and mitochondrial DNA. Thus, regulation of respiration is necessarily a highly coordinated process that must organize production, assembly and function of mitochondria to meet an organism's energetic needs. Here I review the role of OXPHOS in metabolic adaptation and diversification of higher animals. On a physiological timescale, endocrine-initiated signaling pathways allow organisms to modulate respiratory enzyme concentration and function under changing environmental conditions. On an evolutionary timescale, mitochondrial enzymes are targets of natural selection, balancing cytonuclear coevolutionary constraints against physiological innovation. By synthesizing our knowledge of biochemistry, physiology and evolution of respiratory regulation, I propose that we can now explore questions at the interface of these fields, from molecular translation of environmental cues to selection on mitochondrial haplotype variation.}, } @article {pmid16918441, year = {2006}, author = {Salvioli, S and Capri, M and Valensin, S and Tieri, P and Monti, D and Ottaviani, E and Franceschi, C}, title = {Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology.}, journal = {Current pharmaceutical design}, volume = {12}, number = {24}, pages = {3161-3171}, doi = {10.2174/138161206777947470}, pmid = {16918441}, issn = {1381-6128}, mesh = {Aging/*physiology ; Animals ; Cytokines/genetics/*physiology ; Humans ; Inflammation/genetics/*physiopathology ; Mitochondria/*physiology ; Phylogeny ; Polymorphism, Genetic/genetics ; Systems Biology/methods ; }, abstract = {In this article we summarise present knowledge on the role of pro-inflammatory cytokines on chronic inflammation leading to organismal aging, a phenomenon we proposed to call "inflamm-aging". In particular, we review genetic data regarding polymorphisms of genes encoding for cytokines and proteins involved in natural immunity (such as Toll-like Receptors and Heat Shock Proteins) obtained from large population studies including young, old and very old people in good health status or affected by age-related diseases such as Alzheimer's Disease and Type II Diabetes. On the whole, despite some controversial results, the available data are in favour of the hypothesis that pro-inflammatory cytokines play an important role in aging and longevity. Further, we present a possible hypothesis to reconcile energetic dysfunction, including mitochondria, and inflamm-aging. New perspectives for future studies, including phylogenetic studies in animal models and in silico studies on mathematical and bioinformatic models inspired by the systems biology approach, are also proposed.}, } @article {pmid16773565, year = {2006}, author = {Saxena, R and de Bakker, PI and Singer, K and Mootha, V and Burtt, N and Hirschhorn, JN and Gaudet, D and Isomaa, B and Daly, MJ and Groop, L and Ardlie, KG and Altshuler, D}, title = {Comprehensive association testing of common mitochondrial DNA variation in metabolic disease.}, journal = {American journal of human genetics}, volume = {79}, number = {1}, pages = {54-61}, pmid = {16773565}, issn = {0002-9297}, mesh = {Body Mass Index ; Case-Control Studies ; DNA, Mitochondrial/*genetics ; Diabetes Mellitus, Type 2/*genetics ; Humans ; Metabolic Diseases/*genetics ; Polymorphism, Single Nucleotide ; }, abstract = {Many lines of evidence implicate mitochondria in phenotypic variation: (a) rare mutations in mitochondrial proteins cause metabolic, neurological, and muscular disorders; (b) alterations in oxidative phosphorylation are characteristic of type 2 diabetes, Parkinson disease, Huntington disease, and other diseases; and (c) common missense variants in the mitochondrial genome (mtDNA) have been implicated as having been subject to natural selection for adaptation to cold climates and contributing to "energy deficiency" diseases today. To test the hypothesis that common mtDNA variation influences human physiology and disease, we identified all 144 variants with frequency >1% in Europeans from >900 publicly available European mtDNA sequences and selected 64 tagging single-nucleotide polymorphisms that efficiently capture all common variation (except the hypervariable D-loop). Next, we evaluated the complete set of common mtDNA variants for association with type 2 diabetes in a sample of 3,304 diabetics and 3,304 matched nondiabetic individuals. Association of mtDNA variants with other metabolic traits (body mass index, measures of insulin secretion and action, blood pressure, and cholesterol) was also tested in subsets of this sample. We did not find a significant association of common mtDNA variants with these metabolic phenotypes. Moreover, we failed to identify any physiological effect of alleles that were previously proposed to have been adaptive for energy metabolism in human evolution. More generally, this comprehensive association-testing framework can readily be applied to other diseases for which mitochondrial dysfunction has been implicated.}, } @article {pmid16620376, year = {2006}, author = {Tan, DJ and Chang, J and Liu, LL and Bai, RK and Wang, YF and Yeh, KT and Wong, LJ}, title = {Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer.}, journal = {BMC cancer}, volume = {6}, number = {}, pages = {93}, pmid = {16620376}, issn = {1471-2407}, support = {R01 CA100023/CA/NCI NIH HHS/United States ; R01CA100023/CA/NCI NIH HHS/United States ; R21CA87327/CA/NCI NIH HHS/United States ; }, mesh = {Adenocarcinoma/genetics ; Adult ; Aged ; Amino Acid Sequence ; Base Sequence ; Carcinoma, Adenosquamous/genetics ; Carcinoma, Squamous Cell/genetics ; DNA/genetics ; DNA Mutational Analysis ; DNA, Mitochondrial/*genetics ; Electrophoresis ; Esophageal Neoplasms/*genetics ; Evolution, Molecular ; Female ; Frameshift Mutation ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; *Mutation ; Mutation, Missense ; Reactive Oxygen Species ; Sequence Analysis, DNA ; Temperature ; }, abstract = {BACKGROUND: The roles of mitochondria in energy metabolism, the generation of ROS, aging, and the initiation of apoptosis have implicated their importance in tumorigenesis. In this study we aim to establish the mutation spectrum and to understand the role of somatic mtDNA mutations in esophageal cancer.

METHODS: The entire mitochondrial genome was screened for somatic mutations in 20 pairs (18 esophageal squamous cell carcinomas, one adenosquamous carcinoma and one adenocarcinoma) of tumor/surrounding normal tissue of esophageal cancers, using temporal temperature gradient gel electrophoresis (TTGE), followed by direct DNA sequencing to identify the mutations.

RESULTS: Fourteen somatic mtDNA mutations were identified in 55% (11/20) of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively. Nine mutations (64%) were in the D-loop region. Numerous germline variations were found, at least 10 of them were novel and five were missense mutations, some of them occurred in evolutionarily conserved domains. Using real-time quantitative PCR analysis, the mtDNA content was found to increase in some tumors and decrease in others. Analysis of molecular and other clinicopathological findings does not reveal significant correlation between somatic mtDNA mutations and mtDNA content, or between mtDNA content and metastatic status.

CONCLUSION: Our results demonstrate that somatic mtDNA mutations in esophageal cancers are frequent. Some missense and frameshift mutations may play an important role in the tumorigenesis of esophageal carcinoma. More extensive biochemical and molecular studies will be necessary to determine the pathological significance of these somatic mutations.}, } @article {pmid16553311, year = {2006}, author = {Ginger, ML}, title = {Niche metabolism in parasitic protozoa.}, journal = {Philosophical transactions of the Royal Society of London. Series B, Biological sciences}, volume = {361}, number = {1465}, pages = {101-118}, pmid = {16553311}, issn = {0962-8436}, mesh = {Animals ; Biological Evolution ; *Energy Metabolism ; Eukaryota/genetics/*metabolism ; Genome, Protozoan ; Host-Parasite Interactions ; Parasitic Diseases/metabolism/*parasitology ; }, abstract = {Complete or partial genome sequences have recently become available for several medically and evolutionarily important parasitic protozoa. Through the application of bioinformatics complete metabolic repertoires for these parasites can be predicted. For experimentally intractable parasites insight provided by metabolic maps generated in silico has been startling. At its more extreme end, such bioinformatics reckoning facilitated the discovery in some parasites of mitochondria remodelled beyond previous recognition, and the identification of a non-photosynthetic chloroplast relic in malarial parasites. However, for experimentally tractable parasites, mapping of the general metabolic terrain is only a first step in understanding how the parasite modulates its streamlined, yet still often puzzlingly complex, metabolism in order to complete life cycles within host, vector, or environment. This review provides a comparative overview and discussion of metabolic strategies used by several different parasitic protozoa in order to subvert and survive host defences, and illustrates how genomic data contribute to the elucidation of parasite metabolism.}, } @article {pmid16436509, year = {2006}, author = {Li, W and Sun, L and Liang, Q and Wang, J and Mo, W and Zhou, B}, title = {Yeast AMID homologue Ndi1p displays respiration-restricted apoptotic activity and is involved in chronological aging.}, journal = {Molecular biology of the cell}, volume = {17}, number = {4}, pages = {1802-1811}, pmid = {16436509}, issn = {1059-1524}, mesh = {*Apoptosis ; Electron Transport ; Electron Transport Complex I ; Gene Deletion ; Mitochondria/*metabolism ; NADH Dehydrogenase/classification/genetics/*metabolism ; Phylogeny ; Reactive Oxygen Species/*metabolism ; Saccharomyces cerevisiae/enzymology/*growth & development/ultrastructure ; Saccharomyces cerevisiae Proteins/classification/genetics/*metabolism ; Superoxide Dismutase/genetics ; Time Factors ; Transcriptional Activation ; }, abstract = {Apoptosis-inducing factor (AIF) and AIF-homologous mitochondrion-associated inducer of death (AMID) are both mitochondrial flavoproteins that trigger caspase-independent apoptosis. Phylogenetic analysis suggests that these two proteins evolutionarily diverge back from their common prokaryote ancestor. Compared with AIF, the proapoptotic nature of AMID and its mode of action are much less clarified. Here, we show that overexpression of yeast AMID homologue internal NADH dehydrogenase (NDI1), but not external NADH dehydrogenase (NDE1), can cause apoptosis-like cell death, and this effect can be repressed by increased respiration on glucose-limited media. This result indicates that the regulatory network of energy metabolism, in particular the cross-talk between mitochondria and the rest of the cell, is involved in Ndi1p-induced yeast cell apoptosis. The apoptotic effect of NDI1 overexpression is associated with increased production of reactive oxygen species (ROS) in mitochondria. In addition, NDI1 overexpression in sod2 background causes cell lethality in both fermentable and semifermentable media. Interruption of certain components in the electron transport chain can suppress the growth inhibition from Ndi1p overexpression. We finally show that disruption of NDI1 or NDE1 decreases ROS production and elongates the chronological life span of yeast, accompanied by the loss of survival fitness. Implication of these findings for Ndi1p-induced apoptosis is discussed.}, } @article {pmid16283555, year = {2005}, author = {Mozo, J and Emre, Y and Bouillaud, F and Ricquier, D and Criscuolo, F}, title = {Thermoregulation: what role for UCPs in mammals and birds?.}, journal = {Bioscience reports}, volume = {25}, number = {3-4}, pages = {227-249}, doi = {10.1007/s10540-005-2887-4}, pmid = {16283555}, issn = {0144-8463}, mesh = {Acclimatization ; Adipose Tissue, Brown/metabolism ; Animals ; Birds/*physiology ; Body Temperature Regulation/*physiology ; Carrier Proteins/chemistry/classification/genetics/*metabolism ; Cold Temperature ; Energy Metabolism/physiology ; Hormones/metabolism ; Humans ; Ion Channels ; Mammals/*physiology ; Membrane Proteins/chemistry/classification/genetics/*metabolism ; Mitochondria/metabolism ; Mitochondrial Proteins ; Obesity/genetics/metabolism ; Phylogeny ; Protein Isoforms/chemistry/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Uncoupling Protein 1 ; }, abstract = {Mammals and birds are endotherms and respond to cold exposure by the means of regulatory thermogenesis, either shivering or non-shivering. In this latter case, waste of cell energy as heat can be achieved by uncoupling of mitochondrial respiration. Uncoupling proteins, which belong to the mitochondrial carrier family, are able to transport protons and thus may assume a thermogenic function. The mammalian UCP1 physiological function is now well understood and gives to the brown adipose tissue the capacity for heat generation. But is it really the case for its more recently discovered isoforms UCP2 and UCP3? Additionally, whereas more and more evidence suggests that non-shivering also exists in birds, is the avian UCP also involved in response to cold exposure? In this review, we consider the latest advances in the field of UCP biology and present putative functions for UCP1 homologues.}, } @article {pmid16274729, year = {2006}, author = {Hipkiss, AR}, title = {On the mechanisms of ageing suppression by dietary restriction-is persistent glycolysis the problem?.}, journal = {Mechanisms of ageing and development}, volume = {127}, number = {1}, pages = {8-15}, doi = {10.1016/j.mad.2005.09.006}, pmid = {16274729}, issn = {0047-6374}, mesh = {Aging/*physiology ; Animals ; Biological Evolution ; *Caloric Restriction ; Glycolysis/*physiology ; Glyoxal/analogs & derivatives/metabolism ; Humans ; Stress, Physiological/physiopathology ; }, abstract = {The mechanism(s) by which dietary restriction (DR) suppresses ageing and onset of age-related pathologies are discussed in relation to frequency of glycolysis, and the reactivity of glycolytic intermediates. Most glycolytic intermediates are potentially toxic and readily modify (i.e. glycate) proteins and other macromolecules non-enzymically. Attention is drawn to the reactivity of methyglyoxal (MG) which is formed predominantly from the glycolytic intermediates dihydroxyacetone- and glyceraldehyde-3-phosphates. MG rapidly glycates proteins, damages mitochondria and induces a pro-oxidant state, similar to that observed in aged cells. It is suggested that because DR animals' energy metabolism is less glycolytic than in those fed ad libitum, intracellular MG levels are lowered by DR The decreased glycolysis during DR may delay senescence by lowering intracellular MG concentration compared to ad libitum-fed animals. Because of the reactivity MG and glycolytic intermediates, occasional glycolysis could be hormetic where glyoxalase, carnosine synthetase and ornithine decarboxylase are upregulated to control cellular MG concentration. It is suggested that in ad libitum-fed animals persistent glycolysis permanently raises MG levels which progressively overwhelm protective processes, particularly in non-mitotic tissues, to create the senescent state earlier than in DR animals. The possible impact of diet and intracellular glycating agents on age-related mitochondrial dysfunction is also discussed.}, } @article {pmid16188310, year = {2005}, author = {Uda, K and Tanaka, K and Bailly, X and Zal, F and Suzuki, T}, title = {Phosphagen kinase of the giant tubeworm Riftia pachyptila. Cloning and expression of cytoplasmic and mitochondrial isoforms of taurocyamine kinase.}, journal = {International journal of biological macromolecules}, volume = {37}, number = {1-2}, pages = {54-60}, doi = {10.1016/j.ijbiomac.2005.08.009}, pmid = {16188310}, issn = {0141-8130}, mesh = {Amino Acid Sequence ; Animals ; Annelida ; Arginine/chemistry ; Catalysis ; Cloning, Molecular ; Creatine/chemistry ; Cytoplasm/*metabolism ; DNA, Complementary/metabolism ; Evolution, Molecular ; Gene Library ; Glycine/analogs & derivatives/chemistry ; Helminths ; Kinetics ; Mitochondria/*metabolism ; Molecular Sequence Data ; Phosphotransferases (Nitrogenous Group Acceptor)/biosynthesis/*chemistry/*genetics ; Phylogeny ; Protein Isoforms ; Recombinant Proteins/chemistry ; Sequence Homology, Amino Acid ; Serine/analogs & derivatives/chemistry ; Temperature ; }, abstract = {The giant tubeworm Riftia pachyptila lives at deep-sea hydrothermal vents along the East Pacific Rise and the Galapagos Rift. The large size and high growth rate of R. pachyptila is supported by an endosymbiotic relationship with a chemosynthetic bacterium. Elucidation of the regulation of energy metabolism of the giant tubeworm remains an interesting problem. The purpose of this study is to determine the cDNA sequence of phosphagen kinase, one of the most important enzymes in energy metabolism, and to characterize its function. Two phosphagen kinase cDNA sequences amplified from the cDNA library of R. pachyptila showed high derived amino acid sequence identity (74%) with those of cytoplasmic taurocyamine kinase (TK) and mitochondrial TK from an annelid Arenicola brasiliensis. The cytoplasmic form of the Riftia recombinant enzyme showed stronger activity for the substrates taurocyamine and also considerable activity for lombricine (21% that of taurocyamine). The mitochondrial form, which was structurally similar to mitochondrial creatine kinase, showed stronger activity for taurocyamine, and a broader activity for various guanidine compounds: glycocyamine (35% that of taurocyamine), lombricine (31%) and arginine (3%). Both forms showed no activity for creatine. The difference in substrate specificities between the cytoplasmic and mitochondrial forms might be attributable to the large difference in the amino acid sequence of the GS region and/or several key amino acid residues for establishing guanidine substrate specificity. Based on these results, we conclude that Riftia contains at least two forms of TK as phosphagen kinase. We also report the kinetic parameters, Km and kcat, of Arenicola and Riftia TKs for the first time. The Km values for taurocyamine of Arenicola and Riftia TKs ranged from 0.9 to 4.0 mM and appear to be comparable to those of other annelid-specific enzymes, lombricine kinase and glycocyamine kinase, but are significantly lower than those of Neanthes cytoplasmic and mitochondrial creatine kinases. Comparison of kcat/Km value in various annelid phosphagen kinases indicates that Arenicola mitochondrial TK has the highest catalytic efficiency (16.2 s-1 mM-1). In Arenicola TKs, the mitochondrial form has seven-fold higher efficiency than the cytoplasmic form.}, } @article {pmid16155230, year = {2005}, author = {Darveau, CA and Hochachka, PW and Roubik, DW and Suarez, RK}, title = {Allometric scaling of flight energetics in orchid bees: evolution of flux capacities and flux rates.}, journal = {The Journal of experimental biology}, volume = {208}, number = {Pt 18}, pages = {3593-3602}, doi = {10.1242/jeb.01777}, pmid = {16155230}, issn = {0022-0949}, mesh = {Animals ; Bees/metabolism/*physiology ; *Biological Evolution ; Cell Respiration/physiology ; Energy Metabolism/*physiology ; Enzymes/*metabolism ; Flight, Animal/*physiology ; Mitochondria/metabolism ; Muscles/enzymology/*physiology ; Panama ; Spectrophotometry, Ultraviolet ; }, abstract = {The evolution of metabolic pathways involved in energy production was studied in the flight muscles of 28 species of orchid bees. Previous work revealed that wingbeat frequencies and mass-specific metabolic rates decline in parallel by threefold as body mass increases interspecifically over a 20-fold range. We investigated the correlated evolution of metabolic rates during hovering flight and the flux capacities, i.e. V(max) values, of flight muscle enzymes involved in substrate catabolism, the Krebs cycle and the electron transport chain. V(max) at the hexokinase (HK) step scales allometrically with an exponent almost identical to those obtained for wingbeat frequency and mass-specific metabolic rate. Analysis of this relationship using phylogenetically independent contrasts supports the hypothesis of correlated evolution between HK activity and mass-specific metabolic rate. Although other enzymes scale allometrically with respect to body mass, e.g. trehalase, glycogen phosphorylase and citrate synthase, no other enzyme activities were correlated with metabolic rate after controlling for phylogenetic relatedness. Pathway flux rates were used with enzyme V(max) values to estimate fractional velocities (fraction of V(max) at which enzymes operate) for various reactions to gain insights into enzyme function and how this varies with body mass. Fractional velocity is highly conserved across species at the HK step, but varied at all other steps examined. These results are discussed in the context of the regulation and evolution of pathways of energy metabolism.}, } @article {pmid16155228, year = {2005}, author = {Suarez, RK and Darveau, CA and Welch, KC and O'Brien, DM and Roubik, DW and Hochachka, PW}, title = {Energy metabolism in orchid bee flight muscles: carbohydrate fuels all.}, journal = {The Journal of experimental biology}, volume = {208}, number = {Pt 18}, pages = {3573-3579}, doi = {10.1242/jeb.01775}, pmid = {16155228}, issn = {0022-0949}, mesh = {3-Hydroxyacyl CoA Dehydrogenases/metabolism ; Animals ; Bees/enzymology/*physiology ; Carbohydrate Metabolism/*physiology ; Carbon Dioxide/metabolism ; Energy Metabolism/*physiology ; Flight, Animal/*physiology ; Glycogen Phosphorylase/metabolism ; Hexokinase/metabolism ; Mitochondria/metabolism ; Muscles/enzymology/*physiology ; Oxygen Consumption/physiology ; Panama ; Species Specificity ; Spectrophotometry, Ultraviolet ; Trehalase/metabolism ; }, abstract = {The widely accepted idea that bees fuel flight through the oxidation of carbohydrate is based on studies of only a few species. We tested this hypothesis as part of our research program to investigate the size-dependence of flight energetics in Panamanian orchid bees. We succeeded in measuring rates of O(2) consumption and CO(2) production in vivo during hovering flight, as well as maximal activities (V(max) values) in vitro of key enzymes in flight muscle energy metabolism in nine species belonging to four genera. Respiratory quotients (ratios of rates of CO(2) production to O(2) consumption) in all nine species are close to 1.0. This indicates that carbohydrate is the main fuel used for flight. Trehalase, glycogen phosphorylase and hexokinase activities are sufficient to account for the glycolytic flux rates estimated from rates of CO(2) production. High activities of other glycolytic enzymes, as well as high activities of mitochondrial oxidative enzymes, are consistent with the estimated rates of carbohydrate-fueled oxidative metabolism. In contrast, hydroxyacylCoA dehydrogenase, an enzyme involved in fatty acid oxidation, was not detectable in any species. Thoracic homogenates displayed ADP-stimulated oxidition of pyruvate + proline, but did not oxidize palmitoyl l-carnitine + proline as substrates. A metabolic map, based on data reported herein and information from the literature, is presented. The evidence available supports the hypothesis that carbohydrate serves as the main fuel for flight in bees.}, } @article {pmid15855395, year = {2005}, author = {Weibel, ER and Hoppeler, H}, title = {Exercise-induced maximal metabolic rate scales with muscle aerobic capacity.}, journal = {The Journal of experimental biology}, volume = {208}, number = {Pt 9}, pages = {1635-1644}, doi = {10.1242/jeb.01548}, pmid = {15855395}, issn = {0022-0949}, mesh = {Animals ; Capillaries/*anatomy & histology ; Energy Metabolism/*physiology ; Fractals ; Mammals/*physiology ; Mitochondria/*physiology ; *Models, Biological ; Muscle, Skeletal/blood supply/*physiology ; Oxygen Consumption/physiology ; Physical Exertion/*physiology ; Species Specificity ; }, abstract = {The logarithmic nature of the allometric equation suggests that metabolic rate scaling is related to some fractal properties of the organism. Two universal models have been proposed, based on (1) the fractal design of the vasculature and (2) the fractal nature of the 'total effective surface' of mitochondria and capillaries. According to these models, basal and maximal metabolic rates must scale as M3/4. This is not what we find. In 34 eutherian mammalian species (body mass Mb ranging from 7 g to 500 kg) we found VO2max to scale with the 0.872 (+/-0.029) power of body mass, which is significantly different from 3/4 power scaling. Integrated structure-function studies on a subset of eleven species (Mb 20 g to 450 kg) show that the variation of VO2max with body size is tightly associated with the total volume of mitochondria and of the locomotor musculature capillaries. In athletic species the higher VO2max is linked to proportionally larger mitochondrial and capillary volumes. As a result, VO2max is linearly related to both total mitochondrial and capillary erythrocyte volumes, as well as to their surface areas. Consequently, the allometric variation of maximal metabolic rate is directly related to the scaling of the total effective surfaces of mitochondria and capillaries, thus confirming the basic conjecture of the second fractal models but refuting the arguments for 3/4 power scaling. We conclude that the scaling of maximal metabolic rate is determined by the energy needs of the cells active during maximal work. The vascular supply network is adapted to the needs of the cells at their working limit. We conjecture that the optimization of the arterial tree by fractal design is the result rather than the cause of the evolution of metabolic rate scaling. The remaining question is why the energy needs of locomotion scale with the 0.872 or 7/8 power of body mass.}, } @article {pmid15846094, year = {2005}, author = {Robey, RB and Hay, N}, title = {Mitochondrial hexokinases: guardians of the mitochondria.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {4}, number = {5}, pages = {654-658}, doi = {10.4161/cc.4.5.1678}, pmid = {15846094}, issn = {1551-4005}, support = {AG016927/AG/NIA NIH HHS/United States ; CA090764/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; Biological Evolution ; Cell Survival ; Energy Metabolism ; Gene Expression Regulation, Enzymologic ; Glucose/metabolism ; Hexokinase/genetics/*physiology ; *Homeostasis ; Humans ; Mitochondria/*enzymology/*physiology ; Models, Biological ; Proto-Oncogene Proteins c-akt/*physiology ; }, abstract = {There is accumulating evidence that cell survival and energy metabolism are inexorably linked. As a major mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt (also known as protein kinase B or PKB) is particularly well-suited to coordinate the regulation of these interrelated processes. Recent demonstrations that growth factors and Akt require glucose (Glc) to prevent apoptosis and promote cell survival are compatible with this contention, as is a positive correlation between Akt-regulated mitochondrial hexokinase (mtHK) association and apoptotic resistance. From a phylogenetic perspective, the ability of Akt to regulate cellular energy metabolism apparently preceded the capacity to control cell survival, suggesting an evolutionary basis for the Glc dependent anti-apoptotic effects of Akt. We speculate that, somewhere in the course of evolution, the metabolic regulatory function of Akt evolved into an adaptive sensing system involving mtHK that ensures mitochondrial homeostasis, thereby coupling metabolism to cell survival. We also propose that this "guardian" function of mtHK may be specifically exploited for therapeutic purposes.}, } @article {pmid15674770, year = {2004}, author = {Portner, HO}, title = {Climate variability and the energetic pathways of evolution: the origin of endothermy in mammals and birds.}, journal = {Physiological and biochemical zoology : PBZ}, volume = {77}, number = {6}, pages = {959-981}, doi = {10.1086/423742}, pmid = {15674770}, issn = {1522-2152}, mesh = {Adaptation, Physiological ; Animals ; *Biological Evolution ; Birds/*physiology ; Cell Membrane/physiology ; *Climate ; Environment ; Invertebrates/physiology ; Mammals/*physiology ; Mitochondria/physiology ; Oxygen ; Reptiles/physiology ; Thermogenesis/*genetics/*physiology ; }, abstract = {Large-scale climate oscillations in earth's history have influenced the directions of evolution, last but not least, through mass extinction events. This analysis tries to identify some unifying forces behind the course of evolution that favored an increase in organismic complexity and performance, paralleled by an increase in energy turnover, and finally led to endothermy. The analysis builds on the recent concept of oxygen-limited thermal tolerance and on the hypothesis that unifying principles exist in the temperature-dependent biochemical design of the eukaryotic cell in animals. The comparison of extant water-breathing and air-breathing animal species from various climates provides a cause-and-effect understanding of the trade-offs and constraints in thermal adaptation and their energetic consequences. It is hypothesized that the high costs of functional adaptation to fluctuating temperatures, especially in the cold (cold eurythermy), cause an increase in energy turnover and, at the same time, mobility and agility. These costs are associated with elevated mitochondrial capacities at minimized levels of activation enthalpies for proton leakage. Cold eurythermy is seen as a precondition for the survival of evolutionary crises elicited by repeated cooling events during extreme climate fluctuations. The costs of cold eurythermy appear as the single most important reason why metazoan evolution led to life forms with high energy turnover. They also explain why dinosaurs were able to live in subpolar climates. Finally, they give insight into the pathways, benefits, and trade-offs involved in the evolution of constant, elevated body temperature maintained by endothermy. Eurythermy, which encompasses cold tolerance, is thus hypothesized to be the "missing link" between ectothermy and endothermy. Body temperatures between 32 degrees and 42 degrees C in mammals and birds then result from trade-offs between the limiting capacities of ventilation and circulation and the evolutionary trend to maximize performance at the warm end of the thermal tolerance window.}, } @article {pmid15576054, year = {2004}, author = {Gabaldón, T and Huynen, MA}, title = {Shaping the mitochondrial proteome.}, journal = {Biochimica et biophysica acta}, volume = {1659}, number = {2-3}, pages = {212-220}, doi = {10.1016/j.bbabio.2004.07.011}, pmid = {15576054}, issn = {0006-3002}, mesh = {Animals ; *Biological Evolution ; Biological Transport ; Energy Metabolism ; Eukaryotic Cells/physiology ; Humans ; Mitochondria/*physiology ; Phylogeny ; Proteome/*physiology ; }, abstract = {Mitochondria are eukaryotic organelles that originated from a single bacterial endosymbiosis some 2 billion years ago. The transition from the ancestral endosymbiont to the modern mitochondrion has been accompanied by major changes in its protein content, the so-called proteome. These changes included complete loss of some bacterial pathways, amelioration of others and gain of completely new complexes of eukaryotic origin such as the ATP/ADP translocase and most of the mitochondrial protein import machinery. This renewal of proteins has been so extensive that only 14-16% of modern mitochondrial proteome has an origin that can be traced back to the bacterial endosymbiont. The rest consists of proteins of diverse origin that were eventually recruited to function in the organelle. This shaping of the proteome content reflects the transformation of mitochondria into a highly specialized organelle that, besides ATP production, comprises a variety of functions within the eukaryotic metabolism. Here we review recent advances in the fields of comparative genomics and proteomics that are throwing light on the origin and evolution of the mitochondrial proteome.}, } @article {pmid15481813, year = {2004}, author = {Carafoli, E}, title = {The ambivalent nature of the calcium signal.}, journal = {Journal of endocrinological investigation}, volume = {27}, number = {6 Suppl}, pages = {134-136}, pmid = {15481813}, issn = {0391-4097}, mesh = {Animals ; Apoptosis/physiology ; Calcium Signaling/*physiology ; Cell Communication/physiology ; Cell Death/physiology ; Energy Metabolism/physiology ; Humans ; Necrosis ; }, abstract = {In the couse of evolution, calcium has emerged as the most versatile intracellular messenger. Its concentration within cells is controlled by reversible binding to specific protein acting as sensors to decode its information. The decoding operation is based on specific conformational changes in these sensor proteins. Other proteins intrinsic to membranes (plasma membrane, endosarcoplasmic reticulum, mitochondria, nuclear envelope) simply control calcium concentration by transporting it across membrane boundaries. Calcium is an ambivalent signaling agent. It carries information to all processes important to cell life, including excitation-contraction coupling, secretion, gene transcription and enzyme activity through protein phosphorylation-dephosphorylation. However, it also transmits signals that promote programmed demise of cells and, when escaping control, it may also precipitate toxic cell death.}, } @article {pmid15459382, year = {2004}, author = {Armbrust, EV and Berges, JA and Bowler, C and Green, BR and Martinez, D and Putnam, NH and Zhou, S and Allen, AE and Apt, KE and Bechner, M and Brzezinski, MA and Chaal, BK and Chiovitti, A and Davis, AK and Demarest, MS and Detter, JC and Glavina, T and Goodstein, D and Hadi, MZ and Hellsten, U and Hildebrand, M and Jenkins, BD and Jurka, J and Kapitonov, VV and Kröger, N and Lau, WW and Lane, TW and Larimer, FW and Lippmeier, JC and Lucas, S and Medina, M and Montsant, A and Obornik, M and Parker, MS and Palenik, B and Pazour, GJ and Richardson, PM and Rynearson, TA and Saito, MA and Schwartz, DC and Thamatrakoln, K and Valentin, K and Vardi, A and Wilkerson, FP and Rokhsar, DS}, title = {The genome of the diatom Thalassiosira pseudonana: ecology, evolution, and metabolism.}, journal = {Science (New York, N.Y.)}, volume = {306}, number = {5693}, pages = {79-86}, doi = {10.1126/science.1101156}, pmid = {15459382}, issn = {1095-9203}, mesh = {Adaptation, Physiological ; Algal Proteins/chemistry/genetics/physiology ; Animals ; *Biological Evolution ; Cell Nucleus/genetics ; Chromosomes ; DNA/genetics ; Diatoms/chemistry/cytology/*genetics/metabolism ; *Ecosystem ; Energy Metabolism ; *Genome ; Iron/metabolism ; Light ; Light-Harvesting Protein Complexes/chemistry/genetics/metabolism ; Mitochondria/genetics ; Molecular Sequence Data ; Nitrogen/metabolism ; Photosynthesis ; Plastids/genetics ; Restriction Mapping ; Sequence Alignment ; *Sequence Analysis, DNA ; Silicic Acid/metabolism ; Symbiosis ; Urea/metabolism ; }, abstract = {Diatoms are unicellular algae with plastids acquired by secondary endosymbiosis. They are responsible for approximately 20% of global carbon fixation. We report the 34 million-base pair draft nuclear genome of the marine diatom Thalassiosira pseudonana and its 129 thousand-base pair plastid and 44 thousand-base pair mitochondrial genomes. Sequence and optical restriction mapping revealed 24 diploid nuclear chromosomes. We identified novel genes for silicic acid transport and formation of silica-based cell walls, high-affinity iron uptake, biosynthetic enzymes for several types of polyunsaturated fatty acids, use of a range of nitrogenous compounds, and a complete urea cycle, all attributes that allow diatoms to prosper in aquatic environments.}, } @article {pmid15297626, year = {2004}, author = {Meeusen, S and McCaffery, JM and Nunnari, J}, title = {Mitochondrial fusion intermediates revealed in vitro.}, journal = {Science (New York, N.Y.)}, volume = {305}, number = {5691}, pages = {1747-1752}, doi = {10.1126/science.1100612}, pmid = {15297626}, issn = {1095-9203}, support = {S10 RR019409-01/RR/NCRR NIH HHS/United States ; R01-GM62942A/GM/NIGMS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Energy Metabolism ; GTP Phosphohydrolases/genetics/metabolism ; Green Fluorescent Proteins ; Guanosine Triphosphate/metabolism ; Intracellular Membranes/*physiology/ultrastructure ; Luminescent Proteins/metabolism ; *Membrane Fusion ; Membrane Potentials ; Membrane Proteins/genetics/metabolism ; Microscopy, Fluorescence ; Mitochondria/*physiology/*ultrastructure ; Mitochondrial Proteins ; Models, Biological ; Saccharomyces cerevisiae/genetics/*physiology/ultrastructure ; Saccharomyces cerevisiae Proteins ; }, abstract = {The events that occur during the fusion of double-membraned mitochondria are unknown. As an essential step toward determining the mechanism of mitochondrial fusion, we have captured this event in vitro. Mitochondrial outer and inner membrane fusion events were separable and mechanistically distinct, but both required guanosine 5'-triphosphate hydrolysis. Homotypic trans interactions of the ancient outer transmembrane guanosine triphosphatase, Fzo1, were required to promote the fusion of mitochondrial outer membranes, whereas electrical potential was also required for fusion of inner membranes. Our conclusions provide fundamental insights into the molecular events driving mitochondrial fusion and advance our understanding of the evolution of mitochondrial fusion in eukaryotic cells.}, } @article {pmid15273991, year = {2004}, author = {Armstrong, JS and Whiteman, M and Yang, H and Jones, DP}, title = {The redox regulation of intermediary metabolism by a superoxide-aconitase rheostat.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {26}, number = {8}, pages = {894-900}, doi = {10.1002/bies.20071}, pmid = {15273991}, issn = {0265-9247}, mesh = {Aconitate Hydratase/*metabolism ; Animals ; Citric Acid/metabolism ; Evolution, Molecular ; Hydrogen Peroxide/metabolism ; Mice ; Mice, Knockout ; Mitochondria/*metabolism ; Oxidants/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Superoxide Dismutase/genetics/metabolism ; Superoxides/*metabolism ; }, abstract = {In this article, we discuss a hypothesis to explain the preferential synthesis of the superoxide sensitive form of aconitase in mitochondria and the phenotype observed in manganese superoxide dismutase mutant mice, which show a gross over accumulation of stored fat in liver. The model proposes that intermediary metabolism is redox regulated by mitochondrial superoxide generated during mitochondrial respiration. This regulates the level of reducing equivalents (NADH) entering the electron transport chain (ETC) through the reversible inactivation of mitochondrial aconitase. This control mechanism has a dual function; firstly, it regulates levels of superoxide generated by the ETC and, secondly, it fine-tunes metabolism by channeling citrate either for the production of NADH for energy metabolism or diverting it for the synthesis of fats. In this setting, the mitochondrial redox state influences metabolic decisions via a superoxide-aconitase rheostat.}, } @article {pmid15247075, year = {2004}, author = {Brunet Rossinni, AK}, title = {Testing the free radical theory of aging in bats.}, journal = {Annals of the New York Academy of Sciences}, volume = {1019}, number = {}, pages = {506-508}, doi = {10.1196/annals.1297.093}, pmid = {15247075}, issn = {0077-8923}, mesh = {*Aging ; Animals ; Chiroptera/*metabolism ; *Free Radicals ; Hydrogen Peroxide/pharmacology ; Oxidative Stress ; Oxygen/metabolism ; Oxygen Consumption ; Shrews ; Time Factors ; }, abstract = {The extended longevity of bats, despite their high metabolic rates, may provide insight to patterns and mechanisms of aging. I tested the free radical theory of aging as an explanation for the extreme longevity of the little brown bat, Myotis lucifugus (maximum life span potential [MLSP] = 34 years). In a comparative study, I measured whole-organism oxygen consumption and mitochondrial hydrogen peroxide production in brain, heart, and kidney tissues from M. lucifugus and short-tailed shrews, Blarina brevicauda (MLSP = 2 years). As predicted by the free radical theory of aging, M. lucifugus produced approximately half the amount of hydrogen peroxide as B. brevicauda. In addition, I compared oxygen consumption and hydrogen peroxide production of adult (approximately 1 year) and juvenile (fully developed and fledged young of the year) M. lucifugus to assess oxidative damage to mitochondria (measured as an increase in hydrogen peroxide production) due to the high metabolic rate associated with flight. Contrary to my prediction, juveniles had significantly higher levels of hydrogen peroxide production than adults. I propose that the decreased free radical production in adults is the result of within-individual selection of efficient mitochondria due to selective pressure created by the high energetic demands of flight.}, } @article {pmid15235010, year = {2004}, author = {Dawson, TJ and Mifsud, B and Raad, MC and Webster, KN}, title = {Aerobic characteristics of red kangaroo skeletal muscles: is a high aerobic capacity matched by muscle mitochondrial and capillary morphology as in placental mammals?.}, journal = {The Journal of experimental biology}, volume = {207}, number = {Pt 16}, pages = {2811-2821}, doi = {10.1242/jeb.01115}, pmid = {15235010}, issn = {0022-0949}, mesh = {Analysis of Variance ; Animals ; Biological Evolution ; Blood Volume ; Body Constitution ; Body Weights and Measures ; Capillaries/*anatomy & histology ; Macropodidae/*anatomy & histology/*physiology ; Microscopy, Electron ; Mitochondria, Muscle/*physiology ; Muscle, Skeletal/*physiology/ultrastructure ; Oxygen Consumption/*physiology ; }, abstract = {Marsupials and placentals together comprise the Theria, the advanced mammals, but they have had long independent evolutionary histories, with the last common ancestor occurring more than 125 million years ago. Although in the past the marsupials were considered to be metabolically 'primitive', the red kangaroo Macropus rufus has been reported to have an aerobic capacity (VO2max) comparable to that of the most 'athletic' of placentals such as dogs. However, kangaroos travel at moderate speeds with lower relative cost than quadrupedal placentals. Given the long independent evolution of the two therian groups, and their unusual locomotor energetics, do kangaroos achieve their high aerobic capacity using the same structural and functional mechanisms used by (athletic) placentals? Red kangaroo skeletal muscle morphometry matched closely the general aerobic characteristics of placental mammals. The relationship between total mitochondrial volume in skeletal muscle and VO2max during exercise was identical to that in quadrupedal placentals, and differed from that in bipedal humans. As for placentals generally, red kangaroo mitochondrial oxygen consumption at VO2max was 4.7 ml O2 min(-1) ml(-1) of mitochondria. Also, the inner mitochondrial membrane densities were 35.8 +/- 0.7 m2 ml(-1) of mitochondria, which is the same as for placental mammals, and the same pattern of similarity was seen for capillary densities and volumes. The overall data for kangaroos was equivalent to that seen in athletic placentals such as dogs and pronghorns. Total skeletal muscle mass was high, being around 50% of body mass, and was concentrated around the pelvis and lower back. The majority of the muscles sampled had relatively high mitochondrial volume densities, in the range 8.8-10.6% in the major locomotor muscles. Again, capillary densities and capillary blood volumes followed the pattern seen for mitochondria. Our results indicate that the red kangaroo, despite its locomotion and extreme body form, shows fundamental aerobic/muscular relationships that appear common to both marsupials and placentals. The evolution of such metabolic relationships apparently predates the divergence of the therian groups in the early Cretaceous, and perhaps evolved in the mammal-like reptiles during the Triassic (220 million years ago) before the actual evolution of the mammals.}, } @article {pmid15120112, year = {2004}, author = {Hourton-Cabassa, C and Rita Matos, A and Zachowski, A and Moreau, F}, title = {The plant uncoupling protein homologues: a new family of energy-dissipating proteins in plant mitochondria.}, journal = {Plant physiology and biochemistry : PPB}, volume = {42}, number = {4}, pages = {283-290}, doi = {10.1016/j.plaphy.2004.01.007}, pmid = {15120112}, issn = {0981-9428}, mesh = {Carrier Proteins/chemistry/genetics/metabolism ; Energy Metabolism ; Ion Channels ; Membrane Proteins/chemistry/genetics/metabolism ; Mitochondrial Proteins/chemistry/*genetics/*metabolism ; Phylogeny ; Plant Proteins/chemistry/*genetics/*metabolism ; Uncoupling Protein 1 ; }, abstract = {Uncoupling proteins (UCPs) form a subfamily within the mitochondrial carrier protein family, which catalyze a free fatty acid-mediated proton recycling and can modulate the tightness of coupling between mitochondrial respiration and ATP synthesis. As in mammalian tissues, UCPs are rather ubiquitous in the plant kingdom and widespread in plant tissues in which they could have various physiological roles, such as heat production or protection against free oxygen radicals. The simultaneous occurrence in plant mitochondria of two putative energy-dissipating systems, namely UCP which dissipates the proton motive force, and alternative oxidase (AOX) which dissipates the redox potential, raises the question of their functional interactions.}, } @article {pmid15094398, year = {2004}, author = {Sona, S and Suzuki, T and Ellington, WR}, title = {Cloning and expression of mitochondrial and protoflagellar creatine kinases from a marine sponge: implications for the origin of intracellular energy transport systems.}, journal = {Biochemical and biophysical research communications}, volume = {317}, number = {4}, pages = {1207-1214}, doi = {10.1016/j.bbrc.2004.03.176}, pmid = {15094398}, issn = {0006-291X}, mesh = {Amino Acid Sequence ; Animals ; Biological Transport ; Ciona intestinalis/enzymology ; Cloning, Molecular ; Creatine Kinase/*biosynthesis/chemistry/*genetics ; Cytoplasm/*enzymology ; Dimerization ; Energy Metabolism ; Escherichia coli/metabolism ; Isoenzymes ; Mice ; Mitochondria/*enzymology ; Molecular Sequence Data ; Phylogeny ; Polychaeta/enzymology ; Porifera/*enzymology ; Recombinant Proteins/biosynthesis/chemistry/genetics ; Sequence Alignment ; Sequence Homology, Amino Acid ; }, abstract = {Creatine kinase (CK) plays a central role in energy transactions in cells displaying high and variable rates of ATP turnover. Cytoplasmic and mitochondrial CK genes code for isoforms which are targeted to distinct intracellular compartments often in close physical proximity to sites of ATP hydrolysis or synthesis. In certain lower groups a third CK gene is present which codes for a flagellar CK isoform consisting of three complete, fused CK domains. Recent work has shown that cytoplasmic, mitochondrial, and flagellar CKs are present in protochordates and in deuterostome and protostome invertebrates. We report here that the marine sponge Tethya aurantia, a representative of the oldest of all multi-cellular animal groups, expresses three unique CK transcripts. One of these CK transcripts codes for protein that has a mitochondrial targeting sequence and in a phylogenetic analysis is positioned at the base of the cluster containing mitochondrial CK sequences from invertebrates, protochordates, and vertebrates; it is clearly a mitochondrial CK. When expressed in Escherichia coli the mitochondrial form from T. aurantia was found to be dimeric unlike all other mitochondrial CKs which are typically octameric. The other two T. aurantia transcripts code for proteins that appear to be more closely related to flagellar CKs. These protoflagellar CKs were found to be dimers when expressed in Escherichia coli. Sponges last shared a common ancestor with higher animals as long as one billion years ago. The antiquity of intracellular localization, as evidenced by the presence of a true mitochondrial CK and protoflagellar CKs in the sponge T. aurantia, indicates that physical constraints on cellular energy transport were key, early driving forces in the evolution of this key enzyme system.}, } @article {pmid14993600, year = {2004}, author = {Parker, JD and Parker, KM and Sohal, BH and Sohal, RS and Keller, L}, title = {Decreased expression of Cu-Zn superoxide dismutase 1 in ants with extreme lifespan.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {101}, number = {10}, pages = {3486-3489}, pmid = {14993600}, issn = {0027-8424}, mesh = {Aging/*genetics/*metabolism ; Amino Acid Sequence ; Animals ; Ants/*enzymology/*genetics ; Cloning, Molecular ; Drosophila melanogaster/enzymology/genetics ; Female ; Gene Expression ; Longevity ; Male ; Molecular Sequence Data ; Sequence Homology, Amino Acid ; Superoxide Dismutase/*genetics/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Reactive oxygen species, the by-products of oxidative energy metabolism, are considered a main proximate cause of aging. Accordingly, overexpression of the enzyme Cu-Zn superoxide dismutase 1 (SOD1) can lengthen lifespan of Drosophila melanogaster in the laboratory. However, the role of SOD1 as a main determinant of lifespan has been challenged on the grounds that overexpression might be effective only in compromised genetic backgrounds. Moreover, interspecific comparisons show lower levels of antioxidant activities in longer-lived species, suggesting that life-span extension may evolve through less reactive oxygen species generation from the mitochondria rather than higher expression of SOD1. The tremendous variation in lifespan between ant castes, ranging over 2 orders of magnitude, coupled with the fact that all individuals share the same genome, provides a system to investigate the role of SOD1 in the wild. We used the ant Lasius niger as a model system, because queens can reach the extreme age of 28 years, whereas workers and males live only 1-2 years and a few weeks, respectively. We cloned SOD1 and found that long-lived queens have a lower level of expression than workers and males. Specific enzyme-activity assays also showed higher SOD1 activity levels in males and workers compared with queens, which had SOD1 activity levels similar to that of D. melanogaster. Altogether, these data show that increased expression of SOD1 is not required for the evolution of extreme lifespan, even in a system in which differential gene expression is the only way to express phenotypes with great lifespan differences.}, } @article {pmid14959454, year = {2003}, author = {de Micheli, A and Chávez, E}, title = {[Ischemia-reperfusion myocardial injury].}, journal = {Archivos de cardiologia de Mexico}, volume = {73}, number = {4}, pages = {284-290}, pmid = {14959454}, issn = {1405-9940}, mesh = {Electrophysiology ; Humans ; Mitochondria/metabolism ; *Myocardial Reperfusion Injury/metabolism/pathology/physiopathology/therapy ; Oxidative Stress ; }, abstract = {In this article, we present some considerations on the myocardial damage due to a deficit of oxygen supply. In fact, this damage properly constitutes a partial diastolic depolarization or injury, i.e., a moderate reduction of the rest transmembrane potential. This phenomenon is characteristic of the acute phase of the myocardial infarction syndrome and is responsible for the main electrical manifestations appearing in this phase: disorders of rhythm and conduction, as well as a reduced contractility of the involved myocardial fibers. All the mentioned phenomena are due to a defect of the myocardial energetic mechanisms, owing to the mitochondrial alterations in myocytes: early reduction of the nicotinamide adenine nucleotides, accumulation of calcium ("calcium overload") into mitochondria, and a drop in oxidative phosphorylation. These changes can present again, more exaggerated, in a following phase of evolution of the myocardial infarction due to myocardial reperfusion. Its severity is related to the duration of the initial ischemia period. Moreover, consequences of the oxidative stress can add producing cellular damage by liberation of reactive oxygen species. Oxidant stress causes also alterations in the mitochondrial DNA, i.e., mutations due to oxidation of nitrogenous bases. During the initial ischemia phase, as well as during reperfusion, metabolic therapy can be very useful as, for example, glucose-insulin-potassium solutions (G-I-K). These could act as scavengers of the free radicals derived from oxygen and avoid or reduce the myocardial damage due to reperfused myocytes. Metabolic drugs, as for example trimetazidine, antioxidants, etc, can also be used in the myocardial reperfusion phase.}, } @article {pmid14756315, year = {2003}, author = {Atteia, A and van Lis, R and Mendoza-Hernández, G and Henze, K and Martin, W and Riveros-Rosas, H and González-Halphen, D}, title = {Bifunctional aldehyde/alcohol dehydrogenase (ADHE) in chlorophyte algal mitochondria.}, journal = {Plant molecular biology}, volume = {53}, number = {1-2}, pages = {175-188}, pmid = {14756315}, issn = {0167-4412}, support = {TW01176/TW/FIC NIH HHS/United States ; }, mesh = {Alcohol Dehydrogenase/*genetics/metabolism ; Aldehyde Dehydrogenase/*genetics/metabolism ; Amino Acid Sequence ; Blotting, Northern ; Chlorophyta/enzymology/*genetics ; DNA, Complementary/chemistry/genetics/isolation & purification ; Electrophoresis, Gel, Two-Dimensional ; Gene Expression Regulation, Enzymologic ; Hydrogen-Ion Concentration ; Mitochondria/*enzymology ; Mitochondrial Proteins/metabolism ; Molecular Sequence Data ; Multienzyme Complexes/genetics/metabolism ; Oxidative Phosphorylation ; Phylogeny ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Solubility ; }, abstract = {Protein profiles of mitochondria isolated from the heterotrophic chlorophyte Polytomella sp. grown on ethanol at pH 6.0 and pH 3.7 were analyzed by Blue Native and denaturing polyacrylamide gel electrophoresis. Steady-state levels of oxidative phosphorylation complexes were influenced by external pH. Levels of an abundant, soluble, mitochondrial protein of 85 kDa and its corresponding mRNA increased at pH 6.0 relative to pH 3.7. N-terminal and internal sequencing of the 85 kDa mitochondrial protein together with the corresponding cDNA identified it as a bifunctional aldehyde/alcohol dehydrogenase (ADHE) with strong similarity to homologues from eubacteria and amitochondriate protists. A mitochondrial targeting sequence of 27 amino acids precedes the N-terminus of the mature mitochondrial protein. A gene encoding an ADHE homologue was also identified in the genome of Chlamydomonas reinhardtii, a photosynthetic relative of Polytomella. ADHE reveals a complex picture of sequence similarity among homologues. The lack of ADHE from archaebacteria indicates a eubacterial origin for the eukaryotic enzyme. Among eukaryotes, ADHE has hitherto been characteristic of anaerobes since it is essential to cytosolic energy metabolism of amitochondriate protists such as Giardia intestinalis and Entamoeba histolytica. Its abundance and expression pattern suggest an important role for ADHE in mitochondrial metabolism of Polytomella under the conditions studied. The current data are compatible with the view that Polytomella ADHE could be involved either in ethanol production or assimilation, or both, depending upon environmental conditions. Presence of ADHE in an oxygen-respiring algal mitochondrion and co-expression at ambient oxygen levels with respiratory chain components is unexpected with respect to the view that eukaryotes acquired ADHE genes specifically as an adaptation to an anaerobic lifestyle.}, } @article {pmid14716012, year = {2004}, author = {Ruiz-Pesini, E and Mishmar, D and Brandon, M and Procaccio, V and Wallace, DC}, title = {Effects of purifying and adaptive selection on regional variation in human mtDNA.}, journal = {Science (New York, N.Y.)}, volume = {303}, number = {5655}, pages = {223-226}, doi = {10.1126/science.1088434}, pmid = {14716012}, issn = {1095-9203}, support = {AG13154/AG/NIA NIH HHS/United States ; HL64017/HL/NHLBI NIH HHS/United States ; NS21328/NS/NINDS NIH HHS/United States ; NS37167/NS/NINDS NIH HHS/United States ; }, mesh = {*Adaptation, Physiological ; Africa ; Arctic Regions ; Asia ; *Climate ; Cold Climate ; Conserved Sequence ; DNA, Mitochondrial/*genetics ; Emigration and Immigration ; Energy Metabolism ; Europe ; Genetic Predisposition to Disease ; *Genetic Variation ; Haplotypes ; Humans ; Longevity ; Metabolic Diseases/genetics ; Mitochondria/metabolism ; Mutation ; Neurodegenerative Diseases/genetics ; Phenotype ; Phylogeny ; Racial Groups/genetics ; *Selection, Genetic ; Siberia ; }, abstract = {A phylogenetic analysis of 1125 global human mitochondrial DNA (mtDNA) sequences permitted positioning of all nucleotide substitutions according to their order of occurrence. The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.}, } @article {pmid14699090, year = {2004}, author = {Gentle, I and Gabriel, K and Beech, P and Waller, R and Lithgow, T}, title = {The Omp85 family of proteins is essential for outer membrane biogenesis in mitochondria and bacteria.}, journal = {The Journal of cell biology}, volume = {164}, number = {1}, pages = {19-24}, pmid = {14699090}, issn = {0021-9525}, mesh = {Bacteria/genetics ; Cell Survival/genetics ; Energy Metabolism/genetics ; Eukaryotic Cells/*metabolism/ultrastructure ; Gene Expression Regulation, Fungal/genetics ; Immunohistochemistry ; Intracellular Membranes/*metabolism/ultrastructure ; Microscopy, Electron ; Mitochondria/*metabolism/ultrastructure ; Mitochondrial Membrane Transport Proteins/genetics/metabolism ; Mitochondrial Proteins/genetics/*metabolism ; Molecular Sequence Data ; Mutation/genetics ; Phylogeny ; Porins/genetics/metabolism ; Protein Transport/genetics ; Saccharomyces cerevisiae/genetics/*metabolism/ultrastructure ; Saccharomyces cerevisiae Proteins/biosynthesis/genetics/*metabolism ; Sequence Homology, Amino Acid ; Voltage-Dependent Anion Channels ; }, abstract = {Integral proteins in the outer membrane of mitochondria control all aspects of organelle biogenesis, being required for protein import, mitochondrial fission, and, in metazoans, mitochondrial aspects of programmed cell death. How these integral proteins are assembled in the outer membrane had been unclear. In bacteria, Omp85 is an essential component of the protein insertion machinery, and we show that members of the Omp85 protein family are also found in eukaryotes ranging from plants to humans. In eukaryotes, Omp85 is present in the mitochondrial outer membrane. The gene encoding Omp85 is essential for cell viability in yeast, and conditional omp85 mutants have defects that arise from compromised insertion of integral proteins like voltage-dependent anion channel (VDAC) and components of the translocase in the outer membrane of mitochondria (TOM) complex into the mitochondrial outer membrane.}, } @article {pmid14662295, year = {2003}, author = {Johnston, IA}, title = {Muscle metabolism and growth in Antarctic fishes (suborder Notothenioidei): evolution in a cold environment.}, journal = {Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology}, volume = {136}, number = {4}, pages = {701-713}, doi = {10.1016/s1096-4959(03)00258-6}, pmid = {14662295}, issn = {1096-4959}, mesh = {Animals ; Antarctic Regions ; *Biological Evolution ; *Cold Temperature ; Fishes/*metabolism ; Muscle, Skeletal/*growth & development/*metabolism ; Oxygen Consumption ; Phylogeny ; }, abstract = {The radiation of notothenioid fishes (order Perciformes) in the Southern Ocean provides a model system for investigating evolution and adaptation to a low temperature environment. The Notothenioid fishes comprising eight families, 43 genera and 122 species dominate the fish fauna in Antarctica. The diversification of the clade probably began 15-20 million years ago after the formation of the Antarctic Polar Front. The radiation was, therefore, associated with climatic cooling down to the present day temperature of -1.86 degrees C. Origins and Evolution of the Antarctic Biota Geological Society Special Publication No. 47, Geological Society of London. pp. 253-268). The success of the group has been closely linked with the evolution of glycopeptide and peptide antifreezes, which are amongst the most abundant proteins in blood and interstitial fluid. The radiation of the clade has been associated with disaptation (evolutionary loss of function) and recovery. For example, it is thought that the icefishes (Channichyidae) lost haemoglobin through a single mutational event leading to the deletion of the entire beta-globin gene and the 5' end of the linked alpha-globin gene, resulting in compensatory adaptations of the cardiovascular system. Phylogenetically based statistical methods also indicate a progressive and dramatic reduction in the number of skeletal muscle fibres (FN(max)) at the end of the recruitment phase of growth in basal compared to derived families. The reduction in FN(max) is associated with a compensatory increase in the maximum fibre diameter, which can reach 100 microm in slow and 600 microm in fast muscle fibres. At -1 to 0 degrees C, the oxygen consumption of isolated mitochondria per mg mitochondrial protein shows no evidence of up-regulation relative to mitochondria from temperate and tropical Perciform fishes. The mitochondria content of slow muscle fibres in Antarctic notothenioids is towards the upper end of the range reported for teleosts with similar lifestyles, reaching 50% in Channichthyids. High mitochondrial densities facilitate ATP production and oxygen diffusion through the membrane lipid compartment of the fibre. Modelling studies suggest that adequate oxygen flux in the large diameter muscle fibres of notothenioids is possible because of the reduced metabolic demand and enhanced solubility of oxygen associated with low temperature. At the whole animal level size-corrected resting metabolic rate fits on the same temperature relationship as for Perciformes from warmer climates. It seems likely that the additional energetic costs associated with antifreeze synthesis and high mitochondrial densities are compensated for by reductions in other energy requiring processes: a hypothesis that could be tested with detailed energy budget studies. One plausible candidate is a reduction in membrane leak pathways linked to the loss of muscle fibres, which would serve to minimise the cost of maintaining ionic gradients.}, } @article {pmid14630958, year = {2003}, author = {Cardol, P and Gloire, G and Havaux, M and Remacle, C and Matagne, R and Franck, F}, title = {Photosynthesis and state transitions in mitochondrial mutants of Chlamydomonas reinhardtii affected in respiration.}, journal = {Plant physiology}, volume = {133}, number = {4}, pages = {2010-2020}, pmid = {14630958}, issn = {0032-0889}, mesh = {Animals ; Chlamydomonas reinhardtii/*genetics/metabolism ; Darkness ; Energy Metabolism ; Kinetics ; Light ; Mitochondria/*genetics ; Oxygen Consumption/*genetics ; Photosynthesis/*physiology ; }, abstract = {Photosynthetic activities were analyzed in Chlamydomonas reinhardtii mitochondrial mutants affected in different complexes (I, III, IV, I + III, and I + IV) of the respiratory chain. Oxygen evolution curves showed a positive relationship between the apparent yield of photosynthetic linear electron transport and the number of active proton-pumping sites in mitochondria. Although no significant alterations of the quantitative relationships between major photosynthetic complexes were found in the mutants, 77 K fluorescence spectra showed a preferential excitation of photosystem I (PSI) compared with wild type, which was indicative of a shift toward state 2. This effect was correlated with high levels of phosphorylation of light-harvesting complex II polypeptides, indicating the preferential association of light-harvesting complex II with PSI. The transition to state 1 occurred in untreated wild-type cells exposed to PSI light or in 3-(3,4-dichlorophenyl)-1,1-dimethylureatreated cells exposed to white light. In mutants of the cytochrome pathway and in double mutants, this transition was only observed in white light in the presence of 3-(3,4-dichlorophenyl)-1,1-dimethylurea. This suggests higher rates of nonphotochemical plastoquinone reduction through the chlororespiratory pathway, which was confirmed by measurements of the complementary area above the fluorescence induction curve in dark-adapted cells. Photo-acoustic measurements of energy storage by PSI showed a stimulation of PSI-driven cyclic electron flow in the most affected mutants. The present results demonstrate that in C. reinhardtii mutants, permanent defects in the mitochondrial electron transport chain stabilize state 2, which favors cyclic over linear electron transport in the chloroplast.}, } @article {pmid14613499, year = {2003}, author = {Hannaert, V and Bringaud, F and Opperdoes, FR and Michels, PA}, title = {Evolution of energy metabolism and its compartmentation in Kinetoplastida.}, journal = {Kinetoplastid biology and disease}, volume = {2}, number = {1}, pages = {11}, pmid = {14613499}, issn = {1475-9292}, abstract = {Kinetoplastida are protozoan organisms that probably diverged early in evolution from other eukaryotes. They are characterized by a number of unique features with respect to their energy and carbohydrate metabolism. These organisms possess peculiar peroxisomes, called glycosomes, which play a central role in this metabolism; the organelles harbour enzymes of several catabolic and anabolic routes, including major parts of the glycolytic and pentosephosphate pathways. The kinetoplastid mitochondrion is also unusual with regard to both its structural and functional properties.In this review, we describe the unique compartmentation of metabolism in Kinetoplastida and the metabolic properties resulting from this compartmentation. We discuss the evidence for our recently proposed hypothesis that a common ancestor of Kinetoplastida and Euglenida acquired a photosynthetic alga as an endosymbiont, contrary to the earlier notion that this event occurred at a later stage of evolution, in the Euglenida lineage alone. The endosymbiont was subsequently lost from the kinetoplastid lineage but, during that process, some of its pathways of energy and carbohydrate metabolism were sequestered in the kinetoplastid peroxisomes, which consequently became glycosomes. The evolution of the kinetoplastid glycosomes and the possible selective advantages of these organelles for Kinetoplastida are discussed. We propose that the possession of glycosomes provided metabolic flexibility that has been important for the organisms to adapt easily to changing environmental conditions. It is likely that metabolic flexibility has been an important selective advantage for many kinetoplastid species during their evolution into the highly successful parasites today found in many divergent taxonomic groups.Also addressed is the evolution of the kinetoplastid mitochondrion, from a supposedly pluripotent organelle, attributed to a single endosymbiotic event that resulted in all mitochondria and hydrogenosomes of extant eukaryotes. Furthermore, indications are presented that Kinetoplastida may have acquired other enzymes of energy and carbohydrate metabolism by various lateral gene transfer events different from those that involved the algal- and alpha-proteobacterial-like endosymbionts responsible for the respective formation of the glycosomes and mitochondria.}, } @article {pmid14531549, year = {2003}, author = {Müller, W and Mennel, HD and Bewermeyer, K and Bewermeyer, H}, title = {Is there a final common pathway in mitochondrial encephalomyopathies? Considerations based on an autopsy case of Kearns-Sayre syndrome.}, journal = {Clinical neuropathology}, volume = {22}, number = {5}, pages = {240-245}, pmid = {14531549}, issn = {0722-5091}, mesh = {Adult ; Atrophy ; Brain/pathology/physiopathology ; Cerebellum/pathology/physiopathology ; Cerebral Infarction/pathology/physiopathology ; Disease Progression ; Dominance, Cerebral/physiology ; Energy Metabolism/*physiology ; Female ; Gliosis/pathology/physiopathology ; Humans ; Kearns-Sayre Syndrome/*pathology/physiopathology ; Mitochondria/pathology/physiology ; Mitochondrial Encephalomyopathies/*pathology/physiopathology ; Neurologic Examination ; Tomography, X-Ray Computed ; }, abstract = {A case of Kearns-Sayre syndrome (KSS) diagnosed 18 years prior to death due to stroke and heart failure with postnatal onset was followed over 15 years and confirmed by postmortem examination. Within the brain, an old cystic infarction of the left hemisphere was found. Other features included white matter gliosis and cerebellar atrophy. Equal or similar features were observed in other conditions thought to be due to failure of mitochondrial metabolism, therefore, a common evolution of neuropathological changes must be discussed.}, } @article {pmid12972297, year = {2003}, author = {Godbole, A and Varghese, J and Sarin, A and Mathew, MK}, title = {VDAC is a conserved element of death pathways in plant and animal systems.}, journal = {Biochimica et biophysica acta}, volume = {1642}, number = {1-2}, pages = {87-96}, doi = {10.1016/s0167-4889(03)00102-2}, pmid = {12972297}, issn = {0006-3002}, mesh = {Animals ; Apoptosis/*physiology ; Cotyledon/drug effects/metabolism ; Cucumis sativus/metabolism ; Energy Metabolism/physiology ; Enzyme Inhibitors/pharmacology ; Eukaryotic Cells/*metabolism ; Evolution, Molecular ; Gene Expression Regulation, Plant/drug effects/physiology ; HeLa Cells ; Humans ; Intracellular Membranes/metabolism ; Jurkat Cells ; Mitochondria/*metabolism ; Oryza/genetics ; Plant Proteins/genetics/metabolism ; Plants/genetics/*metabolism ; Porins/genetics/*metabolism ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors/metabolism ; Voltage-Dependent Anion Channels ; }, abstract = {Programmed cell death (PCD) is very much a part of plant life, although the underlying mechanisms are not so well understood as in animals. In animal cells, the voltage-dependent anion channel (VDAC), a major mitochondrial outer membrane transporter, plays an important role in apoptosis by participating in the release of intermembrane space proteins. To characterize plant PCD pathways by investigating the function of putative components in a mammalian apoptotic context, we have overexpressed a rice VDAC (osVDAC4) in the Jurkat T-cell line. Overexpression of osVDAC4 induces apoptosis, which can be blocked by Bcl-2 and the VDAC inhibitor DIDS. Modifying endogenous VDAC function by DIDS and hexokinase II (HxKII) in Jurkat cells inhibits mitochondria-mediated apoptotic pathways. Finally, we show that DIDS also abrogates heat-induced PCD in cucumber cotyledons. Our data suggest that VDAC is a conserved mitochondrial element of the death machinery in both plant and animal cells.}, } @article {pmid12765765, year = {2003}, author = {Kadenbach, B}, title = {Intrinsic and extrinsic uncoupling of oxidative phosphorylation.}, journal = {Biochimica et biophysica acta}, volume = {1604}, number = {2}, pages = {77-94}, doi = {10.1016/s0005-2728(03)00027-6}, pmid = {12765765}, issn = {0006-3002}, mesh = {Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Biological Evolution ; Electron Transport Complex IV/metabolism ; Energy Metabolism ; Fatty Acids/metabolism ; Intracellular Membranes/metabolism ; Membrane Potentials ; Membrane Proteins/metabolism ; Mitochondria/drug effects/metabolism ; Models, Biological ; *Oxidative Phosphorylation/drug effects ; Proton Pumps/drug effects/metabolism ; Proton-Translocating ATPases/metabolism ; Protons ; Reactive Oxygen Species/metabolism ; Thyroid Hormones/metabolism ; Uncoupling Agents/*metabolism/pharmacology ; }, abstract = {This article reviews parameters of extrinsic uncoupling of oxidative phosphorylation (OxPhos) in mitochondria, based on induction of a proton leak across the inner membrane. The effects of classical uncouplers, fatty acids, uncoupling proteins (UCP1-UCP5) and thyroid hormones on the efficiency of OxPhos are described. Furthermore, the present knowledge on intrinsic uncoupling of cytochrome c oxidase (decrease of H(+)/e(-) stoichiometry=slip) is reviewed. Among the three proton pumps of the respiratory chain of mitochondria and bacteria, only cytochrome c oxidase is known to exhibit a slip of proton pumping. Intrinsic uncoupling was shown after chemical modification, by site-directed mutagenesis of the bacterial enzyme, at high membrane potential DeltaPsi, and in a tissue-specific manner to increase thermogenesis in heart and skeletal muscle by high ATP/ADP ratios, and in non-skeletal muscle tissues by palmitate. In addition, two mechanisms of respiratory control are described. The first occurs through the membrane potential DeltaPsi and maintains high DeltaPsi values (150-200 mV). The second occurs only in mitochondria, is suggested to keep DeltaPsi at low levels (100-150 mV) through the potential dependence of the ATP synthase and the allosteric ATP inhibition of cytochrome c oxidase at high ATP/ADP ratios, and is reversibly switched on by cAMP-dependent phosphorylation. Finally, the regulation of DeltaPsi and the production of reactive oxygen species (ROS) in mitochondria at high DeltaPsi values (150-200 mV) are discussed.}, } @article {pmid12694174, year = {2003}, author = {Emelyanov, VV}, title = {Mitochondrial connection to the origin of the eukaryotic cell.}, journal = {European journal of biochemistry}, volume = {270}, number = {8}, pages = {1599-1618}, doi = {10.1046/j.1432-1033.2003.03499.x}, pmid = {12694174}, issn = {0014-2956}, mesh = {Amino Acid Sequence ; Animals ; Conserved Sequence ; Energy Metabolism ; Eukaryotic Cells/metabolism ; Glycolysis/genetics ; Humans ; Mitochondria/genetics/*metabolism ; Molecular Sequence Data ; Phylogeny ; Sequence Alignment ; Valine-tRNA Ligase/chemistry/genetics ; }, abstract = {Phylogenetic evidence is presented that primitively amitochondriate eukaryotes containing the nucleus, cytoskeleton, and endomembrane system may have never existed. Instead, the primary host for the mitochondrial progenitor may have been a chimeric prokaryote, created by fusion between an archaebacterium and a eubacterium, in which eubacterial energy metabolism (glycolysis and fermentation) was retained. A Rickettsia-like intracellular symbiont, suggested to be the last common ancestor of the family Rickettsiaceae and mitochondria, may have penetrated such a host (pro-eukaryote), surrounded by a single membrane, due to tightly membrane-associated phospholipase activity, as do present-day rickettsiae. The relatively rapid evolutionary conversion of the invader into an organelle may have occurred in a safe milieu via numerous, often dramatic, changes involving both partners, which resulted in successful coupling of the host glycolysis and the symbiont respiration. Establishment of a potent energy-generating organelle made it possible, through rapid dramatic changes, to develop genuine eukaryotic elements. Such sequential, or converging, global events could fill the gap between prokaryotes and eukaryotes known as major evolutionary discontinuity.}, } @article {pmid12678440, year = {2002}, author = {Almeida, AM and Navet, R and Jarmuszkiewicz, W and Vercesi, AE and Sluse-Goffart, CM and Sluse, FE}, title = {The energy-conserving and energy-dissipating processes in mitochondria isolated from wild type and nonripening tomato fruits during development on the plant.}, journal = {Journal of bioenergetics and biomembranes}, volume = {34}, number = {6}, pages = {487-498}, pmid = {12678440}, issn = {0145-479X}, mesh = {Adenosine Triphosphate/biosynthesis ; Carrier Proteins/metabolism ; Energy Metabolism ; Fatty Acids, Nonesterified/metabolism ; Ion Channels ; Lycopersicon esculentum/genetics/growth & development/*metabolism ; Membrane Proteins/metabolism ; Mitochondria/metabolism ; Mitochondrial Proteins ; Mutation ; Oxidoreductases/metabolism ; Oxygen Consumption ; Plant Proteins/metabolism ; Uncoupling Protein 1 ; }, abstract = {Bioenergetics of tomato (Lycopersicon esculentum) development on the plant was followed from the early growing stage to senescence in wild type (climacteric) and nonripening mutant (nor, non-climacteric) fruits. Fruit development was expressed in terms of evolution of chlorophyll a content allowing the assessment of a continuous time-course in both cultivars. Measured parameters: the cytochrome pathway-dependent respiration, i.e., the ATP synthesis-sustained respiration (energy-conserving), the uncoupling protein (UCP) activity-sustained respiration (energy-dissipating), the alternative oxidase(AOX)-mediated respiration (energy-dissipating), as well as the protein expression of UCP and AOX, and free fatty acid content exhibited different evolution patterns in the wild type and nor mutant that can be attributed to their climacteric/nonclimacteric properties, respectively. In the wild type, the climacteric respiratory burst observed in vitro depended totally on an increse in the cytochrome pathway activity sustained by ATP synthesis, while the second respiratory rise during the ripening stage was linked to a strong increase in AOX activity accompanied by an overexpression of AOX protein. In wild type mitochondria, the 10-microM linoleic acid-stimulated UCP-activity-dependent respiration remained constant during the whole fruit development except in senescence where general respiratory decay was observed.}, } @article {pmid12574861, year = {2003}, author = {Seligmann, H}, title = {Cost-minimization of amino acid usage.}, journal = {Journal of molecular evolution}, volume = {56}, number = {2}, pages = {151-161}, doi = {10.1007/s00239-002-2388-z}, pmid = {12574861}, issn = {0022-2844}, mesh = {Amino Acids/chemistry/*metabolism ; Animals ; Archaea/genetics/metabolism ; Bacteria/genetics/metabolism ; Base Composition ; Codon ; Energy Metabolism/*physiology ; Eukaryotic Cells/physiology ; Genome ; *Models, Biological ; Molecular Weight ; *Protein Biosynthesis ; Proteins/chemistry ; }, abstract = {The negative correlation between the frequencies of usage of amino acids and their biosynthetic cost suggests that organisms minimize costs of protein biosynthesis. Empirical results support that: (1) free-living organisms (Archaea, Bacteria, and Eucaryota) minimize the usage of heavy amino acids more than intracellular organisms (viruses, chloroplasts, and mitochondria), a result confirmed by comparing intracellular Bacteria with other Bacteria; (2) avoidance of amino acids with low impact on protein structure (Chou-Fasman indices) is greater than for those with equal molecular weight but greater structural impact: constraints on protein function limit cost-minimization; (3) amino acid weight minimization (WM) for a protein correlates positively with the protein's expression level and with its size; (4) preliminary results suggest that for different proteins, the evolutionary rate of amino acid replacements correlates negatively with WM in these proteins; (5) results suggest that WM decreases with genome-size; and (6) developmental rates correlate positively with WM (within primates and rodents), even after confounding factors were accounted for. Effects of biosynthetic cost-minimization at whole-organism levels vary with metabolic and ecological strategies. Biosynthetic cost-minimization is an adaptive hypothesis that yields a semi-mechanistic explanation for small differences in allele fitness.}, } @article {pmid12524465, year = {2003}, author = {Moyes, CD and Hood, DA}, title = {Origins and consequences of mitochondrial variation in vertebrate muscle.}, journal = {Annual review of physiology}, volume = {65}, number = {}, pages = {177-201}, doi = {10.1146/annurev.physiol.65.092101.142705}, pmid = {12524465}, issn = {0066-4278}, mesh = {Animals ; Biological Evolution ; Energy Metabolism/*physiology ; Genetic Variation ; Humans ; Mitochondria/genetics/*metabolism ; Muscle, Skeletal/*metabolism ; Vertebrates ; }, abstract = {This review addresses the mechanisms by which mitochondrial structure and function are regulated, with a focus on vertebrate muscle. We consider the adaptive remodeling that arises during physiological transitions such as differentiation, development, and contractile activity. Parallels are drawn between such phenotypic changes and the pattern of change arising over evolutionary time, as suggested by interspecies comparisons. We address the physiological and evolutionary relationships between ATP production, thermogenesis, and superoxide generation in the context of mitochondrial function. Our discussion of mitochondrial structure focuses on the regulation of membrane composition and maintenance of the three-dimensional reticulum. Current studies of mitochondrial biogenesis strive to integrate muscle functional parameters with signal transduction and molecular genetics, providing insight into the origins of variation arising between physiological states, fiber types, and species.}, } @article {pmid12417132, year = {2002}, author = {Tielens, AG and Rotte, C and van Hellemond, JJ and Martin, W}, title = {Mitochondria as we don't know them.}, journal = {Trends in biochemical sciences}, volume = {27}, number = {11}, pages = {564-572}, doi = {10.1016/s0968-0004(02)02193-x}, pmid = {12417132}, issn = {0968-0004}, mesh = {Adenosine Triphosphate/*biosynthesis ; Animals ; Electron Transport/physiology ; Energy Metabolism ; Eukaryotic Cells/physiology ; Mitochondria/classification/*metabolism ; Oxygen/metabolism ; Phylogeny ; Proton Pumps/metabolism ; Succinate Dehydrogenase/genetics/metabolism ; }, abstract = {Biochemistry textbooks depict mitochondria as oxygen-dependent organelles, but many mitochondria can produce ATP without using any oxygen. In fact, several other types of mitochondria exist and they occur in highly diverse groups of eukaryotes - protists as well as metazoans - and possess an often overlooked diversity of pathways to deal with the electrons resulting from carbohydrate oxidation. These anaerobically functioning mitochondria produce ATP with the help of proton-pumping electron transport, but they do not need oxygen to do so. Recent advances in understanding of mitochondrial biochemistry provide many surprises and furthermore, give insights into the evolutionary history of ATP-producing organelles.}, } @article {pmid12392880, year = {2002}, author = {Opie, LH and Sack, MN}, title = {Metabolic plasticity and the promotion of cardiac protection in ischemia and ischemic preconditioning.}, journal = {Journal of molecular and cellular cardiology}, volume = {34}, number = {9}, pages = {1077-1089}, doi = {10.1006/jmcc.2002.2066}, pmid = {12392880}, issn = {0022-2828}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Energy Metabolism ; Glycolysis ; Humans ; *Ischemic Preconditioning, Myocardial ; Mitochondria, Heart/metabolism ; Models, Cardiovascular ; Myocardial Ischemia/*metabolism ; Myocardium/metabolism ; }, abstract = {The concept of metabolic protection of the ischemic myocardium is in constant evolution and has recently been supported by clinical studies. Historically, enhanced glucose metabolism and glycolysis were proposed as anti-ischemic cardioprotection. This hypothesis is supported by the sub-cellular linkage between key glycolytic enzymes and the activity of two survival-promoting membrane-bound pumps, namely the sodium-potassium ATPase, and the calcium uptake pump of the sarcoplasmic reticulum. Moreover, improved resistance against ischemia follows the administration of glucose-insulin-potassium in a variety of animal models and in patients following acute myocardial infarction. The metabolic plasticity paradigm has now been expanded to include (1) the benefit of improved coupling of glycolysis to glucose oxidation, which explains the action of anti-ischemic fatty acid inhibitors such as trimetazidine and ranolazine; (2) the role of malonyl CoA in the glucose-fatty acid interaction; and (3) the anti-apoptotic role of insulin. Furthermore, we argue for a protective role of increased glucose uptake in the preconditioning paradigm. Additionally, we postulate an adaptive role of mitochondrial respiration in the promotion of cardioprotection in the context of ischemic preconditioning. The mechanisms driving these mitochondrial perturbations are still unknown, but are hypothesized to involve an initial modest uncoupling of respiration from the production of mitochondrial ATP. These perturbations are in turn thought to prime the mitochondria to augment mitochondrial respiration during a subsequent ischemic insult to the heart. In this review we discuss studies that demonstrate how metabolic plasticity can promote cardioprotection against ischemia and reperfusion injury and highlight areas that require further characterization.}, } @article {pmid12238891, year = {2002}, author = {Kita, K and Takamiya, S}, title = {Electron-transfer complexes in Ascaris mitochondria.}, journal = {Advances in parasitology}, volume = {51}, number = {}, pages = {95-131}, doi = {10.1016/s0065-308x(02)51004-6}, pmid = {12238891}, issn = {0065-308X}, mesh = {Anaerobiosis/physiology ; Animals ; Ascaris suum/growth & development/*metabolism/physiology ; DNA, Mitochondrial/genetics/metabolism ; Electron Transport/genetics/physiology ; Evolution, Molecular ; Fatty Acid Desaturases/metabolism ; Life Cycle Stages/physiology ; Mitochondria/*metabolism ; Models, Biological ; Models, Molecular ; Oxidoreductases/metabolism ; *Oxidoreductases Acting on CH-CH Group Donors ; Phosphoenolpyruvate Carboxykinase (ATP)/metabolism ; Succinic Acid/metabolism ; Ubiquinone/*analogs & derivatives/physiology ; }, abstract = {Parasites have developed a variety of physiological functions necessary for their survival within the specialized environment of the host. Using metabolic systems that are very different from those of the host, they can adapt to low oxygen tension present within the host animals. Most parasites do not use the oxygen available within the host to generate ATP, but rather employ anaerobic metabolic pathways. In addition, all parasites have a life cycle. In many cases, the parasite employs aerobic metabolism during its free-living stage outside the host. In such systems, parasite mitochondria play diverse roles. In particular, marked changes in the morphology and components of the mitochondria during the life cycle are very interesting elements of biological processes such as developmental control and environmental adaptation. Recent research on the respiratory chain of the parasitic helminth Ascaris suum has shown that the mitochondrial NADH-fumarate reductase system plays an important role in the anaerobic energy metabolism of adult parasites inhabiting hosts, as well as describing unique features of the developmental changes that occur during its life cycle.}, } @article {pmid12180017, year = {2002}, author = {Kuznetsov, AP and Lebkova, NP}, title = {[On bacterial origin of mitochondria in eukaryotes in the light of current ideas of evolution of the organic world].}, journal = {Izvestiia Akademii nauk. Seriia biologicheskaia}, volume = {}, number = {4}, pages = {501-507}, pmid = {12180017}, issn = {1026-3470}, mesh = {Aerobiosis ; Animals ; *Bacterial Physiological Phenomena ; *Biological Evolution ; Eukaryotic Cells/*physiology ; Mitochondria/*physiology ; Mollusca/physiology ; Symbiosis ; }, abstract = {The hypothesis of bacterial origin of mitochondria, which existed until the end of the 20th century, has been confirmed on the basis of the current concepts of organic world evolution in the open sea hydrosphere and original data on the entry of bacteria (prokaryotes0 in the cells of eukaryotes and their transformation into the mitochondrial mechanism of aerobic energy metabolism. This hypothesis can now be considered as a factually substantiated theory. The process of endocytosis of bacteria in the tissues of eukaryotes, which began at the onset of transition of the anaerobic state of open sea hydrosphere and land atmosphere (Early Proterozoic), is considered as the beginning of symbiotic mode of life of organisms of the Proterozoic and Postproterozoic organic world.}, } @article {pmid12138089, year = {2002}, author = {Besteiro, S and Biran, M and Biteau, N and Coustou, V and Baltz, T and Canioni, P and Bringaud, F}, title = {Succinate secreted by Trypanosoma brucei is produced by a novel and unique glycosomal enzyme, NADH-dependent fumarate reductase.}, journal = {The Journal of biological chemistry}, volume = {277}, number = {41}, pages = {38001-38012}, doi = {10.1074/jbc.M201759200}, pmid = {12138089}, issn = {0021-9258}, mesh = {Animals ; Biomarkers ; Cell Line ; Citric Acid Cycle ; Crithidia fasciculata/metabolism ; Digitonin/pharmacology ; Glucose/metabolism ; Leishmania/metabolism ; Magnetic Resonance Spectroscopy ; Microbodies/*enzymology ; Mitochondria/metabolism ; Molecular Sequence Data ; NADH Dehydrogenase/metabolism ; Oxidoreductases/classification/genetics/*metabolism ; *Oxidoreductases Acting on CH-CH Group Donors ; Phenotype ; Phylogeny ; Protozoan Proteins/classification/genetics/*metabolism ; Rats ; Succinic Acid/*metabolism ; Trypanosoma brucei brucei/cytology/drug effects/genetics/*metabolism ; }, abstract = {In all trypanosomatids, including Trypanosoma brucei, glycolysis takes place in peroxisome-like organelles called glycosomes. These are closed compartments wherein the energy and redox (NAD(+)/NADH) balances need to be maintained. We have characterized a T. brucei gene called FRDg encoding a protein 35% identical to Saccharomyces cerevisiae fumarate reductases. Microsequencing of FRDg purified from glycosome preparations, immunofluorescence, and Western blot analyses clearly identified this enzyme as a glycosomal protein that is only expressed in the procyclic form of T. brucei but is present in all the other trypanosomatids studied, i.e. Trypanosoma congolense, Crithidia fasciculata and Leishmania amazonensis. The specific inactivation of FRDg gene expression by RNA interference showed that FRDg is responsible for the NADH-dependent fumarate reductase activity detected in glycosomal fractions and that at least 60% of the succinate secreted by the T. brucei procyclic form (in the presence of d-glucose as the sole carbon source) is produced in the glycosome by FRDg. We conclude that FRDg plays a key role in the energy metabolism by participating in the maintenance of the glycosomal NAD(+)/NADH balance. We have also detected a significant pyruvate kinase activity in the cytosol of the T. brucei procyclic cells that was not observed previously. Consequently, we propose a revised model of glucose metabolism in procyclic trypanosomes that may also be valid for all other trypanosomatids except the T. brucei bloodstream form. Interestingly, H. Gest has hypothesized previously (Gest, H. (1980) FEMS Microbiol. Lett. 7, 73-77) that a soluble NADH-dependent fumarate reductase has been present in primitive organisms and evolved into the present day fumarate reductases, which are quinol-dependent. FRDg may have the characteristics of such an ancestral enzyme and is the only NADH-dependent fumarate reductase characterized to date.}, } @article {pmid12122455, year = {2002}, author = {Hulbert, AJ and Else, PL and Manolis, SC and Brand, MD}, title = {Proton leak in hepatocytes and liver mitochondria from archosaurs (crocodiles) and allometric relationships for ectotherms.}, journal = {Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology}, volume = {172}, number = {5}, pages = {387-397}, doi = {10.1007/s00360-002-0264-1}, pmid = {12122455}, issn = {0174-1578}, mesh = {Alligators and Crocodiles/*metabolism ; Animals ; Biological Evolution ; Body Constitution ; Body Temperature Regulation/*physiology ; Cell Respiration/physiology ; Energy Metabolism/physiology ; Hepatocytes/*metabolism ; Mitochondria, Liver/chemistry/*metabolism ; Phospholipids/analysis ; Protons ; }, abstract = {It has previously been shown that mitochondrial proton conductance decreases with increasing body mass in mammals and is lower in a 250-g lizard than the laboratory rat. To examine whether mitochondrial proton conductance is extremely low in very large reptiles, hepatocytes and mitochondria were prepared from saltwater crocodiles (Crocodylus porosus) and freshwater crocodiles (Crocodylus johnstoni). Respiration rates of hepatocytes and liver mitochondria were measured at 37 degrees C and compared with values obtained for rat or previously measured for other species. Respiration rates of hepatocytes from either species of crocodile were similar to those reported for lizards and approximately one fifth of the rates measured using cells from mammals (rat and sheep). Ten-to-thirty percent of crocodile hepatocyte respiration was used to drive mitochondrial proton leak, similar to the proportion in other species. Respiration rates of crocodile liver mitochondria were similar to those of mammalian species. Proton leak rate in isolated liver mitochondria was measured as a function of membrane potential. Contrary to our prediction, the mitochondrial proton conductance of liver mitochondria from crocodiles was greater than that of liver mitochondria from lizards and was similar to that of rats. The acyl composition of liver mitochondrial phospholipids from the crocodiles was more similar to that in mitochondria from rats than in mitochondria from lizards. The relatively high mitochondrial proton conductance was associated with a relatively small liver, which seems to be characteristic of crocodilians. Comparison of data from a number of diverse ectothermic species suggested that hepatocyte respiration rate may decrease with body mass, with an allometric exponent of about -0.2, similar to the exponent in mammalian hepatocytes. However, unlike mammals, liver mitochondrial proton conductance in ectotherms showed no allometric relationship with body size.}, } @article {pmid12039439, year = {2002}, author = {Arking, R and Buck, S and Novoseltev, VN and Hwangbo, DS and Lane, M}, title = {Genomic plasticity, energy allocations, and the extended longevity phenotypes of Drosophila.}, journal = {Ageing research reviews}, volume = {1}, number = {2}, pages = {209-228}, doi = {10.1016/s1568-1637(01)00010-1}, pmid = {12039439}, issn = {1568-1637}, mesh = {Aging/*genetics ; Animals ; Drosophila ; Energy Metabolism/*genetics ; Genome ; Longevity/*genetics ; Phenotype ; }, abstract = {The antagonistic pleiotropy theory of the evolution of aging is shown to be too simple to fully apply to the situation in which Drosophila are selected directly for delayed female fecundity and indirectly for extended longevity. We re-evaluated our own previously reported selection experiments using previously unreported data, as well as new data from the literature. The facts that led to this re-evaluation were: (1) the recognition that there are at least three different extended longevity phenotypes; (2) the existence of metabolic and mitochondrial differences between normal- and long-lived organisms; and most importantly; (3) the observation that animals selected for extended longevity are both more fecund and longer-lived than their progenitor control animals. This latter observation appears to contradict the theory. A revised interpretation of the events underlying the selection process indicates that there is a two-step change in energy allocations leading to a complex phenotype. Initial selection first allows the up-regulation of the antioxidant defense system genes and a shift to the use of the pentose shunt. This is later followed by alterations in mitochondrial fatty acid composition and other changes necessary to reduce the leakage of H(2)O(2) from the mitochondria into the cytosol. The recaptured energy available from the latter step is diverted from somatic maintenance back into reproduction, resulting in animals that are both long-lived and fecund. Literature review suggests the involvement of mitochondrial and antioxidant changes are likely universal in the Type 1 extended longevity phenotype.}, } @article {pmid12014002, year = {2002}, author = {Ohta, S}, title = {[The origin of mitochondria].}, journal = {Nihon rinsho. Japanese journal of clinical medicine}, volume = {60 Suppl 4}, number = {}, pages = {799-804}, pmid = {12014002}, issn = {0047-1852}, mesh = {Amino Acyl-tRNA Synthetases/genetics ; Animals ; Biological Evolution ; Cell Nucleus/genetics ; DNA, Mitochondrial ; Energy Metabolism ; Eukaryotic Cells/cytology ; Humans ; *Mitochondria/genetics/physiology ; Oxygen ; }, } @article {pmid11828469, year = {2001}, author = {Ludwig, B and Bender, E and Arnold, S and Hüttemann, M and Lee, I and Kadenbach, B}, title = {Cytochrome C oxidase and the regulation of oxidative phosphorylation.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {2}, number = {6}, pages = {392-403}, doi = {10.1002/1439-7633(20010601)2:6<392::AID-CBIC392>3.0.CO;2-N}, pmid = {11828469}, issn = {1439-4227}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Bacterial Proteins/chemistry/*metabolism ; Diiodothyronines/metabolism ; Electron Transport Complex IV/chemistry/classification/*metabolism ; Heart/physiology ; Humans ; Membrane Potentials/physiology ; Mitochondria/enzymology/*metabolism ; Models, Molecular ; *Oxidative Phosphorylation ; Oxygen/metabolism ; Phylogeny ; Protein Structure, Tertiary ; Protein Subunits ; Reactive Oxygen Species/metabolism ; }, abstract = {Life of higher organisms is essentially dependent on the efficient synthesis of ATP by oxidative phosphorylation in mitochondria. An important and as yet unsolved question of energy metabolism is how are the variable rates of ATP synthesis at maximal work load during exercise or mental work and at rest or during sleep regulated. This article reviews our present knowledge on the structure of bacterial and eukaryotic cytochrome c oxidases and correlates it with recent results on the regulatory functions of nuclear-coded subunits of the eukaryotic enzyme, which are absent from the bacterial enzyme. A new molecular hypothesis on the physiological regulation of oxidative phosphorylation is proposed, assuming a hormonally controlled dynamic equilibrium in vivo between two states of energy metabolism, a relaxed state with low ROS (reactive oxygen species) formation, and an excited state with elevated formation of ROS, which are known to accelerate aging and to cause degenerative diseases and cancer. The hypothesis is based on the allosteric ATP inhibition of cytochrome c oxidase at high intramitochondrial ATP/ADP ratios ("second mechanism of respiratory control"), which is switched on by cAMP-dependent phosphorylation and switched off by calcium-induced dephosphorylation of the enzyme.}, } @article {pmid11820431, year = {2001}, author = {Pérez-Castiñeira, JR and Gómez-García, R and López-Marqués, RL and Losada, M and Serrano, A}, title = {Enzymatic systems of inorganic pyrophosphate bioenergetics in photosynthetic and heterotrophic protists: remnants or metabolic cornerstones?.}, journal = {International microbiology : the official journal of the Spanish Society for Microbiology}, volume = {4}, number = {3}, pages = {135-142}, doi = {10.1007/s10123-001-0028-x}, pmid = {11820431}, issn = {1139-6709}, mesh = {Animals ; Biological Evolution ; Diphosphates/*metabolism ; Energy Metabolism ; Eukaryota/*enzymology/genetics/metabolism ; Intracellular Membranes/enzymology ; Mitochondria/enzymology ; Molecular Sequence Data ; Photosynthesis ; Phylogeny ; Plastids/enzymology ; Pyrophosphatases/chemistry/*physiology ; }, abstract = {An increasing body of biochemical and genetic evidence suggests that inorganic pyrophosphate (PPi) plays an important role in protist bioenergetics. In these organisms, two types of inorganic pyrophosphatases [EC 3.6.1.1, namely soluble PPases (sPPases) and proton-translocating PPases (H+-PPases)] that hydrolyse the PPi generated by cell anabolism, thereby replenishing the orthophosphate pool needed for phosphorylation reactions, are present in different cellular compartments. Photosynthetic and heterotrophic protists possess sPPases located in cellular organelles (plastids and mitochondria), where many anabolic and biosynthetic reactions take place, in addition to H+-PPases, which are integral membrane proteins of the vacuolysosomal membranes and use the chemical energy of PPi to generate an electrochemical proton gradient useful in cell bioenergetics. This last category of proton pumps was considered to be restricted to higher plants and some primitive photosynthetic bacteria, but it has been found recently in many protists (microalgae and protozoa) and bacteria, thus indicating that H+-PPases are much more widespread than previously thought. No cytosolic sPPase (in bacteria, fungi and animal cells) has been shown to occur in these lower eukaryotes. The widespread occurrence of these key enzymes of PPi metabolism among evolutionarily divergent protists strongly supports the ancestral character of the bioenergetics based on this simple energy-rich compound, which may play an important role in survival under different biotic and abiotic stress conditions.}, } @article {pmid11803022, year = {2002}, author = {Kita, K and Hirawake, H and Miyadera, H and Amino, H and Takeo, S}, title = {Role of complex II in anaerobic respiration of the parasite mitochondria from Ascaris suum and Plasmodium falciparum.}, journal = {Biochimica et biophysica acta}, volume = {1553}, number = {1-2}, pages = {123-139}, doi = {10.1016/s0005-2728(01)00237-7}, pmid = {11803022}, issn = {0006-3002}, mesh = {Amino Acid Sequence ; Anaerobiosis ; Animals ; Ascaris suum/*enzymology ; Electron Transport Complex II ; Energy Metabolism ; Fumarates/metabolism ; Life Cycle Stages ; Mitochondria/metabolism ; Models, Chemical ; Molecular Sequence Data ; Multienzyme Complexes/chemistry/*metabolism ; Oxidoreductases/chemistry/*metabolism ; *Oxidoreductases Acting on CH-CH Group Donors ; Phylogeny ; Plasmodium falciparum/*enzymology ; Sequence Alignment ; Succinate Dehydrogenase/chemistry/*metabolism ; Succinic Acid/metabolism ; }, abstract = {Parasites have developed a variety of physiological functions necessary for existence within the specialized environment of the host. Regarding energy metabolism, which is an essential factor for survival, parasites adapt to low oxygen tension in host mammals using metabolic systems that are very different from that of the host. The majority of parasites do not use the oxygen available within the host, but employ systems other than oxidative phosphorylation for ATP synthesis. In addition, all parasites have a life cycle. In many cases, the parasite employs aerobic metabolism during their free-living stage outside the host. In such systems, parasite mitochondria play diverse roles. In particular, marked changes in the morphology and components of the mitochondria during the life cycle are very interesting elements of biological processes such as developmental control and environmental adaptation. Recent research has shown that the mitochondrial complex II plays an important role in the anaerobic energy metabolism of parasites inhabiting hosts, by acting as quinol-fumarate reductase.}, } @article {pmid11801237, year = {2002}, author = {Sluse, FE and Jarmuszkiewicz, W}, title = {Uncoupling proteins outside the animal and plant kingdoms: functional and evolutionary aspects.}, journal = {FEBS letters}, volume = {510}, number = {3}, pages = {117-120}, doi = {10.1016/s0014-5793(01)03229-x}, pmid = {11801237}, issn = {0014-5793}, mesh = {Acanthamoeba/*metabolism ; Animals ; Candida/*metabolism ; Carrier Proteins/*metabolism ; Dictyostelium/*metabolism ; Energy Metabolism/physiology ; *Evolution, Molecular ; Ion Channels ; Membrane Proteins/*metabolism ; Mitochondria/metabolism ; Mitochondrial Proteins ; Oxidoreductases/metabolism ; Reactive Oxygen Species/metabolism ; Uncoupling Protein 1 ; }, abstract = {The appearance of intracellular oxidative phosphorylation at the time of acquisition of mitochondria in Eukarya was very soon accompanied by the emergence of uncoupling protein, a carrier specialized in free fatty acid-mediated H(+) recycling that can modulate the tightness of coupling between mitochondrial respiration and ATP synthesis, thereby maintaining a balance between energy supply and demand in the cell and defending cells against damaging reactive oxygen species production when electron carriers of the respiratory chain become over-reduced. The simultaneous occurrence of redox free energy-dissipating oxidase, which has the same final effect, could be related to the functional interactions between both dissipative systems.}, } @article {pmid11779548, year = {2001}, author = {Castresana, J}, title = {Comparative genomics and bioenergetics.}, journal = {Biochimica et biophysica acta}, volume = {1506}, number = {3}, pages = {147-162}, doi = {10.1016/s0005-2728(01)00227-4}, pmid = {11779548}, issn = {0006-3002}, mesh = {Archaea/enzymology/*genetics ; Bacteria/enzymology/*genetics ; *Energy Metabolism ; Evolution, Molecular ; *Genomics ; Photosynthesis ; Phylogeny ; }, abstract = {Bacterial and archaeal complete genome sequences have been obtained from a wide range of evolutionary lines, which allows some general conclusions about the phylogenetic distribution and evolution of bioenergetic pathways to be drawn. In particular, I searched in the complete genomes for key enzymes involved in aerobic and anaerobic respiratory pathways and in photosynthesis, and mapped them into an rRNA tree of sequenced species. The phylogenetic distribution of these enzymes is very irregular, and clearly shows the diverse strategies of energy conservation used by prokaryotes. In addition, a thorough phylogenetic analysis of other bioenergetic protein families of wide distribution reveals a complex evolutionary history for the respective genes. A parsimonious explanation for these complex phylogenetic patterns and for the irregular distribution of metabolic pathways is that the last common ancestor of Bacteria and Archaea contained several members of every gene family as a consequence of previous gene or genome duplications, while different patterns of gene loss occurred during the evolution of every gene family. This would imply that the last universal ancestor was a bioenergetically sophisticated organism. Finally, important steps that occurred during the evolution of energetic machineries, such as the early evolution of aerobic respiration and the acquisition of eukaryotic mitochondria from a proteobacterium ancestor, are supported by the analysis of the complete genome sequences.}, } @article {pmid11767942, year = {2001}, author = {Martin, W and Hoffmeister, M and Rotte, C and Henze, K}, title = {An overview of endosymbiotic models for the origins of eukaryotes, their ATP-producing organelles (mitochondria and hydrogenosomes), and their heterotrophic lifestyle.}, journal = {Biological chemistry}, volume = {382}, number = {11}, pages = {1521-1539}, doi = {10.1515/BC.2001.187}, pmid = {11767942}, issn = {1431-6730}, mesh = {Adenosine Triphosphate/*biosynthesis ; *Biological Evolution ; Mitochondria/*metabolism ; Models, Biological ; Organelles/*metabolism ; *Plant Physiological Phenomena ; Plants/*metabolism/ultrastructure ; }, abstract = {The evolutionary processes underlying the differentness of prokaryotic and eukaryotic cells and the origin of the latter's organelles are still poorly understood. For about 100 years, the principle of endosymbiosis has figured into thoughts as to how these processes might have occurred. A number of models that have been discussed in the literature and that are designed to explain this difference are summarized. The evolutionary histories of the enzymes of anaerobic energy metabolism (oxygen-independent ATP synthesis) in the three basic types of heterotrophic eukaryotes those that lack organelles of ATP synthesis, those that possess mitochondria and those that possess hydrogenosomes--play an important role in this issue. Traditional endosymbiotic models generally do not address the origin of the heterotrophic lifestyle and anaerobic energy metabolism in eukaryotes. Rather they take it as a given, a direct inheritance from the host that acquired mitochondria. Traditional models are contrasted to an alternative endosymbiotic model (the hydrogen hypothesis), which addresses the origin of heterotrophy and the origin of compartmentalized energy metabolism in eukaryotes.}, } @article {pmid11560369, year = {2001}, author = {Heininger, K}, title = {The deprivation syndrome is the driving force of phylogeny, ontogeny and oncogeny.}, journal = {Reviews in the neurosciences}, volume = {12}, number = {3}, pages = {217-287}, doi = {10.1515/revneuro.2001.12.3.217}, pmid = {11560369}, issn = {0334-1763}, mesh = {Aging/physiology ; Animals ; Apoptosis/physiology ; Cell Communication/physiology ; Cell Differentiation/physiology ; Energy Metabolism/*physiology ; General Adaptation Syndrome/*physiopathology ; Homeostasis ; Mitochondria/metabolism ; Mutagenesis ; Neoplasms/*physiopathology ; *Phylogeny ; Prokaryotic Cells/*physiology ; Sex ; Signal Transduction/physiology ; *Stress, Physiological ; }, abstract = {Energy is the motor of life. Energy ensures the organism's survival and competitive advantage for reproductive success. For almost 3 billion years, unicellular organisms were the only life form on earth. Competition for limited energy resources and raw materials exerted an incessant selective pressure on organisms. In the adverse environment and due to their 'feast and famine' life style, hardiness to a variety of stressors, particularly to nutrient deprivation, was the selection principle. Both resistance and mutagenic adaptation to stressors were established as survival strategies by means of context-specific processes creating stability or variability of DNA sequence. The conservation of transduction pathways and functional homology of effector molecules clearly bear witness that the principles of life established during prokaryotic and eukaryotic unicellular evolution, although later diversified, have been unshakably cast to persist during metazoan phylogenesis. A wealth of evidence suggests that unicellular organisms evolved the phenomena of differentiation and apoptosis, sexual reproduction, and even aging, as responses to environmental challenges. These evolutionary accomplishments were elaborated from the dichotomous resistance/mutagenesis response and sophisticated the capacity of cells to tune their genetic information to changing environmental conditions. Notably, the social deprivation responses, differentiation and apoptosis, evolved as intercellularly coordinated events: a multitude of differentiation processes were elaborated from sporulation, the prototypic stress resistance response, while apoptosis, contrary to current concepts, is no altruistic cell suicide but was programmed as a mutagenic survival response; this response, however, is socially thwarted leading into mutagenic error catastrophe. In the hybrid differentiation-apoptosis process, cytocide and cannibalism of apoptotic cells thus serve the purpose of fueling the survival of the selfish genes in the differentiating cells. However, successful mutagenesis, although repressed, persisted in the asocial stress response of carcinogenesis as a regression to primitive unicellular behavior following failure of intercellular communication. While somatic mutagenesis was largely prevented, Metazoa elaborated germ cell mutagenesis as an evolutionary vehicle. Genetic competence, a primitive, stress-induced mating behavior, evolved into sexual reproduction which harnessed mutagenesis by subjecting highly mutable germ cells to a rigid viability selection. These processes were programmatically fixed as life- and cell-cycle events but retained their deprivation response phenotypes. Thus, the differentiation-apoptosis tandem evolved as the 'clay' to mold the specialized structures and functions of a multicellular organism while sexual reproduction elaborated the principle of quality-checked mutagenesis to create the immense diversity of Metazoa following the Cambrian explosion. Throughout these events, reactive oxygen and nitrogen species, which are regulated by energy homeostasis, shape the genetic information in a regulated but random, uncoded process providing the fitness-related feedback of phenotype to genotype. The interplay of genes and environment establishes a dynamic stimulus-response feedback cycle which, in animate nature, may be the organizing principle to contrive the reciprocal duality of energy and matter.}, } @article {pmid11557797, year = {2001}, author = {Tachezy, J and Sánchez, LB and Müller, M}, title = {Mitochondrial type iron-sulfur cluster assembly in the amitochondriate eukaryotes Trichomonas vaginalis and Giardia intestinalis, as indicated by the phylogeny of IscS.}, journal = {Molecular biology and evolution}, volume = {18}, number = {10}, pages = {1919-1928}, doi = {10.1093/oxfordjournals.molbev.a003732}, pmid = {11557797}, issn = {0737-4038}, support = {AI11942/AI/NIAID NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Bacterial Proteins/genetics ; Carbon-Sulfur Lyases/*genetics/metabolism ; DNA, Protozoan/chemistry/genetics ; Giardia lamblia/enzymology/*genetics ; Iron-Sulfur Proteins/*biosynthesis ; Mitochondria/*metabolism ; Molecular Sequence Data ; *Phylogeny ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Trichomonas vaginalis/enzymology/*genetics ; }, abstract = {Pyridoxal-5'-phosphate-dependent cysteine desulfurase (IscS) is an essential enzyme in the assembly of FeS clusters in bacteria as well as in the mitochondria of eukaryotes. Although FeS proteins are particularly important for the energy metabolism of amitochondrial anaerobic eukaryotes, there is no information about FeS cluster formation in these organisms. We identified and sequenced two IscS homologs of Trichomonas vaginalis (TviscS-1 and TviscS-2) and one of Giardia intestinalis (GiiscS). TviscS-1, TviscS-2, and GiiscS possess the typical conserved regions implicated in cysteine desulfurase activity. N-termini of TviscS-1 and TviscS-2 possess eight amino acid extensions, which resemble the N-terminal presequences that target proteins to hydrogenosomes in trichomonads. No presequence was evident in GiiscS from Giardia, an organism that apparently lacks hydrogenosmes or mitochondria. Phylogenetic analysis showed a close relationship among all eukaryotic IscS genes including those of amitochondriates. IscS of proteobacteria formed a sister group to the eukaryotic clade, suggesting that isc-related genes were present in the proteobacterial endosymbiotic ancestor of mitochondria and hydrogenosomes. NifS genes of nitrogen-fixing bacteria, which are IscS homologs required for specific formation of FeS clusters in nitrogenase, formed a more distant group. The phylogeny indicates the presence of a common mechanism for FeS cluster formation in mitochondriates as well as in amitochondriate eukaryotes. Furthermore, the analyses support a common origin of Trichomonas hydrogenosomes and mitochondria, as well as secondary loss of mitochondrion/hydrogenosome-like organelles in Giardia.}, } @article {pmid11508688, year = {2001}, author = {Emelyanov, VV}, title = {Rickettsiaceae, rickettsia-like endosymbionts, and the origin of mitochondria.}, journal = {Bioscience reports}, volume = {21}, number = {1}, pages = {1-17}, doi = {10.1023/a:1010409415723}, pmid = {11508688}, issn = {0144-8463}, mesh = {Animals ; Bacteria/cytology/genetics/metabolism ; Chaperonin 60/genetics/metabolism ; Energy Metabolism/genetics ; Eukaryotic Cells/*cytology/metabolism ; Humans ; Mitochondria/genetics/metabolism/*ultrastructure ; *Phylogeny ; Rickettsiaceae/*cytology/genetics/metabolism ; Symbiosis/*genetics ; }, abstract = {Accumulating evolutionary data point to a monophyletic origin of mitochondria from the order Rickettsiales. This large group of obligate intracellular alpha-Proteobacteria includes the family Rickettsiaceae and several rickettsia-like endosymbionts (RLEs). Detailed phylogenetic analysis of small subunit (SSU) rRNA and chaperonin 60 (Cpn60) sequences testify to polyphyly of the Rickettsiales, and consistently indicate a sisterhood of Rickettsiaceae and mitochondria that excludes RLEs. Thus RLEs are considered as the nearest extant relatives of an extinct last common ancestor of mitochondria and rickettsiae. Phylogenetic inferences prompt the following assumptions. (1) Mitochondrial origin has been predisposed by the long-term endosymbiotic relationship between rickettsia-like bacteria and proto-eukaryotes, in which many endosymbiont genes have been lost while some indispensable genes have been transferred to the host genome. (2) The obligate dependence of rickettsiae upon a eukaryotic host rests on the import of proteins encoded by these transferred genes. The nature of a proto-eukaryotic cell still remains elusive. The divergence of Rickettsiaceae and mitochondria based on Cpn60, and the evolutionary history of two aminoacyl-tRNA synthetases favor the hypothesis that it was a chimera created by fusion of an archaebacterium and a eubacterium not long before an endosymbiotic event. These and other, mostly biochemical data suggest that all the mitochondrion-related organelles, i.e., both aerobically and anaerobically respiring mitochondria and hydrogenosomes, have originated from the same RLE, while hydrogenosomal energy metabolism may have a separate origin resulting from a eubacterial fusion partner.}, } @article {pmid11457448, year = {2001}, author = {Emelyanov, VV}, title = {Evolutionary relationship of Rickettsiae and mitochondria.}, journal = {FEBS letters}, volume = {501}, number = {1}, pages = {11-18}, doi = {10.1016/s0014-5793(01)02618-7}, pmid = {11457448}, issn = {0014-5793}, mesh = {Energy Metabolism ; Genome ; Mitochondria/genetics/metabolism/*physiology ; *Models, Biological ; *Phylogeny ; Rickettsia/classification/genetics/*physiology ; Symbiosis ; }, abstract = {Phylogenetic data support an origin of mitochondria from the alpha-proteobacterial order Rickettsiales. This high-rank taxon comprises exceptionally obligate intracellular endosymbionts of eukaryotic cells, and includes family Rickettsiaceae and a group of microorganisms termed Rickettsia-like endosymbionts (RLEs). Most detailed phylogenetic analyses of small subunit rRNA and chaperonin 60 sequences consistently show the RLEs to have emerged before Rickettsiaceae and mitochondria sister clades. These data suggest that the origin of mitochondria and Rickettsiae has been preceded by the long-term mutualistic relationship of an intracellular bacterium with a pro-eukaryote, in which an invader has lost many dispensable genes, yet evolved carrier proteins to exchange respiration-derived ATP for host metabolites as envisaged in classic endosymbiont theory.}, } @article {pmid11377800, year = {2001}, author = {Scheffler, IE}, title = {Mitochondria make a come back.}, journal = {Advanced drug delivery reviews}, volume = {49}, number = {1-2}, pages = {3-26}, doi = {10.1016/s0169-409x(01)00123-5}, pmid = {11377800}, issn = {0169-409X}, mesh = {Animals ; Biological Evolution ; DNA, Mitochondrial/drug effects/*physiology/ultrastructure ; Electron Transport/drug effects/physiology ; Energy Metabolism ; Enzyme Inhibitors/pharmacology ; Eukaryotic Cells/drug effects/*physiology/ultrastructure ; Humans ; Mitochondria/drug effects/*physiology/ultrastructure ; Molecular Biology ; Oxidative Phosphorylation/drug effects ; }, abstract = {This review attempts to summarize our present state of knowledge of mitochondria in relation to a number of areas of biology, and to indicate where future research might be directed. In the evolution of eukaryotic cells mitochondria have for a long time played a prominent role. Nowadays their integration into many activities of a cell, and their dynamic behavior as subcellular organelles within a cell and during cell division are a major focus of attention. The crystal structures of the major complexes of the electron transport chain (except complex I) have been established, permitting increasingly detailed analyses of the important mechanism of proton pumping coupled to electron transport. The mitochondrial genome and its replication and expression are beginning to be understood in considerable detail, but more questions remain with regard to mutations and their repair, and the segregation of the mtDNA in oogenesis and development. Much emphasis and a large effort have recently been devoted to understand the role of mitochondria in programmed cell death (apoptosis). The understanding of their central role in mitochondrial diseases is a major achievement of the past decade. Finally, various drugs have traditionally played a part in understanding biochemical mechanisms within mitochondria; the repertoire of drugs with novel and interesting targets is expanding.}, } @article {pmid11357388, year = {2001}, author = {Kuznetsov, AP and Lebkova, NP}, title = {[Significance of the energy of symbiotic bacteria in metabolism of hydrothermal and other chemotrophic biota of the ocean].}, journal = {Izvestiia Akademii nauk. Seriia biologicheskaia}, volume = {}, number = {2}, pages = {220-226}, pmid = {11357388}, issn = {1026-3470}, mesh = {Aerobiosis ; Animals ; Bacteria/*metabolism ; Biological Evolution ; Ecosystem ; *Energy Metabolism ; Microscopy, Electron ; Mitochondria/*metabolism ; Mollusca/*metabolism/microbiology/ultrastructure ; Oceans and Seas ; Symbiosis ; }, abstract = {The bacterial origin of eukaryotic mitochondria, specifically in Metazoa, as a mechanism of their basic (aerobic) respiration and the role of symbiotic bacteria during the supply of energy to the metazoan host is proved for the first time from the viewpoint of the monophyletic development of the organic world and the origin of eukaryotes as descendants of prokaryotes Representatives of the hydrothermal bacteriochemosymbiotrophic bottom fauna of the open sea were used as examples.}, } @article {pmid11212890, year = {2000}, author = {Beech, PL and Landweber, LF and Gilson, PR}, title = {Meeting report: XIIIth meeting of the International Society for Evolutionary Protistology, Ceské Budejovice, Czech Republic, July 31-August 4, 2000.}, journal = {Protist}, volume = {151}, number = {4}, pages = {299-305}, doi = {10.1078/S1434-4610(04)70028-0}, pmid = {11212890}, issn = {1434-4610}, support = {GM59708/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Biological Evolution ; Chloroplasts/physiology ; Ciliophora/physiology ; *Energy Metabolism ; Euglenida/physiology ; Eukaryota/*physiology ; Eukaryotic Cells/*physiology ; Microsporidia/physiology ; Mitochondria/metabolism ; Organelles/metabolism ; Trypanosoma/physiology ; }, } @article {pmid11121736, year = {2000}, author = {Schneider, A and Maréchal-Drouard, L}, title = {Mitochondrial tRNA import: are there distinct mechanisms?.}, journal = {Trends in cell biology}, volume = {10}, number = {12}, pages = {509-513}, doi = {10.1016/s0962-8924(00)01854-7}, pmid = {11121736}, issn = {0962-8924}, mesh = {Animals ; Biological Transport ; Cell Nucleus/genetics/metabolism ; Humans ; Mitochondria/*genetics/metabolism ; Models, Biological ; Nucleic Acid Conformation ; Phylogeny ; RNA/genetics/*metabolism ; RNA, Mitochondrial ; RNA, Transfer/genetics/*metabolism ; }, abstract = {Sequence information from an increasing number of complete mitochondrial genomes indicates that a large number of evolutionary distinct organisms import nucleus-encoded tRNAs. In the past five years, much research has been initiated on the features of imported tRNAs, the mechanism and the energetics of the process as well as on the components of the import machinery. In summary, these studies show that the import systems of different species exhibit some unique features, suggesting that more than one mechanism might exist to import tRNAs.}, } @article {pmid11104819, year = {2000}, author = {Kurland, CG and Andersson, SG}, title = {Origin and evolution of the mitochondrial proteome.}, journal = {Microbiology and molecular biology reviews : MMBR}, volume = {64}, number = {4}, pages = {786-820}, pmid = {11104819}, issn = {1092-2172}, mesh = {Alphaproteobacteria/genetics ; *Biological Evolution ; Energy Metabolism ; Eukaryotic Cells ; *Mitochondria/genetics ; Models, Biological ; *Proteome ; Saccharomyces cerevisiae/physiology ; Symbiosis ; }, abstract = {The endosymbiotic theory for the origin of mitochondria requires substantial modification. The three identifiable ancestral sources to the proteome of mitochondria are proteins descended from the ancestral alpha-proteobacteria symbiont, proteins with no homology to bacterial orthologs, and diverse proteins with bacterial affinities not derived from alpha-proteobacteria. Random mutations in the form of deletions large and small seem to have eliminated nonessential genes from the endosymbiont-mitochondrial genome lineages. This process, together with the transfer of genes from the endosymbiont-mitochondrial genome to nuclei, has led to a marked reduction in the size of mitochondrial genomes. All proteins of bacterial descent that are encoded by nuclear genes were probably transferred by the same mechanism, involving the disintegration of mitochondria or bacteria by the intracellular membranous vacuoles of cells to release nucleic acid fragments that transform the nuclear genome. This ongoing process has intermittently introduced bacterial genes to nuclear genomes. The genomes of the last common ancestor of all organisms, in particular of mitochondria, encoded cytochrome oxidase homologues. There are no phylogenetic indications either in the mitochondrial proteome or in the nuclear genomes that the initial or subsequent function of the ancestor to the mitochondria was anaerobic. In contrast, there are indications that relatively advanced eukaryotes adapted to anaerobiosis by dismantling their mitochondria and refitting them as hydrogenosomes. Accordingly, a continuous history of aerobic respiration seems to have been the fate of most mitochondrial lineages. The initial phases of this history may have involved aerobic respiration by the symbiont functioning as a scavenger of toxic oxygen. The transition to mitochondria capable of active ATP export to the host cell seems to have required recruitment of eukaryotic ATP transport proteins from the nucleus. The identity of the ancestral host of the alpha-proteobacterial endosymbiont is unclear, but there is no indication that it was an autotroph. There are no indications of a specific alpha-proteobacterial origin to genes for glycolysis. In the absence of data to the contrary, it is assumed that the ancestral host cell was a heterotroph.}, } @article {pmid11063052, year = {2000}, author = {Fiskum, G}, title = {Mitochondrial participation in ischemic and traumatic neural cell death.}, journal = {Journal of neurotrauma}, volume = {17}, number = {10}, pages = {843-855}, doi = {10.1089/neu.2000.17.843}, pmid = {11063052}, issn = {0897-7151}, support = {NS34152/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*physiology ; Astrocytes/metabolism ; Brain Injuries/*metabolism/pathology/physiopathology ; Brain Ischemia/*metabolism/pathology/physiopathology ; Calcium/metabolism ; Cytochrome c Group/metabolism ; Energy Metabolism/physiology ; Humans ; Mitochondria/*metabolism/pathology ; Nerve Degeneration/*metabolism/pathology/physiopathology ; Neurons/metabolism ; Neurotoxins/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondria play critical roles in cerebral energy metabolism and in the regulation of cellular Ca2+ homeostasis. They are also the primary intracellular source of reactive oxygen species, due to the tremendous number of oxidation-reduction reactions and the massive utilization of O2 that occur there. Metabolic trafficking among cells is also highly dependent upon normal, well-controlled mitochondrial activities. Alterations of any of these functions can cause cell death directly or precipitate death indirectly by compromising the ability of cells to withstand stressful stimuli. Abnormal accumulation of Ca2+ by mitochondria in response to exposure of neurons to excitotoxic levels of excitatory neurotransmitters, for example, glutamate, is a primary mediator of mitochondrial dysfunction and delayed cell death. Excitoxicity, along with inflammatory reactions, mechanical stress, and altered trophic signal transduction, all likely contribute to mitochondrial damage observed during the evolution of traumatic brain injury. The release of apoptogenic proteins from mitochondria into the cytosol serves as a primary mechanism responsible for inducing apoptosis, a form of cell death that contributes significantly to neurologic impairment following neurotrauma. Although several signals for the release of mitochondrial cell death proteins have been identified, the mechanisms by which these signals increase the permeability of the mitochondrial outer membrane to apoptogenic proteins is controversial. Elucidation of the precise biochemical mechanisms responsible for mitochondrial dysfunction during neurotrauma and the roles that mitochondria play in both necrotic and apoptotic cell death should provide new molecular targets for neuroprotective interventions.}, } @article {pmid10867997, year = {2000}, author = {Schipke, JD and Birkenkamp-Demtröder, K and Schwanke, U}, title = {[Myocardial hibernation: another view].}, journal = {Zeitschrift fur Kardiologie}, volume = {89}, number = {4}, pages = {259-263}, doi = {10.1007/s003920050482}, pmid = {10867997}, issn = {0300-5860}, mesh = {Animals ; Biological Evolution ; Coronary Circulation/*physiology ; Energy Metabolism/*physiology ; Humans ; Myocardial Stunning/*physiopathology ; Opioid Peptides/physiology ; Oxygen Consumption/*physiology ; }, abstract = {In the following, three newer concepts are brought together: myocardial hibernation, heterogeneity in myocardial blood flow and oxidative metabolism, and effects of hibernating animal serum on non-hibernators. Myocardial hibernation is viewed as a protective mechanism that helps to maintain myocardial integrity and viability by down-regulating contractile function as an adaptation to reduced blood flow. Myocardial flow is considerably heterogeneous. Consequently, oxygen supply to the myocardium is also heterogeneous. Many lines of evidence show a close correlation between regional flow and regional metabolism. In low-flow/low-metabolism areas, myocardial function must be reduced, since the myocardium would otherwise undergo necrosis. Thus, others and we hypothesize that function must be down-regulated to induce hibernation in low-flow areas. Because no regional histologic differences exist (the mitochondria are uniformly distributed within the myocardium), the pattern of heterogeneity seems to shift over time. Hence, we hypothesize that such very regional hibernation presents an evolutionary, protective mechanism, permitting subsequent myocardial areas to rest within the ceaselessly working heart. We also hypothesize that this mechanism ensures the down-regulation of function following myocardial ischemia in order to induce myocardial hibernation on a broader level. Surprisingly, a substance (opioid in nature) contained in hibernator serum both induced hibernation-like state in non-hibernators and suppressed myocardial oxygen consumption. Thus, we lastly hypothesize that myocardial hibernation is a remnant of the early stages of evolution and is closer to physiologic hibernation than traditionally viewed.}, } @article {pmid10713172, year = {2000}, author = {Dyall, SD and Koehler, CM and Delgadillo-Correa, MG and Bradley, PJ and Plümper, E and Leuenberger, D and Turck, CW and Johnson, PJ}, title = {Presence of a member of the mitochondrial carrier family in hydrogenosomes: conservation of membrane-targeting pathways between hydrogenosomes and mitochondria.}, journal = {Molecular and cellular biology}, volume = {20}, number = {7}, pages = {2488-2497}, pmid = {10713172}, issn = {0270-7306}, support = {T32 AI007323/AI/NIAID NIH HHS/United States ; R01 AI027857/AI/NIAID NIH HHS/United States ; AI07323/AI/NIAID NIH HHS/United States ; AI27857/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R37 AI027857/AI/NIAID NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Carrier Proteins/chemistry/*genetics/metabolism ; Cloning, Molecular ; Energy Metabolism ; Evolution, Molecular ; Fungal Proteins/chemistry ; Membrane Proteins/chemistry/genetics/metabolism ; Mitochondria/*metabolism ; Mitochondrial ADP, ATP Translocases/chemistry/genetics/metabolism ; Molecular Sequence Data ; Phylogeny ; Protein Sorting Signals/chemistry/metabolism ; Protozoan Proteins/chemistry/*genetics/metabolism ; *Saccharomyces cerevisiae Proteins ; Sequence Alignment ; Trichomonas vaginalis/*chemistry/cytology ; }, abstract = {A number of microaerophilic eukaryotes lack mitochondria but possess another organelle involved in energy metabolism, the hydrogenosome. Limited phylogenetic analyses of nuclear genes support a common origin for these two organelles. We have identified a protein of the mitochondrial carrier family in the hydrogenosome of Trichomonas vaginalis and have shown that this protein, Hmp31, is phylogenetically related to the mitochondrial ADP-ATP carrier (AAC). We demonstrate that the hydrogenosomal AAC can be targeted to the inner membrane of mitochondria isolated from Saccharomyces cerevisiae through the Tim9-Tim10 import pathway used for the assembly of mitochondrial carrier proteins. Conversely, yeast mitochondrial AAC can be targeted into the membranes of hydrogenosomes. The hydrogenosomal AAC contains a cleavable, N-terminal presequence; however, this sequence is not necessary for targeting the protein to the organelle. These data indicate that the membrane-targeting signal(s) for hydrogenosomal AAC is internal, similar to that found for mitochondrial carrier proteins. Our findings indicate that the membrane carriers and membrane protein-targeting machinery of hydrogenosomes and mitochondria have a common evolutionary origin. Together, they provide strong evidence that a single endosymbiont evolved into a progenitor organelle in early eukaryotic cells that ultimately give rise to these two distinct organelles and support the hydrogen hypothesis for the origin of the eukaryotic cell.}, } @article {pmid10644738, year = {2000}, author = {Saas, J and Ziegelbauer, K and von Haeseler, A and Fast, B and Boshart, M}, title = {A developmentally regulated aconitase related to iron-regulatory protein-1 is localized in the cytoplasm and in the mitochondrion of Trypanosoma brucei.}, journal = {The Journal of biological chemistry}, volume = {275}, number = {4}, pages = {2745-2755}, doi = {10.1074/jbc.275.4.2745}, pmid = {10644738}, issn = {0021-9258}, mesh = {Aconitate Hydratase/*genetics/metabolism ; Amino Acid Sequence ; Animals ; Base Sequence ; Cloning, Molecular ; Cytoplasm/*enzymology ; DNA, Complementary ; *Gene Expression Regulation, Enzymologic ; Iron Regulatory Protein 1 ; Iron-Regulatory Proteins ; Iron-Sulfur Proteins/*genetics ; Kinetics ; Mitochondria/*enzymology ; Molecular Sequence Data ; Open Reading Frames ; Phylogeny ; RNA-Binding Proteins/*genetics ; Recombinant Proteins/genetics/metabolism ; Sequence Homology, Amino Acid ; Trypanosoma brucei brucei/*enzymology ; }, abstract = {Mitochondrial energy metabolism and Krebs cycle activities are developmentally regulated in the life cycle of the protozoan parasite Trypanosoma brucei. Here we report cloning of a T. brucei aconitase gene that is closely related to mammalian iron-regulatory protein 1 (IRP-1) and plant aconitases. Kinetic analysis of purified recombinant TbACO expressed in Escherichia coli resulted in a K(m) (isocitrate) of 3 +/- 0.4 mM, similar to aconitases of other organisms. This was unexpected since an arginine conserved in the aconitase protein family and crucial for substrate positioning in the catalytic center and for activity of pig mitochondrial aconitase (Zheng, L., Kennedy, M. C., Beinert, H., and Zalkin, H. (1992) J. Biol. Chem. 267, 7895-7903) is substituted by leucine in the TbACO sequence. Expression of the 98-kDa TbACO was shown to be lowest in the slender bloodstream stage of the parasite, 8-fold elevated in the stumpy stage, and increased a further 4-fold in the procyclic stage. The differential expression of TbACO protein contrasted with only minor changes in TbACO mRNA, indicating translational or post-translational mechanisms of regulation. Whereas animal cells express two distinct compartmentalized aconitases, mitochondrial aconitase and cytoplasmic aconitase/IRP-1, TbACO accounts for total aconitase activity in trypanosomes. By cell fractionation and immunofluorescence microscopy, we show that native as well as a transfected epitope-tagged TbACO localizes in both the mitochondrion (30%) and in the cytoplasm (70%). Together with phylogenetic reconstructions of the aconitase family, this suggests that animal IRPs have evolved from a multicompartmentalized ancestral aconitase. The possible functions of a cytoplasmic aconitase in trypanosomes are discussed.}, } @article {pmid10629653, year = {1999}, author = {Rocchi, E and Vigo, J and Viallet, P and Bonnard, I and Banaigs, B and Salmon, JM}, title = {Multiwavelength videomicrofluorometric study of cytotoxic properties of a marine peptide, didemnin B, using adriamycin as reference compound.}, journal = {Anticancer research}, volume = {19}, number = {4C}, pages = {3559-3568}, pmid = {10629653}, issn = {0250-7005}, mesh = {Apoptosis ; Benzimidazoles/metabolism ; Cell Cycle/drug effects ; Cell Nucleus/drug effects ; *Depsipeptides ; Dose-Response Relationship, Drug ; Doxorubicin/*chemistry/pharmacokinetics/pharmacology ; Fluorescent Dyes/metabolism ; Fluorometry ; Humans ; Inhibitory Concentration 50 ; Microscopy, Video ; Mitochondria/drug effects ; Oxazines/metabolism ; Peptides, Cyclic/*chemistry/*pharmacokinetics/pharmacology ; Rhodamine 123/metabolism ; Time Factors ; Tumor Cells, Cultured ; }, abstract = {Didemnin B (DB), a marine natural product, has very encouraging biological activity in vitro (Antineoplastic, immunosuppressive, antiviral). To learn more about its intracellular effects and targets, videomicrofluorometry on single living cells and a protocol of multiple labeling: Hoechst 342 for nuclear DNA, Rhodamine 123 for mitochondria and Nile Red for plasma membrane, have been used. DB behaves differently from Adriamycin, inducing at its IC50 dose of (20 nM) an accumulation of the CEM-WT lymphoblasts in the S phase of the cell cycle while we observed a 50% decrease of the mitochondrial labeling by R123, showing a decrease of the mitochondrial energetic state. Cytostatic dose of DB (250 nM) confirms these observations. However the treatment with a dose reported as apoptotic (1000 nM) induces a much faster effect (corresponding to that of 72 hours at the IC50 dose), 24 hours incubation induced a drastic decrease of nuclear DNA content as well as of the mitochondria energetic state. The evolution of NAD(P)H cellular content exhibited an increase that seems to indicate that the decrease of mitochondrial energetic state was dependent on inhibition of the mitochondrial activity due to an effect of DB at the mitochondrial level, either direct or mediated. Furthermore, the decrease of mitochondrial labeling appears as a very early event in the mechanisms leading to apoptosis.}, } @article {pmid10620491, year = {2000}, author = {Ricquier, D and Bouillaud, F}, title = {The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP.}, journal = {The Biochemical journal}, volume = {345 Pt 2}, number = {Pt 2}, pages = {161-179}, pmid = {10620491}, issn = {0264-6021}, mesh = {Adipose Tissue, Brown/metabolism ; Amino Acid Sequence ; Animals ; Carrier Proteins/classification/genetics/*metabolism ; Energy Metabolism/*physiology ; Evolution, Molecular ; Hot Temperature ; Humans ; Mice ; Mitochondria/*metabolism ; Molecular Sequence Data ; Oxygen Consumption ; Plant Proteins/classification/genetics/metabolism ; Uncoupling Agents/*metabolism ; }, abstract = {Animal and plant uncoupling protein (UCP) homologues form a subfamily of mitochondrial carriers that are evolutionarily related and possibly derived from a proton/anion transporter ancestor. The brown adipose tissue (BAT) UCP1 has a marked and strongly regulated uncoupling activity, essential to the maintenance of body temperature in small mammals. UCP homologues identified in plants are induced in a cold environment and may be involved in resistance to chilling. The biochemical activities and biological functions of the recently identified mammalian UCP2 and UCP3 are not well known. However, recent data support a role for these UCPs in State 4 respiration, respiration uncoupling and proton leaks in mitochondria. Moreover, genetic studies suggest that UCP2 and UCP3 play a part in energy expenditure in humans. The UCPs may also be involved in adaptation of cellular metabolism to an excessive supply of substrates in order to regulate the ATP level, the NAD(+)/NADH ratio and various metabolic pathways, and to contain superoxide production. A major goal will be the analysis of mice that either lack the UCP2 or UCP3 gene or overexpress these genes. Other aims will be to investigate the possible roles of UCP2 and UCP3 in response to oxidative stress, lipid peroxidation, inflammatory processes, fever and regulation of temperature in certain specific parts of the body.}, } @article {pmid10508728, year = {1999}, author = {Andersson, SG and Kurland, CG}, title = {Origins of mitochondria and hydrogenosomes.}, journal = {Current opinion in microbiology}, volume = {2}, number = {5}, pages = {535-541}, doi = {10.1016/s1369-5274(99)00013-2}, pmid = {10508728}, issn = {1369-5274}, mesh = {*Evolution, Molecular ; Genome, Bacterial ; Hydrogen/*metabolism ; Mitochondria/*genetics ; Organelles/*genetics ; }, abstract = {Complete genome sequences for many mitochondria, as well as for some bacteria, together with the nuclear genome sequence of yeast have provided a coherent view of the origin of mitochondria. In particular, conventional phylogenetic reconstructions with genes coding for proteins active in energy metabolism and translation have confirmed the simplest version of the endosymbiosis hypothesis. In contrast, the hydrogen and the syntrophy hypotheses for the origin of mitochondria do not receive support from the available data. It remains to be seen how the evolution of hydrogenosomes is related to that of mitochondria.}, } @article {pmid10486982, year = {1999}, author = {Horner, DS and Hirt, RP and Embley, TM}, title = {A single eubacterial origin of eukaryotic pyruvate: ferredoxin oxidoreductase genes: implications for the evolution of anaerobic eukaryotes.}, journal = {Molecular biology and evolution}, volume = {16}, number = {9}, pages = {1280-1291}, doi = {10.1093/oxfordjournals.molbev.a026218}, pmid = {10486982}, issn = {0737-4038}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Anaerobiosis ; Animals ; Base Sequence ; Clostridium/enzymology/genetics ; DNA Primers/genetics ; Diplomonadida/enzymology/genetics ; Eukaryotic Cells ; *Evolution, Molecular ; Gene Duplication ; Gene Transfer, Horizontal ; *Genes, Bacterial ; Genes, Protozoan ; Giardia lamblia/enzymology/genetics ; Ketone Oxidoreductases/*genetics ; Models, Genetic ; Molecular Sequence Data ; Phylogeny ; Pyruvate Synthase ; }, abstract = {The iron sulfur protein pyruvate: ferredoxin oxidoreductase (PFO) is central to energy metabolism in amitochondriate eukaryotes, including those with hydrogenosomes. Thus, revealing the evolutionary history of PFO is critical to understanding the origin(s) of eukaryote anaerobic energy metabolism. We determined a complete PFO sequence for Spironucleus barkhanus, a large fragment of a PFO sequence from Clostridium pasteurianum, and a fragment of a new PFO from Giardia lamblia. Phylogenetic analyses of eubacterial and eukaryotic PFO genes suggest a complex history for PFO, including possible gene duplications and horizontal transfers among eubacteria. Our analyses favor a common origin for eukaryotic cytosolic and hydrogenosomal PFOs from a single eubacterial source, rather than from separate horizontal transfers as previously suggested. However, with the present sampling of genes and species, we were unable to infer a specific eubacterial sister group for eukaryotic PFO. Thus, we find no direct support for the published hypothesis that the donor of eukaryote PFO was the common alpha-proteobacterial ancestor of mitochondria and hydrogenosomes. We also report that several fungi and protists encode proteins with PFO domains that are likely monophyletic with PFOs from anaerobic protists. In Saccharomyces cerevisiae, PFO domains combine with fragments of other redox proteins to form fusion proteins which participate in methionine biosynthesis. Our results are consistent with the view that PFO, an enzyme previously considered to be specific to energy metabolism in amitochondriate protists, was present in the common ancestor of contemporary eukaryotes and was retained, wholly or in part, during the evolution of oxygen-dependent and mitochondrion-bearing lineages.}, } @article {pmid10467746, year = {1999}, author = {Vellai, T and Vida, G}, title = {The origin of eukaryotes: the difference between prokaryotic and eukaryotic cells.}, journal = {Proceedings. Biological sciences}, volume = {266}, number = {1428}, pages = {1571-1577}, pmid = {10467746}, issn = {0962-8452}, mesh = {Animals ; *Biological Evolution ; DNA/genetics ; Eukaryotic Cells/*classification ; Genome ; Models, Genetic ; Phylogeny ; Prokaryotic Cells/*classification ; }, abstract = {Eukaryotes have long been thought to have arisen by evolving a nucleus, endomembrane, and cytoskeleton. In contrast, it was recently proposed that the first complex cells, which were actually proto-eukaryotes, arose simultaneously with the acquisition of mitochondria. This so-called symbiotic association hypothesis states that eukaryotes emerged when some ancient anaerobic archaebacteria (hosts) engulfed respiring alpha-proteobacteria (symbionts), which evolved into the first energy-producing organelles. Therefore, the intracellular compartmentalization of the energy-converting metabolism that was bound originally to the plasma membrane appears to be the key innovation towards eukaryotic genome and cellular organization. The novel energy metabolism made it possible for the nucleotide synthetic apparatus of cells to be no longer limited by subsaturation with substrates and catalytic components. As a consequence, a considerable increase has occurred in the size and complexity of eukaryotic genomes, providing the genetic basis for most of the further evolutionary changes in cellular complexity. On the other hand, the active uptake of exogenous DNA, which is general in bacteria, was no longer essential in the genome organization of eukaryotes. The mitochondrion-driven scenario for the first eukaryotes explains the chimera-like composition of eukaryotic genomes as well as the metabolic and cellular organization of eukaryotes.}, } @article {pmid10430918, year = {1999}, author = {Karlin, S and Brocchieri, L and Mrázek, J and Campbell, AM and Spormann, AM}, title = {A chimeric prokaryotic ancestry of mitochondria and primitive eukaryotes.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {96}, number = {16}, pages = {9190-9195}, pmid = {10430918}, issn = {0027-8424}, support = {R01 GM010452/GM/NIGMS NIH HHS/United States ; 5R01GM10452-34/GM/NIGMS NIH HHS/United States ; 5R01HG00335-11/HG/NHGRI NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Archaea/*genetics ; Bacteria/*genetics ; *Biological Evolution ; *Chimera ; Clostridium/genetics ; DNA, Mitochondrial/*genetics ; Energy Metabolism/genetics ; Eukaryotic Cells ; Heat-Shock Proteins/genetics ; Humans ; Mitochondria/*genetics ; *Models, Genetic ; Proteins/chemistry/genetics ; Sulfolobus/genetics ; Vertebrates ; }, abstract = {We provide data and analysis to support the hypothesis that the ancestor of animal mitochondria (Mt) and many primitive amitochondrial (a-Mt) eukaryotes was a fusion microbe composed of a Clostridium-like eubacterium and a Sulfolobus-like archaebacterium. The analysis is based on several observations: (i) The genome signatures (dinucleotide relative abundance values) of Clostridium and Sulfolobus are compatible (sufficiently similar) and each has significantly more similarity in genome signatures with animal Mt sequences than do all other available prokaryotes. That stable fusions may require compatibility in genome signatures is suggested by the compatibility of plasmids and hosts. (ii) The expanded energy metabolism of the fusion organism was strongly selective for cementing such a fusion. (iii) The molecular apparatus of endospore formation in Clostridium serves as raw material for the development of the nucleus and cytoplasm of the eukaryotic cell.}, } @article {pmid10400536, year = {1999}, author = {Hederstedt, L}, title = {Respiration without O2.}, journal = {Science (New York, N.Y.)}, volume = {284}, number = {5422}, pages = {1941-1942}, doi = {10.1126/science.284.5422.1941}, pmid = {10400536}, issn = {0036-8075}, mesh = {Anaerobiosis ; Bacillus subtilis/enzymology ; Binding Sites ; Cell Membrane/enzymology ; Crystallography, X-Ray ; Dimerization ; Electron Transport ; *Energy Metabolism ; Escherichia coli/*enzymology ; Evolution, Molecular ; Fumarates/metabolism ; Mitochondria/enzymology ; Oxidation-Reduction ; Oxygen Consumption ; Protein Conformation ; Protein Structure, Secondary ; Succinate Dehydrogenase/*chemistry/*metabolism ; Succinic Acid/metabolism ; }, } @article {pmid9914833, year = {1998}, author = {Azzone, GF}, title = {From bioenergetics to philosophy of science: a brief report of an exciting cultural journey.}, journal = {BioFactors (Oxford, England)}, volume = {8}, number = {3-4}, pages = {305-316}, doi = {10.1002/biof.5520080319}, pmid = {9914833}, issn = {0951-6433}, mesh = {Animals ; Biological Evolution ; *Energy Metabolism ; History, 20th Century ; Humans ; Italy ; Membrane Potentials ; Mitochondria/*physiology ; Physiology/history ; Proton Pumps ; }, } @article {pmid9859981, year = {1998}, author = {Embley, TM and Martin, W}, title = {A hydrogen-producing mitochondrion.}, journal = {Nature}, volume = {396}, number = {6711}, pages = {517-519}, doi = {10.1038/24994}, pmid = {9859981}, issn = {0028-0836}, mesh = {Adenosine Triphosphate/biosynthesis ; Anaerobiosis ; Animals ; Biological Evolution ; Ciliophora/genetics/*metabolism/ultrastructure ; Cockroaches/parasitology ; DNA, Mitochondrial ; DNA, Protozoan ; Energy Metabolism ; Hydrogen/*metabolism ; Mitochondria/genetics/*metabolism ; Organelles/metabolism ; }, } @article {pmid9746319, year = {1998}, author = {Qin, W and Khuchua, Z and Cheng, J and Boero, J and Payne, RM and Strauss, AW}, title = {Molecular characterization of the creatine kinases and some historical perspectives.}, journal = {Molecular and cellular biochemistry}, volume = {184}, number = {1-2}, pages = {153-167}, pmid = {9746319}, issn = {0300-8177}, mesh = {Amino Acid Sequence ; Cloning, Molecular ; Creatine Kinase/*genetics ; Evolution, Molecular ; Gene Expression Regulation, Enzymologic/genetics ; Humans ; Isoenzymes ; Mitochondria/*genetics ; Molecular Sequence Data ; Muscles/*metabolism ; RNA, Messenger/genetics ; Sequence Alignment ; }, abstract = {Over the last 15 years, molecular characterization of the creatine kinase (CK) gene family has paralleled the molecular revolution of understanding gene structure, function, and regulation. In this review, we present a summary of advances in molecular analysis of the CK gene family with a few vignettes of historical interest. We describe how the muscle CK gene provided an essential model system to examine myogenic regulatory mechanisms, leading to the discovery of the binding site for the MyoD family of basic helix-loop-helix transcription factors essential in skeletal myogenesis and the characterization of the MEF2 family of factors with an A/T rich consensus binding site essential in skeletal myogenesis and cardiogenesis. Cloning and characterization of the four mRNAs and nuclear genes encoding the cytosolic CKs, muscle and brain CKs, and the mitochondrial (Mt) CKs, sarcomeric MtCK and ubiquitous MtCK, has allowed intriguing study of tissue-specific and cell-specific expression of the different CKs and analysis of structural, functional, regulatory, and evolutionary relationships among both the four CK proteins and genes. Current and future studies focus on understanding both cellular energetics facilitated by the CK enzymes, especially energy channelling from the site of production, the mitochondrial matrix and inner membrane, to various cytosolic foci of utilization, and regulation of MtCK gene expression at the cell and tissue-specific level as models of regulation of energy producing genes.}, } @article {pmid9714744, year = {1998}, author = {Di Lisa, F and Menabò, R and Canton, M and Petronilli, V}, title = {The role of mitochondria in the salvage and the injury of the ischemic myocardium.}, journal = {Biochimica et biophysica acta}, volume = {1366}, number = {1-2}, pages = {69-78}, doi = {10.1016/s0005-2728(98)00121-2}, pmid = {9714744}, issn = {0006-3002}, mesh = {Adenosine Triphosphate/metabolism ; Calcium/metabolism ; Cell Death/*physiology ; Cytochrome c Group/metabolism ; Energy Metabolism ; Humans ; Membrane Potentials ; Mitochondria, Heart/*physiology ; Mitochondrial ADP, ATP Translocases/metabolism ; Myocardial Ischemia/physiopathology ; Myocardial Reperfusion Injury/physiopathology ; Oxygen Consumption ; Proton-Translocating ATPases/metabolism ; }, abstract = {The relationships between mitochondrial derangements and cell necrosis are exemplified by the changes in the function and metabolism of mitochondria that occur in the ischemic heart. From a mitochondrial point of view, the evolution of ischemic damage can be divided into three phases. The first is associated with the onset of ischemia, and changes mitochondria from ATP producers into powerful ATP utilizers. During this phase, the inverse operation of F0F1 ATPase maintains the mitochondrial membrane potential by using the ATP made available by glycolysis. The second phase can be identified from the functional and structural alterations of mitochondria caused by prolongation of ischemia, such as decreased utilization of NAD-linked substrates, release of cytochrome c and involvement of mitochondrial channels. These events indicate that the relationship between ischemic damage and mitochondria is not limited to the failure in ATP production. Finally, the third phase links mitochondria to the destiny of the myocytes upon post-ischemic reperfusion. Indeed, depending on the duration and the severity of ischemia, not only is mitochondrial function necessary for cell recovery, but it can also exacerbate cell injury.}, } @article {pmid9693729, year = {1998}, author = {Andersson, SG}, title = {Bioenergetics of the obligate intracellular parasite Rickettsia prowazekii.}, journal = {Biochimica et biophysica acta}, volume = {1365}, number = {1-2}, pages = {105-111}, doi = {10.1016/s0005-2728(98)00050-4}, pmid = {9693729}, issn = {0006-3002}, mesh = {Citric Acid/metabolism ; Electron Transport ; Energy Metabolism/genetics/*physiology ; Genome, Bacterial ; Mitochondria/physiology ; Mitochondrial ADP, ATP Translocases/genetics ; Operon ; Oxidation-Reduction ; Proton-Translocating ATPases/genetics ; Rickettsia prowazekii/genetics/*physiology ; }, abstract = {Mitochondria are thought to be derived from an ancestor of the alpha-proteobacteria and more specifically from the Rickettsiaceae. The bioenergetic repertoire of the obligate intracellular parasite Rickettsia prowazekii is consistent with its postulated role as the ancestor of the mitochondria. For example, the R. prowazekii genome contains genes encoding components of the tricarboxylic acid cycle as well as of the electron transport system, but lacks genes to support glycolysis. In addition, the R. prowazekii genome contains multiple genes coding for adenine nucleotide translocators which enables this intracellular parasite to exploit the cytoplasmic ATP of its host cell as a source of energy. The aim of this review is to describe the different aspects of the bioenergetic system in R. prowazekii and to discuss the results of phylogenetic reconstructions based on a variety of bioenergetic molecules which shed light on the origin and evolution of the mitochondrial genomes.}, } @article {pmid9545461, year = {1998}, author = {Vellai, T and Takács, K and Vida, G}, title = {A new aspect to the origin and evolution of eukaryotes.}, journal = {Journal of molecular evolution}, volume = {46}, number = {5}, pages = {499-507}, doi = {10.1007/pl00006331}, pmid = {9545461}, issn = {0022-2844}, mesh = {*Biological Evolution ; DNA Replication ; Energy Metabolism ; Escherichia coli/genetics/growth & development ; Eukaryotic Cells/*physiology ; Genetic Vectors ; *Genome, Bacterial ; *Models, Biological ; Organelles/metabolism ; Prokaryotic Cells/*physiology ; }, abstract = {One of the most important omissions in recent evolutionary theory concerns how eukaryotes could emerge and evolve. According to the currently accepted views, the first eukaryotic cell possessed a nucleus, an endomembrane system, and a cytoskeleton but had an inefficient prokaryotic-like metabolism. In contrast, one of the most ancient eukaryotes, the metamonada Giardia lamblia, was found to have formerly possessed mitochondria. In sharp contrast with the traditional views, this paper suggests, based on the energetic aspect of genome organization, that the emergence of eukaryotes was promoted by the establishment of an efficient energy-converting organelle, such as the mitochondrion. Mitochondria were acquired by the endosymbiosis of ancient alpha-purple photosynthetic Gram-negative eubacteria that reorganized the prokaryotic metabolism of the archaebacterial-like ancestral host cells. The presence of an ATP pool in the cytoplasm provided by this cell organelle allowed a major increase in genome size. This evolutionary change, the remarkable increase both in genome size and complexity, explains the origin of the eukaryotic cell itself. The loss of cell wall and the appearance of multicellularity can also be explained by the acquisition of mitochondria. All bacteria use chemiosmotic mechanisms to harness energy; therefore the periplasm bounded by the cell wall is an essential part of prokaryotic cells. Following the establishment of mitochondria, the original plasma membrane-bound metabolism of prokaryotes, as well as the funcion of the periplasm providing a compartment for the formation of different ion gradients, has been transferred into the inner mitochondrial membrane and intermembrane space. After the loss of the essential function of periplasm, the bacterial cell wall could also be lost, which enabled the naked cells to establish direct connections among themselves. The relatively late emergence of mitochondria may be the reason why multicellularity evolved so slowly.}, } @article {pmid9580216, year = {1997}, author = {Chagoya de Sánchez, V and Hernández-Muñoz, R and López-Barrera, F and Yañez, L and Vidrio, S and Suárez, J and Cota-Garza, MD and Aranda-Fraustro, A and Cruz, D}, title = {Sequential changes of energy metabolism and mitochondrial function in myocardial infarction induced by isoproterenol in rats: a long-term and integrative study.}, journal = {Canadian journal of physiology and pharmacology}, volume = {75}, number = {12}, pages = {1300-1311}, pmid = {9580216}, issn = {0008-4212}, mesh = {Animals ; Blood Pressure/drug effects ; *Cardiotonic Agents ; Edema/complications/pathology ; Electrophysiology ; Energy Metabolism/*drug effects ; Heart/*drug effects/physiology ; Heart Rate/drug effects ; *Isoproterenol ; Male ; Microscopy, Electron ; Mitochondria, Heart/*drug effects/metabolism/pathology/ultrastructure ; Myocardial Infarction/*chemically induced/enzymology/pathology/physiopathology ; Rats ; Rats, Wistar ; }, abstract = {Acute myocardial infarction is the second cause of mortality in most countries, therefore, it is important to know the evolution and sequence of the physiological and biochemical changes involved in this pathology. This study attempts to integrate these changes and to correlate them in a long-term model (96 h) of isoproterenol-induced myocardial cell damage in the rat. We achieved an infarct-like damage in the apex region of the left ventricle, occurring 12-24 h after isoproterenol administration. The lesion was defined by histological criteria, continuous telemetric ECG recordings, and the increase in serum marker enzymes, specific for myocardial damage. A distinction is made among preinfarction, infarction, and postinfarction. Three minutes after drug administration, there was a 60% increase in heart rate and a lowering of blood pressure, resulting possibly in a functional ischemia. Ultrastructural changes and mitochondrial swelling were evident from the first hour of treatment, but functional alterations in isolated mitochondria, such as decreases in oxygen consumption, respiratory quotient, ATP synthesis, and membrane potential, were noticed only 6 h after drug administration and lasted until 72 h later. Mitochondrial proteins decreased after 3 h of treatment, reaching almost a 50% diminution, which was maintained during the whole study. An energy imbalance, reflected by a decrease in energy charge and in the creatine phosphate/creatine ratio, was observed after 30 min of treatment; however, ATP and total adenine nucleotides diminished clearly only after 3 h of treatment. All these alterations reached a maximum at the onset of infarction and were accompanied by damage to the myocardial function, drastically decreasing left ventricular pressure and shortening the atrioventricular interval. During postinfarction, a partial recovery of energy charge, creatine phosphate/creatine ratio, membrane potential, and myocardial function occurred, but not of mitochondrial oxygen consumption, rate of ATP synthesis, total adenine nucleotides, or mitochondrial proteins. Interesting correlations of the sequential changes in heart and mitochondrial functions with energy metabolism were obtained at different stages of the isoproterenol-induced cardiotoxicity. These correlations could be useful to study and understand the cellular events involved in this pathology.}, } @article {pmid9504342, year = {1998}, author = {Brown, DM and Upcroft, JA and Edwards, MR and Upcroft, P}, title = {Anaerobic bacterial metabolism in the ancient eukaryote Giardia duodenalis.}, journal = {International journal for parasitology}, volume = {28}, number = {1}, pages = {149-164}, doi = {10.1016/s0020-7519(97)00172-0}, pmid = {9504342}, issn = {0020-7519}, mesh = {Amino Acids/metabolism ; Animals ; Bacteria, Anaerobic/*metabolism ; Biological Evolution ; Electron Transport ; Energy Metabolism ; Fermentation ; Giardia/genetics/*metabolism ; Models, Biological ; Oxidation-Reduction ; Oxidative Stress ; Oxygen Consumption ; }, abstract = {The protozoan parasite, Giardia duodenalis, shares many metabolic and genetic attributes of the bacteria, including fermentative energy metabolism which relies heavily on pyrophosphate rather than adenosine triphosphate and as a result contains two typically bacterial glycolytic enzymes which are pyrophosphate dependent. Pyruvate decarboxylation and subsequent electron transport to as yet unidentified anaerobic electron acceptors relies on a eubacterial-like pyruvate:ferredoxin oxidoreductase and an archaebacterial/eubacterial-like ferredoxin. The presence of another 2-ketoacid oxidoreductase (with a preference for alpha-ketobutyrate) and multiple ferredoxins in Giardia is also a trait shared with the anaerobic bacteria. Giardia pyruvate:ferredoxin oxidoreductase is distinct from the pyruvate dehydrogenase multienzyme complex invariably found in mitochondria. This is consistent with a lack of mitochondria, citric acid cycle, oxidative phosphorylation and glutathione in Giardia. Giardia duodenalis actively consumes oxygen and yet lacks the conventional mechanisms of oxidative stress management, including superoxide dismutase, catalase, peroxidase, and glutathione cycling, which are present in most eukaryotes. In their place Giardia contains a prokaryotic H2O-producing NADH oxidase, a membrane-associated NADH peroxidase, a broad-range prokaryotic thioredoxin reductase-like disulphide reductase and the low molecular weight thiols, cysteine, thioglycolate, sulphite and coenzyme A. NADH oxidase is a major component of the electron transport pathway of Giardia which, in conjunction with disulphide reductase, protects oxygen-labile proteins such as ferredoxin and pyruvate:ferredoxin oxidoreductase against oxidative stress by maintaining a reduced intracellular environment. As the terminal oxidase, NADH oxidase provides a means of removing excess H+, thereby enabling continued pyruvate decarboxylation and the resultant production of acetate and adenosine triphosphate. A further example of the bacterial-like metabolism of Giardia is the utilisation of the amino acid arginine as an energy source. Giardia contain the arginine dihydrolase pathway, which occurs in a number of anaerobic prokaryotes, but not in other eukaryotes apart from trichomonads and Chlamydomonas reinhardtii. The pathway includes substrate level phosphorylation and is sufficiently active to make a major contribution to adenosine triphosphate production. Two enzymes of the pathway, arginine deiminase and carbamate kinase, are rare in eukaryotes and do not occur in higher animals. Arginine is transported into the trophozoite via a bacterial-like arginine:ornithine antiport. Together these metabolic pathways in Giardia provide a wide range of potential drug targets for future consideration.}, } @article {pmid9503641, year = {1998}, author = {Moyes, CD and Battersby, BJ and Leary, SC}, title = {Regulation of muscle mitochondrial design.}, journal = {The Journal of experimental biology}, volume = {201}, number = {Pt 3}, pages = {299-307}, pmid = {9503641}, issn = {0022-0949}, mesh = {Animals ; Base Sequence ; Biological Evolution ; DNA, Mitochondrial/genetics ; DNA-Binding Proteins/genetics/metabolism ; Electron Transport Complex IV/genetics/metabolism ; Energy Metabolism ; Gene Expression Regulation ; Humans ; Mitochondria, Muscle/genetics/*metabolism ; Nuclear Respiratory Factors ; Oxidative Phosphorylation ; Trans-Activators/genetics/metabolism ; }, abstract = {Mitochondria are responsible for the generation of ATP to fuel muscle contraction. Hypermetabolic stresses imposed upon muscles can lead to mitochondrial proliferation, but the resulting mitochondria greatly resemble their progenitors. During the mitochondrial biogenesis that accompanies phenotypic adaptation, the stoichiometric relationships between functional elements are preserved through shared sensitivities of respiratory genes to specific transcription factors. Although the properties of muscle mitochondria are generally thought to be highly conserved across species, there are many examples of mitochondrial differences between muscle types, species and developmental states and even within single cells. In this review, we discuss (1) the nature and regulation of gene families that allow coordinated expression of genes for mitochondrial products and (2) the regulatory mechanisms by which mitochondrial differences can arise over physiological and evolutionary time.}, } @article {pmid9467721, year = {1998}, author = {Miquel, J}, title = {An update on the oxygen stress-mitochondrial mutation theory of aging: genetic and evolutionary implications.}, journal = {Experimental gerontology}, volume = {33}, number = {1-2}, pages = {113-126}, doi = {10.1016/s0531-5565(97)00060-0}, pmid = {9467721}, issn = {0531-5565}, mesh = {Aging/*genetics ; Animals ; *Biological Evolution ; DNA, Mitochondrial/*genetics ; Drosophila/genetics ; Energy Metabolism/physiology ; Humans ; Mutation ; Oxidative Stress/drug effects/*physiology ; Stochastic Processes ; }, abstract = {The acceleration of fixed-postmitotic cell aging by a high metabolic rate and the age related loss of mitochondria found in that cell type led us to propose an oxygen stress-mitochondrial mutation theory of aging, according to which senescence may be linked to mutations of the mitochondrial genome (mtDNA) of the irreversibly differentiated cells. This extranuclear somatic gene mutation concept of aging is supported by the fact that mtDNA synthesis takes place at the inner mitochondrial membrane near the sites of formation of highly reactive oxygen species. Mitochondrial DNA may be unable to prevent the intrinsic mutagenesis caused by those byproducts of respiration because, in contrast to the nuclear genome, it lacks excision and recombination repair. The resulting mitochondrial impairment and concomitant cell bioenergetic decline may cause the senescent loss of physiological performance and may play a key role in the pathogenesis of many age-related degenerative diseases. These concepts are integrated with classic and contemporary hypotheses in a unitary theory that reconciles programmed and stochastic concepts of aging. Thus, it is suggested that cells are programmed to differentiate, and then they accumulate mitochondrial-genetic damage because of their high levels of oxyradical stress and the loss of the organelle rejuvenating power of mitosis.}, } @article {pmid9374771, year = {1997}, author = {Consolini, AE and Márquez, MT and Ponce-Hornos, JE}, title = {Energetics of heart muscle contraction under high K perfusion: verapamil and Ca effects.}, journal = {The American journal of physiology}, volume = {273}, number = {5}, pages = {H2343-50}, doi = {10.1152/ajpheart.1997.273.5.H2343}, pmid = {9374771}, issn = {0002-9513}, mesh = {Animals ; Calcium/*pharmacology ; Calorimetry ; Electric Stimulation ; Energy Metabolism/drug effects ; Female ; Heart/*physiology ; Heart Ventricles ; In Vitro Techniques ; Kinetics ; Male ; Mitochondria, Heart/drug effects/*metabolism ; Myocardial Contraction/drug effects/*physiology ; Perfusion ; Potassium/*pharmacology ; Rats ; Rats, Wistar ; Verapamil/*pharmacology ; }, abstract = {Tension-dependent (TDH) and tension-independent heat (TIH) release were measured during single isovolumetric contractions in the arterially perfused rat ventricle. Under perfusion with 7 mM K-0.5 mM Ca, TDH showed only one component (H3), whereas TIH could be divided into two components (H1 and H2) of short evolution (similar to the classically identified activation heat) and one component (H4) of long duration (dependent on mitochondrial respiration). Under 25 mM K, TIH components (i.e., H1, H2, and H4) increased with the increase in extracellular Ca concentration ([Ca]o) from 0.5 to 4 mM, and H3 correlated with pressure at all [Ca]o, with regression parameters similar to those observed under 7 mM K. Under 25 mM K-2 mM Ca, peak pressure development (P), H1, H2, and H3, plotted against the number of beats under 0.4 microM verapamil, exponentially decreased, but H4 decreased to 5.5 +/- 2.9% in the first contraction and remained constant thereafter. Under hypoxia, P, H1, H2, and H3 progressively decreased for about six contractions, but H4 was not detectable from the second contraction. The results suggest that increasing extracellular K concentration decreases contractile economy mainly by increasing energy expenditure related to a Ca-dependent (verapamil-sensitive) mitochondrial activity that is not related to force generation.}, } @article {pmid9387093, year = {1997}, author = {Golshani-Hebroni, SG and Bessman, SP}, title = {Hexokinase binding to mitochondria: a basis for proliferative energy metabolism.}, journal = {Journal of bioenergetics and biomembranes}, volume = {29}, number = {4}, pages = {331-338}, pmid = {9387093}, issn = {0145-479X}, mesh = {Adenosine Triphosphate/biosynthesis ; Animals ; *Energy Metabolism ; Glycolysis ; Hexokinase/*metabolism ; Insulin/metabolism ; Mitochondria/*metabolism ; NAD/metabolism ; NADP/metabolism ; Protein Biosynthesis ; Tumor Cells, Cultured ; }, abstract = {Current thought is that proliferating cells undergo a shift from oxidative to glycolytic metabolism, where the energy requirements of the rapidly dividing cell are provided by ATP from glycolysis. Drawing on the hexokinase-mitochondrial acceptor theory of insulin action, this article presents evidence suggesting that the increased binding of hexokinase to porin on mitochondria of cancer cells not only accelerates glycolysis by providing hexokinase with better access to ATP, but also stimulates the TCA cycle by providing the mitochondrion with ADP that acts as an acceptor for phosphoryl groups. Furthermore, this acceleration of the TCA cycle stimulates protein synthesis via two mechanisms: first, by increasing ATP production, and second, by provision of certain amino acids required for protein synthesis, since the amino acids glutamate, alanine, and aspartate are either reduction products or partially oxidized products of the intermediates of glycolysis and the TCA cycle. The utilization of oxygen in the course of the TCA cycle turnover is relatively diminished even though TCA cycle intermediates are being consumed. With partial oxidation of TCA cycle intermediates into amino acids, there is necessarily a reduction in formation of CO2 from pyruvate, seen as a relative diminution in utilization of oxygen in relation to carbon utilization. This has been assumed to be an inhibition of oxygen uptake and therefore a diminution of TCA cycle activity. Therefore a switch from oxidative metabolism to glycolytic metabolism has been assumed (the Crabtree effect). By stimulating both ATP production and protein synthesis for the rapidly dividing cell, the binding of hexokinase to mitochondrial porin lies at the core of proliferative energy metabolism. This article further reviews literature on the binding of the isozymes of hexokinase to porin, and on the evolution of insulin, proposing that intracellular insulin-like proteins directly bind hexokinase to mitochondrial porin.}, } @article {pmid9260887, year = {1997}, author = {Singh, B and Soltys, BJ and Wu, ZC and Patel, HV and Freeman, KB and Gupta, RS}, title = {Cloning and some novel characteristics of mitochondrial Hsp70 from Chinese hamster cells.}, journal = {Experimental cell research}, volume = {234}, number = {2}, pages = {205-216}, doi = {10.1006/excr.1997.3609}, pmid = {9260887}, issn = {0014-4827}, mesh = {Amino Acid Sequence ; Animals ; Antibody Specificity ; Base Sequence ; Biological Transport ; *CHO Cells ; Cloning, Molecular ; Cricetinae ; DNA, Complementary/genetics ; Escherichia coli ; HSP70 Heat-Shock Proteins/*analysis/*genetics/metabolism ; Mitochondria/*chemistry ; Mitochondria, Heart/metabolism ; Molecular Sequence Data ; Phylogeny ; Protein Processing, Post-Translational ; Rats ; Recombinant Fusion Proteins ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; }, abstract = {The cDNA for Chinese hamster mitochondrial Hsp70 (mHsp70) was cloned and sequenced using a polymerase chain reaction probe based on conserved regions in the Hsp70 family of proteins. The encoded protein consists of 679 amino acids which includes a N-terminal mitochondrial targeting sequence of 46 amino acids. The mHsp70 protein contains several sequence signatures that are characteristics of prokaryotic and eukaryotic organellar Hsp70 homologs. In a phylogenetic tree based on Hsp70 sequences, it branches with the gram-negative proteobacteria, supporting the endosymbiotic origin of mitochondria from this group of prokaryotes. The mHsp70 cDNA was transcribed and translated in vitro and its import into isolated rat heart mitochondria was examined. The precursor mHsp70 was converted into a mature form of lower molecular mass (approximately 71 kDa) which became resistant to trypsin digestion. The import of mHsp70 into mitochondria was not observed in the presence of an uncoupler of energy metabolism or when the N-terminal presequence was lacking. The cDNA for mHsp70 was expressed in Escherichia coli and a polyclonal antibody to the purified recombinant protein was raised. The antibody shows no cross-reactivity to recombinant cytosolic Hsp70 protein and in 2-D gel blots it reacted specifically with the mHsp70 protein only. In immunofluorescence experiments, the antibody predominantly labeled mitochondria, and the observed labeling pattern was identical to that seen with a monoclonal antibody to the mitochondrial Hsp60 chaperonin. The affinity-purified antibody to mHsp70 was also employed to examine the subcellular distribution of the protein by cryoelectron microscopy and the immunogold-labeling technique. In these experiments, in addition to mitochondria, labeling with mitochondrial Hsp70 antibody was also observed on the plasma membrane and in unidentified cytoplasmic vesicles and granules. These studies raise the possibility that similar to the Hsp60 chaperonin and a number of other mitochondrial proteins, mHsp70 may have an extramitochondrial role.}, } @article {pmid9249985, year = {1997}, author = {Oh-hama, T}, title = {Evolutionary consideration on 5-aminolevulinate synthase in nature.}, journal = {Origins of life and evolution of the biosphere : the journal of the International Society for the Study of the Origin of Life}, volume = {27}, number = {4}, pages = {405-412}, pmid = {9249985}, issn = {0169-6149}, mesh = {5-Aminolevulinate Synthetase/*genetics/*metabolism ; Acetyltransferases/genetics ; Acyltransferases/genetics ; Animals ; Bacteria/enzymology/genetics ; *Biological Evolution ; Birds ; Energy Metabolism ; Eukaryota/enzymology/genetics ; Eukaryotic Cells ; Gene Expression ; Humans ; Mammals ; Phylogeny ; Plants/enzymology/genetics ; Prokaryotic Cells ; Saccharomyces cerevisiae/enzymology/genetics ; }, abstract = {5-Aminolevulinic acid (ALA), a universal precursor of tetrapyrrole compounds can be synthesized by two pathways: the C5 (glutamate) pathway and ALA synthase. From the phylogenetic distribution it is shown that distribution of ALA synthase is restricted to the alpha subclass of purple bacteria in prokaryotes, and further distributed to mitochondria of eukaryotes. The monophyletic origin of bacterial and eukaryotic ALA synthase is shown by sequence analysis of the enzyme. Evolution of ALA synthase in the alpha subclass of purple bacteria is discussed in relation to the energy-generating and biosynthetic devices in subclasses of this bacteria.}, } @article {pmid9156326, year = {1997}, author = {Giannattasio, S and Jurgelevicius, V and Lattanzio, P and Cimbalistienè, L and Marra, E and Kucinskas, V}, title = {Phenylketonuria mutations and linked haplotypes in the Lithuanian population: origin of the most common R408W mutation.}, journal = {Human heredity}, volume = {47}, number = {3}, pages = {155-160}, doi = {10.1159/000154403}, pmid = {9156326}, issn = {0001-5652}, mesh = {Evolution, Molecular ; Founder Effect ; *Haplotypes ; Humans ; Lithuania ; Minisatellite Repeats/genetics ; Mutation/*genetics ; Phenylalanine Hydroxylase/genetics ; Phenylketonurias/ethnology/*genetics ; Repetitive Sequences, Nucleic Acid/genetics ; }, abstract = {A genealogical study was performed in Lithuanian phenylketonuria (PKU) families with the aim of tracing the origins of the R408W/haplotype 2/VNTR3 allele. The relative frequency of six phenylalanine hydroxylase (PAH) mutations (R408W, R158Q, R261Q, G272X, IVS10nt-11g --> a, and IVS12nt1g --> a) common in Eastern European populations and their association with variable number of tandem repeat (VNTR) and short tandem repeat (STR) sites in the PAH gene were examined in 130 PKU Lithuanian chromosomes, including 95 of Baltic, 28 of Slavonic and 7 of unknown origin. R408W was found to be the most frequent (70%) mutation in both Balts or Slavonians with a uniform frequency distribution. No statistically significant differences in the frequency distribution of the other mutations analysed were found. In Balts and Slavonians, the R408W mutation is strongly associated with the three-copy VNTR and the 240-bp STR allele. The frequency of this association is 68% in both ethnic groups. The genealogical data provided in this paper indicate that the most common R408W/VNTR3/STR240 allele arose in ancient times possibly among pre-Indo-Europeans and suggest that the high frequency of the R408W mutation and associated minihaplotype in Balts of Lithuania is due to a founder effect.}, } @article {pmid9115381, year = {1997}, author = {Sogin, ML}, title = {Organelle origins: energy-producing symbionts in early eukaryotes?.}, journal = {Current biology : CB}, volume = {7}, number = {5}, pages = {R315-7}, doi = {10.1016/s0960-9822(06)00147-3}, pmid = {9115381}, issn = {0960-9822}, mesh = {Animals ; *Biological Evolution ; *Energy Metabolism ; Eukaryotic Cells ; Genes, Protozoan ; Mitochondria/physiology ; Organelles/*physiology ; Symbiosis ; Trichomonas vaginalis/genetics/*physiology/ultrastructure ; }, abstract = {The discovery that Trichomonas vaginalis, an early diverging protist that lacks mitochondria but has energy-producing hydrogenosomes, makes bacterial-like heat shock proteins suggests that symbionts ancestral to mitochondria and hydrogenosomes were present at early stages of eukaryote evolution.}, } @article {pmid9136629, year = {1997}, author = {Danpure, CJ}, title = {Variable peroxisomal and mitochondrial targeting of alanine: glyoxylate aminotransferase in mammalian evolution and disease.}, journal = {BioEssays : news and reviews in molecular, cellular and developmental biology}, volume = {19}, number = {4}, pages = {317-326}, doi = {10.1002/bies.950190409}, pmid = {9136629}, issn = {0265-9247}, mesh = {Alanine Transaminase/*metabolism ; Animals ; Biological Transport ; Catalysis ; Cytosol/enzymology ; Diet ; Dimerization ; Energy Metabolism ; Enzyme Induction ; Evolution, Molecular ; Glucose/metabolism ; Glyoxylates/metabolism ; Humans ; Hyperoxaluria/*enzymology/genetics ; Mammals/*metabolism ; Microbodies/*enzymology ; Mitochondria/*enzymology ; Polymorphism, Genetic ; Protein Sorting Signals/physiology ; Selection, Genetic ; Species Specificity ; *Transaminases ; }, abstract = {Under the putative influence of dietary selection pressure, the subcellular distribution of alanine:glyoxylate aminotransferase 1 (AGT) has changed on many occasions during the evolution of mammals. Depending on the particular species, AGT can be found either in peroxisomes or mitochondria, or in both peroxisomes and mitochondria. This variable localization depends on the differential expression of N-terminal mitochondrial and C-terminal peroxisomal targeting sequences by the use of alternative transcription and translation initiation sites. AGT is peroxisomal in most humans, but it is mistargeted to the mitochondria in a subset of patients suffering from the rare hereditary disease primary hyperoxaluria type 1. Mistargeting is due to the unlikely combination of a normally occurring polymorphism that generates a functionally weak mitochondrial targeting sequence and a disease-specific mutation which, in combination with the polymorphism, inhibits AGT dimerization. The mechanisms by which AGT can be targeted differentially to peroxisomes and/or mitochondria highlight the different molecular requirements for protein import into these two organelles.}, } @article {pmid9404460, year = {1997}, author = {Lestienne, P}, title = {[Do mitochondria play a role in aging?].}, journal = {Comptes rendus des seances de la Societe de biologie et de ses filiales}, volume = {191}, number = {4}, pages = {579-592}, pmid = {9404460}, issn = {0037-9026}, mesh = {Aging/*physiology ; Alzheimer Disease/genetics/metabolism ; Animals ; DNA, Mitochondrial/genetics/metabolism ; Forecasting ; Free Radicals/metabolism ; Humans ; Mitochondria/*metabolism/physiology ; Parkinson Disease/genetics/metabolism ; }, abstract = {Ageing is an unavoidable and complex phenomenon which may be a price to pay to evolution. Thus genetics appear to play a predominant role besides environmental factors. Energetic metabolism slowly declines with ageing supporting a possible active role of mitochondria, the power supply of the cells, to this process. Mitochondrial DNA alterations appear during the mid-life and in degenerative diseases such as in Parkinson's and Alzheimer's; they include large scale deletions and point mutations. Since the respiratory chain plays a major role in the generation of superoxide anions which are converted into hydroxyl radicals that may impair lipids, proteins and DNA function in mitochondria, this vicious cycle may result from both an altered control of mitochondrial biogenesis dependent from the nucleus, and/or from a lack of repair and accumulation of somatic mitochondrial DNA mutations.}, } @article {pmid8663075, year = {1996}, author = {Kobayashi, M and Matsuo, Y and Takimoto, A and Suzuki, S and Maruo, F and Shoun, H}, title = {Denitrification, a novel type of respiratory metabolism in fungal mitochondrion.}, journal = {The Journal of biological chemistry}, volume = {271}, number = {27}, pages = {16263-16267}, doi = {10.1074/jbc.271.27.16263}, pmid = {8663075}, issn = {0021-9258}, mesh = {*Adaptor Proteins, Signal Transducing ; *Adaptor Proteins, Vesicular Transport ; Adenosine Triphosphate/metabolism ; Antimycin A/pharmacology ; Cytochromes/metabolism ; Energy Metabolism ; Fusarium/*metabolism ; Guanine Nucleotide Exchange Factors ; Kinetics ; Microscopy, Fluorescence ; Mitochondria/drug effects/*metabolism ; Mitosporic Fungi/*metabolism ; Nitrate Reductases/antagonists & inhibitors/*metabolism ; Nitrite Reductases/antagonists & inhibitors/*metabolism ; *Oxygen Consumption/drug effects ; Proteins/isolation & purification/*metabolism ; Rotenone/pharmacology ; Shc Signaling Adaptor Proteins ; Spectrophotometry ; Thenoyltrifluoroacetone/pharmacology ; }, abstract = {Subcellular localization and coupling to ATP synthesis were investigated with respect to the denitrifying systems of two fungi, Fusarium oxysporum and Cylindrocarpon tonkinense. Dissimilatory nitrate reductase of F. oxysporum or nitrite reductase of C. tonkinense could be detected in the mitochondrial fraction prepared from denitrifying cells of each fungus. Fluorescence immunolocalization, cofractionation with mitochondrial marker enzymes, and cytochromes provided evidence that the denitrifying enzymes are co-purified with mitochondria. Respiratory substrates such as malate plus pyruvate, succinate, and formate were effective donors of electrons to these activities in the mitochondrial fractions. Moreover, nitrite and nitrate reduction were shown to be coupled to the synthesis of ATP with energy yields (P:NO3- or P:2e ratios) of 0.88 to 1.4, depending upon whether malate/pyruvate or succinate were provided as substrates. Nitrate or nitrite reductase activity was inhibited by inhibitors such as rotenone, antimycin A, and thenoyltrifluoroacetone. Thus, fungal denitrification activities are localized to mitochondria and are coupled to the synthesis of ATP. The existence of these novel respiration systems are discussed with regard to the origin and evolution of mitochondria.}, } @article {pmid8662000, year = {1996}, author = {Allen, JF and Raven, JA}, title = {Free-radical-induced mutation vs redox regulation: costs and benefits of genes in organelles.}, journal = {Journal of molecular evolution}, volume = {42}, number = {5}, pages = {482-492}, pmid = {8662000}, issn = {0022-2844}, mesh = {Aging/genetics ; Cell Nucleus/genetics ; Chloroplasts/genetics ; DNA Repair/genetics ; DNA, Chloroplast/genetics ; DNA, Mitochondrial/genetics ; Electron Transport/genetics ; Energy Metabolism/genetics ; Eukaryotic Cells/metabolism/ultrastructure ; Evolution, Molecular ; Free Radicals ; Mitochondria/genetics ; *Mutation ; Nitrogen Fixation/genetics ; Organelles/*genetics ; Oxidation-Reduction ; Oxidative Stress/*genetics ; Prokaryotic Cells/metabolism/ultrastructure ; Reactive Oxygen Species/metabolism ; Recombination, Genetic ; Symbiosis ; }, } @article {pmid7554586, year = {1995}, author = {Mitchell, GA and Kassovska-Bratinova, S and Boukaftane, Y and Robert, MF and Wang, SP and Ashmarina, L and Lambert, M and Lapierre, P and Potier, E}, title = {Medical aspects of ketone body metabolism.}, journal = {Clinical and investigative medicine. Medecine clinique et experimentale}, volume = {18}, number = {3}, pages = {193-216}, pmid = {7554586}, issn = {0147-958X}, mesh = {3-Hydroxybutyric Acid ; Acetoacetates/metabolism ; Acetone/metabolism ; Biological Evolution ; Brain/metabolism ; Humans ; Hydroxybutyrates/metabolism ; Hypoglycemia/*diagnosis/metabolism ; Ketone Bodies/biosynthesis/*metabolism ; Ketosis/*diagnosis/metabolism/therapy ; Menotropins/metabolism ; Metabolism, Inborn Errors/*diagnosis/metabolism/therapy ; Mitochondria, Liver/enzymology/metabolism ; }, abstract = {Ketone bodies are produced in the liver, mainly from the oxidation of fatty acids, and are exported to peripheral tissues for use as an energy source. They are particularly important for the brain, which has no other substantial non-glucose-derived energy source. The 2 main ketone bodies are 3-hydroxybutyrate (3HB) and acetoacetate (AcAc). Biochemically, abnormalities of ketone body metabolism can present in 3 fashions: ketosis, hypoketotic hypoglycemia, and abnormalities of the 3HB/AcAc ratio. Normally, the presence of ketosis implies 2 things: that lipid energy metabolism has been activated and that the entire pathway of lipid degradation is intact. In rare patients, ketosis reflects an inability to utilize ketone bodies. Ketosis is normal during fasting, after prolonged exercise, and when a high-fat diet is consumed. During the neonatal period, infancy and pregnancy, times at which lipid energy metabolism is particularly active, ketosis develops readily. Pathologic causes of ketosis include diabetes, ketotic hypoglycemia of childhood, corticosteroid or growth hormone deficiency, intoxication with alcohol or salicylates, and several inborn errors of metabolism. The absence of ketosis in a patient with hypoglycemia is abnormal and suggests the diagnosis of either hyperinsulinism or an inborn error of fat energy metabolism. An abnormal elevation of the 3HB/AcAc ratio usually implies a non-oxidized state of the hepatocyte mitochondrial matrix resulting from hypoxia-ischemia or other causes. We summarize the differential diagnosis of abnormalities of ketone body metabolism, as well as pertinent recent advances in research.}, } @article {pmid7599200, year = {1995}, author = {Wallace, DC and Shoffner, JM and Trounce, I and Brown, MD and Ballinger, SW and Corral-Debrinski, M and Horton, T and Jun, AS and Lott, MT}, title = {Mitochondrial DNA mutations in human degenerative diseases and aging.}, journal = {Biochimica et biophysica acta}, volume = {1271}, number = {1}, pages = {141-151}, doi = {10.1016/0925-4439(95)00021-u}, pmid = {7599200}, issn = {0006-3002}, support = {HL45572/HL/NHLBI NIH HHS/United States ; NS21328/NS/NINDS NIH HHS/United States ; NS30164/NS/NINDS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aging/*genetics ; Amino Acid Sequence ; Animals ; *Biological Evolution ; Child ; Conserved Sequence ; DNA, Mitochondrial/*genetics ; Energy Metabolism ; Female ; Humans ; Male ; Middle Aged ; Mitochondria/*metabolism ; Mitochondrial Myopathies/*genetics/metabolism ; Molecular Sequence Data ; *Mutation ; Nervous System Diseases/genetics/metabolism ; Optic Atrophies, Hereditary/*genetics/metabolism ; Oxidative Phosphorylation ; Pedigree ; *Point Mutation ; Sequence Homology, Amino Acid ; }, abstract = {A wide variety of mitochondrial DNA (mtDNA) mutations have recently been identified in degenerative diseases of the brain, heart, skeletal muscle, kidney and endocrine system. Generally, individuals inheriting these mitochondrial diseases are relatively normal in early life, develop symptoms during childhood, mid-life, or old age depending on the severity of the maternally-inherited mtDNA mutation; and then undergo a progressive decline. These novel features of mtDNA disease are proposed to be the product of the high dependence of the target organs on mitochondrial bioenergetics, and the cumulative oxidative phosphorylation (OXPHOS) defect caused by the inherited mtDNA mutation together with the age-related accumulation mtDNA mutations in post-mitotic tissues.}, } @article {pmid7971961, year = {1994}, author = {Shigenaga, MK and Hagen, TM and Ames, BN}, title = {Oxidative damage and mitochondrial decay in aging.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {91}, number = {23}, pages = {10771-10778}, pmid = {7971961}, issn = {0027-8424}, support = {CA39910/CA/NCI NIH HHS/United States ; ESO1896/ES/NIEHS NIH HHS/United States ; }, mesh = {*Aging ; Animals ; DNA, Mitochondrial/chemistry ; Electron Transport ; Energy Metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Immune System/metabolism ; Intracellular Membranes/chemistry ; Lipids/chemistry ; Longevity ; Mitochondria/*physiology ; Mutation ; Neurons/metabolism ; Oxidation-Reduction ; Phylogeny ; Proteins/chemistry ; Superoxides/metabolism ; }, abstract = {We argue for the critical role of oxidative damage in causing the mitochondrial dysfunction of aging. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Several mitochondrial functions decline with age. The contributing factors include the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Acetyl-L-carnitine, a high-energy mitochondrial substrate, appears to reverse many age-associated deficits in cellular function, in part by increasing cellular ATP production. Such evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.}, } @article {pmid8132485, year = {1993}, author = {Klingenberg, M}, title = {Dialectics in carrier research: the ADP/ATP carrier and the uncoupling protein.}, journal = {Journal of bioenergetics and biomembranes}, volume = {25}, number = {5}, pages = {447-457}, pmid = {8132485}, issn = {0145-479X}, mesh = {Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Adipose Tissue, Brown/metabolism ; Amino Acid Sequence ; Animals ; Binding Sites ; Biological Transport ; Carrier Proteins/chemistry/*physiology ; *Energy Metabolism ; Intracellular Membranes/*metabolism ; Ion Channels ; Mammals/metabolism ; Membrane Proteins/chemistry/*physiology ; Mitochondria/*metabolism ; Mitochondrial ADP, ATP Translocases/chemistry/*physiology ; Mitochondrial Proteins ; Molecular Sequence Data ; Phylogeny ; Protein Structure, Tertiary ; Protons ; Structure-Activity Relationship ; Uncoupling Protein 1 ; }, abstract = {A concise review is given of the research in our laboratory on the ADP/ATP carrier (AAC) and the uncoupling protein (UCP). Although homologous proteins, their widely different functions and contrasts are stressed. The pioneer role of research on the AAC, not only for the mitochondrial but also for other carriers, and the present state of their structure-function relationship is reviewed. The function of UCP as a highly regulated H+ carrier is described in contrast to the largely unregulated ADP/ATP exchange in AAC. General principles of carrier catalysis as derived from studies on the AAC and UCP are elucidated.}, } @article {pmid1390679, year = {1992}, author = {Lewandowski, ED}, title = {Metabolic heterogeneity of carbon substrate utilization in mammalian heart: NMR determinations of mitochondrial versus cytosolic compartmentation.}, journal = {Biochemistry}, volume = {31}, number = {37}, pages = {8916-8923}, doi = {10.1021/bi00152a031}, pmid = {1390679}, issn = {0006-2960}, mesh = {Alanine/metabolism ; Animals ; Carbon/*metabolism ; Cell Compartmentation ; Cytosol/metabolism ; Energy Metabolism ; Glutamates/metabolism ; Lactates/metabolism ; Magnetic Resonance Spectroscopy ; Mitochondria, Heart/*metabolism ; Myocardial Contraction ; Myocardium/*metabolism ; Pyruvates/metabolism ; Rabbits ; }, abstract = {Carbon-13 (13C) nuclear magnetic resonance (NMR) spectroscopy can be used to target specific pathways of intermediary metabolism within intact tissues and was employed in this study to evaluate the compartmentation of pyruvate metabolism between the cytosol and mitochondrial matrix. The distribution of 13C into the tissue alanine, lactate, and glutamate pools was evaluated during metabolism of [3-13C]-pyruvate in intact, isolated perfused rabbit hearts with and without activation of pyruvate dehydrogenase activity by dichloroacetate (5 mM). Equilibrium between the intracellular alanine and pyruvate pools was in evidence from the rapid evolution of the steady-state 13C signal arising from the 3-carbon of alanine in intact hearts perfused with 2.5 mM 99.4% [3-13C]pyruvate. Augmented pyruvate oxidation, in response to perfusion with dichloroacetate, was evident within 13C NMR spectra of intact hearts as a relative increase in signal intensity of 53-62% (p less than 0.05) from the 4-carbon resonance of 13C-enriched glutamate when compared to the unaffected alanine signal. The increased bulk flow of [3-13C]pyruvate into the tricarboxylic acid cycle in response to dichloroacetate resulted in elevated fractional enrichment of glutamate from 68% in controls to 83% in the treated group (p less than 0.04), via interconversion with alpha-ketoglutarate, without changes in the actual tissue content of glutamate. Evidence of metabolic heterogeneity of cytosolic and mitochondrial pyruvate pools was also obtained from analysis of tissue extracts with in vitro NMR spectroscopy.(ABSTRACT TRUNCATED AT 250 WORDS)}, } @article {pmid1462374, year = {1992}, author = {Makhmudov, ES and Alimukhamedov, AA and Akhmerov, RI and Babaeva, RN and Baratova, GKh}, title = {[Effect of hyperglycemia and hyperthermia on liver mitochondrial respiration and blood glucose content of rats during postnatal ontogenesis].}, journal = {Ukrainskii biokhimicheskii zhurnal (1978)}, volume = {64}, number = {5}, pages = {77-82}, pmid = {1462374}, issn = {0201-8470}, mesh = {Animals ; Animals, Newborn/growth & development/*metabolism ; Blood Glucose/*metabolism ; Body Temperature/*physiology ; Caprylates/metabolism ; Hyperglycemia/blood/*metabolism ; Malates/metabolism ; Mitochondria, Liver/*metabolism ; Oxygen Consumption/*physiology ; Pyruvates/metabolism ; Pyruvic Acid ; Rats ; Rats, Wistar ; Succinates/metabolism ; Succinic Acid ; }, abstract = {Correlation between glucose level in blood and liver mitochondrial energetics of 1, 10, 20-days rats under hyperglycemia and high environmental temperature (38 degrees C) has been studied. Glucose feeding led to a significant increase of glucose content in blood, this increase being less at hyperthermia. Glucose feeding strengthened the oxidation of such intermediates as succinate (Krebs cycle), pyruvate and malate (hydrocarbonates) and caprylate (lipid). High environmental temperature with hyperglycemia suppresses the liver mitochondria breathing, hydrocarbon and lipid intermediates being used; the suppression is less in the presence of succinate. It is found that liver mitochondria of growing rats at different experimental conditions oxidize different intermediates with various rates. These data can be explained in the light of ontogenetic evolution of the energetic apparatus. It is supposed that exogenic glucose is the factor which activates growing processes of animals and to certain extent diminishes the negative influence of hyperthermia on the organism.}, } @article {pmid1292665, year = {1992}, author = {Müller, M}, title = {Energy metabolism of ancestral eukaryotes: a hypothesis based on the biochemistry of amitochondriate parasitic protists.}, journal = {Bio Systems}, volume = {28}, number = {1-3}, pages = {33-40}, doi = {10.1016/0303-2647(92)90005-j}, pmid = {1292665}, issn = {0303-2647}, support = {AI 11942/AI/NIAID NIH HHS/United States ; RR 07065/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Biological Evolution ; Energy Metabolism ; Entamoeba histolytica/metabolism ; Eukaryotic Cells/*metabolism ; Giardia lamblia/metabolism ; Mitochondria/metabolism ; Models, Biological ; Trichomonas vaginalis/metabolism ; }, abstract = {Parasitic amitochondriate protists, representatives of early branches of eukaryote evolution, differ considerably in their central, energy metabolism from mitochondrion-bearing cells. These differences are: significant metabolic functions of inorganic pyrophosphate, major role of iron-sulfur proteins in key metabolic steps and in hydrogenosome-bearing organisms the disposal of electrons by H2 formation. Cytochrome-mediated electron transport and electron transport-linked phosphorylation are absent. All proteins which have been sequenced so far were found to be homologous to isofunctional proteins from other organisms. A few reactions, however, are catabolized by proteins which are not homologous to enzymes performing similar reactions in other eukaryotes. Two significantly different types of metabolism of amitochondriate protists can be distinguished: (a) without compartmentation and (b) with cytosol/hydrogenosome compartmentation. It is likely that these metabolic types have conserved certain traits present in ancestral eukaryotes before mitochondria became established.}, } @article {pmid1823597, year = {1991}, author = {Henderson, PJ}, title = {Studies of translocation catalysis.}, journal = {Bioscience reports}, volume = {11}, number = {6}, pages = {477-53; discussion 534-8}, doi = {10.1007/BF01130216}, pmid = {1823597}, issn = {0144-8463}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Amino Acid Sequence ; Biological Transport, Active ; *Catalysis ; Energy Metabolism ; Molecular Sequence Data ; Osmosis ; Sequence Homology, Nucleic Acid ; }, abstract = {There is a symbiotic relationship between the evolution of fundamental theory and the winning of experimentally-based knowledge. The impact of the General Chemiosmotic Theory on our understanding of the nature of membrane transport processes is described and discussed. The history of experimental studies on transport catalysed by ionophore antibiotics and the membrane proteins of mitochondria and bacteria are used to illustrate the evolution of knowledge and theory. Recent experimental approaches to understanding the lactose-H+ symport protein of Escherichia coli and other sugar porters are described to show that the lack of experimental knowledge of the three-dimensional structures of the proteins currently limits the development of theories about their molecular mechanism of translocation catalysis.}, } @article {pmid1794596, year = {1991}, author = {Bolgiano, B and Davies, HC and Poole, RK}, title = {Using the bacterium, Paracoccus denitrificans and other 'runaway mitochondria' as classroom models for respiratory electron transport studies.}, journal = {Biochemical Society transactions}, volume = {19}, number = {4}, pages = {976-981}, doi = {10.1042/bst0190976a}, pmid = {1794596}, issn = {0300-5127}, mesh = {Biological Evolution ; Biology/*education ; *Electron Transport ; Energy Metabolism ; Escherichia coli/metabolism ; Mitochondria/metabolism ; Paracoccus denitrificans/*metabolism ; }, abstract = {Our suggestions for experiments demonstrating electron-transport-chain composition and reactions all exploit bacteria which can be prepared quickly, easily and cheaply from cells grown in Erlenmeyer flasks. While they have been designed from a cytochrome oxidase point of view using organisms of our own prejudice, strains containing mutations in other sites could be just as educational. Most bacteria that can grow aerobically have features in common with the mitochondrial respiratory chain. Because of the vital importance of oxygen utilization throughout most of evolution, and consequent conservation of electron-transport complexes and carriers, the teaching of bioenergetics, whether in the laboratory or lecture room, could benefit from the inclusion of micro-organisms in the curriculum.}, } @article {pmid1850242, year = {1991}, author = {Brand, MD and Couture, P and Else, PL and Withers, KW and Hulbert, AJ}, title = {Evolution of energy metabolism. Proton permeability of the inner membrane of liver mitochondria is greater in a mammal than in a reptile.}, journal = {The Biochemical journal}, volume = {275 (Pt 1)}, number = {Pt 1}, pages = {81-86}, pmid = {1850242}, issn = {0264-6021}, mesh = {Adenosine Triphosphate/biosynthesis ; Animals ; *Biological Evolution ; *Energy Metabolism ; Fatty Acids/analysis ; Intracellular Membranes/chemistry/metabolism ; Kinetics ; Lizards/*metabolism ; Membrane Lipids/analysis ; Membrane Potentials ; Mitochondria, Liver/*metabolism/ultrastructure ; Permeability ; *Protons ; Rats ; }, abstract = {Standard metabolic rate is 7-fold greater in the rat (a typical mammal) than in the bearded dragon, Amphibolurus vitticeps (a reptile with the same body mass and temperature). Rat hepatocytes respire 4-fold faster than do hepatocytes from the lizard. The inner membrane of isolated rat liver mitochondrial has a proton permeability that is 4-5-fold greater than the proton permeability of the lizard liver mitochondrial membrane per mg of mitochondrial protein. The greater permeability of rat mitochondria is not caused by differences in the surface area of the mitochondrial inner membrane, but differences in the fatty acid composition of the mitochondrial phospholipids may be involved in the permeability differences. Greater proton permeability of the mitochondrial inner membrane may contribute to the greater standard metabolic rate of mammals.}, } @article {pmid23196279, year = {1991}, author = {Fenchel, T and Finlay, BJ}, title = {The biology of free-living anaerobic ciliates.}, journal = {European journal of protistology}, volume = {26}, number = {3-4}, pages = {201-215}, doi = {10.1016/S0932-4739(11)80143-4}, pmid = {23196279}, issn = {0932-4739}, abstract = {Anaerobic ciliates are incapable of using oxidative phosphorylation in their energy metabolism and they are more or less sensitive to oxygen. All anaerobic ciliates possess mitochondria-like organelles (with a double outer membrane and often a few cristae) but these do not contain typical mitochondrial enzymes (e.g., cytochromes, cytochrome oxidase). In some species these organelles are capable of fermenting pyruvate into acetate and H2 and they are then referred to as hydrogenosomes. At least six orders of ciliates include anaerobic species. It is concluded that the evolution of anaerobic forms has taken place independently within different taxonomic groups and that hydrogenosomes are modified mitochondria. Many anaerobic ciliates harbour ecto- or endosymbiotic bacteria. Several ciliate species which produce hydrogen as a metabolic waste product harbour endosymbiotic methanogenic bacteria; in some cases this symbiosis represents a mutualistic relationship in which the host controls the life cycle of the symbionts and gains from their presence in terms of growth rate and growth efficiency. Many marine anaerobic ciliates harbour ectosymbiotic bacteria, but the nature of these bacteria and the significance of the association is not yet understood. The present paper reviews what is known about the biology of anaerobic ciliates with special emphasis on free-living forms, including a discussion of their habitats and their role in the microbial communities of anoxic environments.}, } @article {pmid2554073, year = {1989}, author = {Villa, RF and Gorini, A and Geroldi, D and Lo Faro, A and Dell'Orbo, C}, title = {Enzyme activities in perikaryal and synaptic mitochondrial fractions from rat hippocampus during development.}, journal = {Mechanisms of ageing and development}, volume = {49}, number = {3}, pages = {211-225}, doi = {10.1016/0047-6374(89)90072-9}, pmid = {2554073}, issn = {0047-6374}, mesh = {Age Factors ; Animals ; Citrate (si)-Synthase/metabolism ; Electron Transport Complex IV/metabolism ; Energy Metabolism ; Female ; Glutamate Dehydrogenase/metabolism ; Hippocampus/*enzymology/growth & development ; In Vitro Techniques ; Malate Dehydrogenase/metabolism ; Mitochondria/*enzymology ; NADH Dehydrogenase/metabolism ; Rats ; Rats, Inbred Strains ; Synapses/enzymology ; }, abstract = {When pharmacological or basic neurochemical systematic characterization of mitochondrial enzymatic systems correlated to energy transduction processes is attempted, studies must be based on subcellular fractions with a high degree of purity from specific brain areas and from individual animals. Distinct populations of mitochondria heterogenous with respect to biochemical enzyme characteristics from rat brain hippocampus are described. Two mitochondrial populations were derived from synaptosomes by lysis and a third consists of free non-synaptic mitochondria. The maximum rate of some cerebral enzyme activities which are part of energy transduction (citrate synthase, malate dehydrogenase; total NADH-cytochrome c reductase, cytochrome oxidase) and amino acid metabolism (glutamate dehydrogenase) were tested on these mitochondrial populations of 8- and 16-week-old rats. A comprehensive analysis of the data suggests that extensive but highly diversified catalytic expressions of the enzymes studied occur in the hippocampus. This is true even when a short period of the rat life span is studied. Hence the varying pattern of evolution of the differing cerebral mitochondria, probably a consequence of different metabolic functions, should be taken into account in any pharmacological study on these systems.}, } @article {pmid2508761, year = {1989}, author = {}, title = {Bioenergetic systems, structure control and evolution. Autumn congress. (Sept. 28-30, 1988, Bombannes, France). Proceedings.}, journal = {Biochimie}, volume = {71}, number = {8}, pages = {877-979}, pmid = {2508761}, issn = {0300-9084}, mesh = {Animals ; Biological Transport ; *Energy Metabolism ; Mitochondria/*metabolism ; Yeasts/*metabolism ; }, } @article {pmid2710162, year = {1989}, author = {Campbell, T and Rubin, N and Komuniecki, R}, title = {Succinate-dependent energy generation in Ascaris suum mitochondria.}, journal = {Molecular and biochemical parasitology}, volume = {33}, number = {1}, pages = {1-12}, doi = {10.1016/0166-6851(89)90036-4}, pmid = {2710162}, issn = {0166-6851}, support = {AI18427/AI/NIAID NIH HHS/United States ; }, mesh = {Adenine Nucleotides/metabolism ; Animals ; Ascaris/*metabolism ; *Energy Metabolism ; Ferricyanides/pharmacology ; Hydrogen Peroxide/pharmacology ; Malates/metabolism ; Mitochondria/*metabolism ; Models, Biological ; Phosphorylation ; Succinates/*metabolism ; Succinic Acid ; }, abstract = {Phosphorylation in isolated Ascaris suum mitochondria was much greater in the presence of malate than succinate, but, in the absence of added adenine nucleotides, incubations in succinate resulted in substantial elevations in intramitochondrial ATP levels. Succinate-dependent phosphorylation was stimulated aerobically and this stimulation was due almost entirely to a site I, rotenone-sensitive, phosphorylation. Increased substrate level phosphorylation, coupled to propionate formation, or additional sites of electron-transport associated ATP synthesis were not significant. Under aerobic conditions, 14CO2 evolution from 1,4-[14C]succinate was stimulated and NADH/NAD+ ratios were elevated, but the formation of [14C]propionate was unchanged. It appears that succinate was metabolized to pyruvate and acetate, and NADH, generated from the decarboxylations of malate and pyruvate, was the primary source of reducing power fueling electron-transport. The terminal oxidase and final electron-acceptor are still not clearly defined. However, ferricyanide, H2O2, and 100% oxygen all stimulated succinate-dependent phosphorylation. A possible role for cytochrome c peroxidase in A. suum mitochondrial metabolism is discussed.}, } @article {pmid3059999, year = {1988}, author = {Müller, M}, title = {Energy metabolism of protozoa without mitochondria.}, journal = {Annual review of microbiology}, volume = {42}, number = {}, pages = {465-488}, doi = {10.1146/annurev.mi.42.100188.002341}, pmid = {3059999}, issn = {0066-4227}, mesh = {Anaerobiosis ; Animals ; Biological Evolution ; Decarboxylation ; Electron Transport ; *Energy Metabolism ; Eukaryota/*metabolism ; Glycolysis ; Mitochondria/metabolism ; Pyruvates/metabolism ; }, } @article {pmid3555260, year = {1986}, author = {Coleman, PS}, title = {Membrane cholesterol and tumor bioenergetics.}, journal = {Annals of the New York Academy of Sciences}, volume = {488}, number = {}, pages = {451-467}, doi = {10.1111/j.1749-6632.1986.tb46578.x}, pmid = {3555260}, issn = {0077-8923}, support = {CA28677/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Cholesterol/*metabolism ; Citrates/metabolism ; Citric Acid ; Citric Acid Cycle ; *Energy Metabolism ; Liver Neoplasms, Experimental/*metabolism ; Membrane Lipids/*metabolism ; Mitochondria, Liver/metabolism ; Rats ; }, abstract = {We have established that a preferential export of pyruvate-generated citrate occurs from cholesterol-rich tumor mitochondria, with both isolated mitochondrial systems as well as with viable tumor tissue slices (i.e., with whole tumors cells). Furthermore, we have demonstrated that the more rapid citrate efflux kinetics (catalyzed by the tricarboxylate exchange carrier) of isolated tumor mitochondria is completely inhibited upon addition of 1,2,3-benzenetricarboxylate (BTC) and have shown that this inhibition is apparently also obtained in viable tumor tissue when the inhibitor is added to the tissue incubation. Upon BTC inhibition of tumor mitochondrial citrate export in viable tumor tissue incubations, the incorporation of [14C]pyruvate into newly synthesized cholesterol is severely inhibited as well. Among the most interesting conclusions drawn from our results, we catalog the following. The preferential export of citrate from isolated tumor mitochondria appears to be coupled, functionally, to a high linear rate of incorporation of 14C from pyruvate to cholesterol in viable tumor tissue slices, simultaneously supporting the postulate of a truncated Krebs cycle and corroborating the well-established deregulated and continuous cholesterogenesis pathway in tumors, especially hepatomas. The extent of [14C]pyruvate flux to newly generated cholesterol in either tumor or normal liver tissue is inversely related to the extent of 14CO2 production. Despite the evolution of some CO2 during cholesterogenesis, the predominant portion presumably arises via metabolic processing of pyruvate-generated citrate during Krebs cycle-linked respiration. Isolated tumor mitochondrial systems, as well as viable tumor tissue incubations, can manifest a reversal in the pattern of enhanced mitochondrial citrate efflux coupled to increased cholesterogenesis, when BTC is added to the system. This implies that BTC, a hydrophobic but negatively charged moiety at pH 7, can indeed penetrate the plasma membrane of cells. Upon entry into the cell, BTC apparently blocks the tricarboxylate carrier of tumor tissue mitochondria, thus forcing the mitochondrial citrate into Krebs cycle-linked respiration rather than permitting it to serve as the predominant provider of an increased supply of cytosolic acetyl CoA precursor required for deregulated cholesterogenesis during the development of the tumor.}, } @article {pmid3908651, year = {1985}, author = {Enoki, Y}, title = {[Physiological mechanisms for effective utilization of ambient oxygen--with a special relevance to its phylogenetic aspects and exercise].}, journal = {Nihon seirigaku zasshi. Journal of the Physiological Society of Japan}, volume = {47}, number = {7}, pages = {268-278}, pmid = {3908651}, issn = {0031-9341}, mesh = {Adenosine Triphosphate/biosynthesis ; Animals ; Biological Evolution ; Capillaries/anatomy & histology ; Cats ; Dogs ; Energy Metabolism ; Erythrocytes/metabolism ; Fishes ; Guinea Pigs ; Hemoglobins/metabolism/physiology ; Mice ; Microcirculation ; Mitochondria/metabolism/ultrastructure ; Muscles/blood supply ; Myoglobin/physiology ; Oxygen/blood/*physiology ; Rabbits ; Rats ; Reptiles ; }, } @article {pmid6521672, year = {1984}, author = {Setälä, K}, title = {Carcinogenesis--devolution towards an ancient nucleated pre-eukaryotic level.}, journal = {Medical hypotheses}, volume = {15}, number = {3}, pages = {209-230}, doi = {10.1016/0306-9877(84)90015-x}, pmid = {6521672}, issn = {0306-9877}, mesh = {Animals ; Biological Evolution ; Carcinogens/pharmacology ; Cell Differentiation ; Energy Metabolism ; Eukaryotic Cells/physiology ; Humans ; Mice ; Mitochondria/*physiology ; Mitosis ; Neoplasms/*pathology/physiopathology ; Precancerous Conditions/pathology ; Skin/drug effects ; Skin Neoplasms/etiology/pathology ; Water ; }, abstract = {Because the mitochondria and the cells housing them are obligatory symbionts, the evolutionary history of cells forms the locus minoris resistentiae which is the prerequisite for the carcinogenetic process. During carcinogenesis, the cells devolve towards an ancient anaerobic nucleated pre-eukaryotic level. True carcinogens cause an accumulation of inclusion bodies in the inner, bacterial, mitochondrial membrane. The mitochondrial damage which is detectable only in the early pretumorous stages, results in the respiratory surface with its enzymes being specifically changed, the mitochondrial and nuclear cycles no longer coinciding, the energy generation being forced to reuse the latent, "prehistoric", mode of respiration and the mitochondrial enzyme systems of soil bacterial origin becoming adapted to use other and more versatile metabolic pathways with a wider variety of end-products than classical glycolysis which produces lactate only. Neither external carcinogens nor oncogens are necessary. An increased, prolonged cell replication activity of physiological type is sufficient to initiate and maintain the process in animals with an inherited neoplastic disposition located in the inner mitochondrial membrane. The neoplastic disposition is inherited maternally: in fertilization the ovum does not receive mitochondria from the spermatocyte. The final results are an overall retardation of cell processes and instability in its structural and functional repertoire, the cytoskeleton (differentiation organelle) of the malignant cell manifesting special patterns. The proposed devolutionary mechanism is feasible as DNA packages are physiological components of soil bacterial membrane and can remain dormant (repressed) for years, or for ever, but under suitable conditions can generate seemingly new species, and particularly because enzyme adaptability is the unique privilege of soil bacteria.}, } @article {pmid7272468, year = {1981}, author = {Schiff, JA}, title = {Evolution of the control of pigment and plastid development in photosynthetic organisms.}, journal = {Bio Systems}, volume = {14}, number = {1}, pages = {123-147}, doi = {10.1016/0303-2647(81)90027-7}, pmid = {7272468}, issn = {0303-2647}, support = {GM14595/GM/NIGMS NIH HHS/United States ; }, mesh = {*Biological Evolution ; Chloroplasts/*metabolism ; Darkness ; Energy Metabolism ; Light ; Mitochondria/metabolism ; *Photosynthesis ; Pigments, Biological/*metabolism ; Plants/*metabolism ; Species Specificity ; }, abstract = {How do bioenergetic organelles relate to the cells they are in and how was this relationship established over the course of evolution? Plastids and mitochondria are viewed as prokaryotic residents in eukaryotic cells. These organelles are semiautonomous: they perpetuate themselves by division but regulate and are subject to regulation by the cell in which they are residents. Although these organelles are usually constitutive, their development is arrested in certain organisms when an inducing substrate is absent (light, for example, in the case of the chloroplast) with the formation of precursor organelles such as proplastids. Various trends in the evolution of photo-control systems are discussed including those concerned with photoperception and photomorphogenesis. The photocontrol of chloroplast development by blue and red light is discussed in relation to its possible evolutionary origins in a system for finding the right light for photosynthesis. Models for various types of cellular regulation by light during chloroplast development are discussed. Also considered is the evolution of plastid pigments in response to available light. A parallel evolution of accessory pigments and chlorophylls is suggested which led to chlorophyll reaction centers serving as energy sinks for light absorbed by accessory pigments and, therefore, having their absorptions pushed to the longest possible wavelengths as accessory pigments evolved to fill the middle of the spectrum in response to ecological selection. An endosymbiotic origin of bioenergetic organelles is suggested based on polyphyletic origins of chloroplasts from a number of oxygenic procaryotic precursors. The similarity between proplastids and these oxygenic procaryotes suggests that the original invading organelle may have resembled a modern proplastid rather than a mature chloroplast.}, } @article {pmid6268221, year = {1981}, author = {Harris, DA}, title = {The coupling ATPase complex: an evolutionary view.}, journal = {Bio Systems}, volume = {14}, number = {1}, pages = {113-121}, doi = {10.1016/0303-2647(81)90026-5}, pmid = {6268221}, issn = {0303-2647}, mesh = {Adenosine Triphosphatases/*metabolism ; Amino Acid Sequence ; Bacteria/metabolism ; *Biological Evolution ; Energy Metabolism ; Ion Channels/metabolism ; Mitochondria/metabolism ; Oxidative Phosphorylation Coupling Factors/*metabolism ; Proton-Translocating ATPases/*metabolism ; Saccharomyces cerevisiae/enzymology ; }, abstract = {Phospholipid micelles and vesicles, present in the primordial soup, formed both primitive (surface) catalyst and primitive replicative life forms. With the adoption of a common energy source, ATP, integrated biochemical systems within these vesicles became possible - cells. Fermentation within these primitive cells was favoured by the evolution, first of ion channels allowing protons to leak out, and then of an active ATP-driven pump. In the prokaryotic/mitochondria/chloroplast line, the proton channel was such as to be blocked by dicyclohexylcarbodiimide and the adenosine 5' triphosphate phosphohydrolase (ATPase) by 4-chloro 7-nitrobenzofurazan (Nbf-C1). The ATPase was initially simple (4 subunits) but later, possibly concomitant with its evolution to an ATP synthetase, became more complex (8 subunits). One of the steps in evolution probably involved gene duplication and divergence of 2 subunits (alpha and beta) from the largest of the ATPase subunits. From this stage, the general form of the ATPase was fixed, although sensitivity to, for example, oligomycin involved later, after divergence of the mitochondrial and chloroplast lines. A regulatory protein, the ATPase inhibitor, is found associated with a wide spectrum of coupling ATPases.}, } @article {pmid6264827, year = {1981}, author = {Whatley, FR}, title = {The establishment of mitochondria: Paracoccus and Rhodopseudomonas.}, journal = {Annals of the New York Academy of Sciences}, volume = {361}, number = {}, pages = {330-340}, doi = {10.1111/j.1749-6632.1981.tb46529.x}, pmid = {6264827}, issn = {0077-8923}, mesh = {Biological Evolution ; Cytochrome c Group/metabolism ; Electron Transport ; *Mitochondria/metabolism ; *Paracoccus/metabolism ; *Rhodobacter sphaeroides/metabolism ; *Symbiosis ; }, abstract = {Many aerobic bacteria (both facultative and obligate) possess a number of those biochemical features of mitochondria which are concerned with energy metabolism. However, only restricted number, notably Paracoccus denitrificans and Rhodopseudomonas spheroides, have the majority of these features. The theory of endosymbiosis proposes that a primitive eukaryote took up bacteria to yield mitochondria. The present-day Paracoccus then resembles the ancestral bacterium in many respects the primitive amoeba, Pelomyxa palustris, which lacks mitochondria but contains a permanent population of unique symbiotic bacteria, has many of the characteristics of a present-day transitional form. The evolution of mitochondria from endosymbiotic bacteria would involve their integration with the host cell both biochemically and structurally: a number of the intermediate steps are discussed. Attention is drawn to the existence in some ciliates of hydrogenosomes, which function as anaerobic mitochondria.}, } @article {pmid6453255, year = {1980}, author = {Wilson, TH and Lin, EC}, title = {Evolution of membrane bioenergetics.}, journal = {Journal of supramolecular structure}, volume = {13}, number = {4}, pages = {421-446}, doi = {10.1002/jss.400130403}, pmid = {6453255}, issn = {0091-7419}, support = {AM-05736/AM/NIADDK NIH HHS/United States ; GM-11983/GM/NIGMS NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Bacteria/metabolism ; *Biological Evolution ; Biological Transport ; Cell Membrane/*metabolism ; DNA/metabolism ; Energy Metabolism ; Hydrogen-Ion Concentration ; Mitochondria/metabolism ; Oxidation-Reduction ; Photosynthesis ; Plants/metabolism ; Potassium/metabolism ; Sodium/metabolism ; Vertebrates ; }, abstract = {One of the first problems encountered by primitive cells was that of volume regulation; the continuous entry of ions, (eg, NaCl) and water in response to the internal colloid osmotic pressure threatening to destroy the cell by lysis. We propose that to meet this environmental challenge cells evolved an ATP-driven proton extrusion system plus a membrane carrier that would exchange external protons with internal Na+. With the appearance of the ability to generate proton gradients, additional mechanisms to harness this source of energy emerged. These would include proton-nutrient cotransport, K+ accumulation, nucleic acid entry, and motility. A more efficient system for the uptake of certain carbohydrates by vectorial phosphorylation via the PEP-phosphotransferase system probably appeared rather early in the evolution of anaerobic bacteria. The reversal of the proton-ATPase reaction to give net ATP synthesis became possible with the development of other types of efficient proton transporting machinery. Either light-driven bacterial rhodopsin or a redox system coupled to proton translocation would have served this function. Oxidation of one substrate coupled to the reduction of another substrate by membrane-bound enzymes evolved in such a manner that protons were extruded from the cell during the reaction. The progressive elaboration of this type of redox proton pump permitted the use of exogenous electron acceptors, such as fumarate, sulfate, and nitrate. The stepwise growth of these electron transport chains required the accretion of several flavoproteins, iron-sulfur proteins, quinones, and cytochromes. With modifications of these four basic components a chlorophyll-dependent photosynthetic system was subsequently evolved. The oxygen that was generated by this photosynthetic system from water would eventually accumulate in the atmosphere of the earth. With molecular oxygen present, the emergence of cytochrome oxidase would complete the respiratory chain. The proton economy of membrane energetics has been retained by most present-day microorganisms, mitochondria, chloroplasts, and cells of higher plants. A secondary use of the energy stored as an electrochemical difference of Na+ for powering membrane events probably also evolved in microorganisms. The exclusive age of the Na+ economy is distinctive of the plasma membrane of animal cells; the Na+-K+ ATPase sets up an electrochemical Na+ gradient that provides the energy for osmoregulation, Na+-nutrient co-transport, and the action potential of excitable cells.}, } @article {pmid113918, year = {1979}, author = {Pinevich, AV and Desnitskiĭ, AG}, title = {[Evolutionary origin of cell organelles].}, journal = {Tsitologiia}, volume = {21}, number = {7}, pages = {755-767}, pmid = {113918}, issn = {0041-3771}, mesh = {Aerobiosis ; Anaerobiosis ; *Biological Evolution ; Cell Compartmentation ; Chloroplasts/metabolism ; Clone Cells/ultrastructure ; Cyanobacteria/metabolism ; Cytogenetics ; Energy Metabolism ; Eukaryotic Cells/ultrastructure ; Mitochondria/metabolism ; Organoids/physiology/*ultrastructure ; Oxygen Consumption ; Phenotype ; Photosynthesis ; Phylogeny ; Symbiosis ; }, abstract = {A review on the evolutionary origin of the energy-yielding eukaryotic organelles is presented. Current autogenetic (endogenous compartmentalization) schemes, as well as different variants of symbiogenesis, are critically envisaged. A new symbiogenetic scheme is put forth, according to which mitochondria and chloroplasts originated divergently from a primordial photosynthetic organelle; the latter was acquired by endosymbiosis of ancient cyanobacteria in the cells of protoeukaryotes.}, } @article {pmid274302, year = {1978}, author = {Cannon, B and Nedergaard, J}, title = {Energy dissipation in brown fat.}, journal = {Experientia. Supplementum}, volume = {32}, number = {}, pages = {107-111}, doi = {10.1007/978-3-0348-5559-4_12}, pmid = {274302}, issn = {0071-335X}, mesh = {Adenosine Triphosphate/biosynthesis ; Adipose Tissue, Brown/drug effects/*metabolism/ultrastructure ; Amino Acids/biosynthesis ; Animals ; Carbon Dioxide/pharmacology ; Citric Acid Cycle ; Cricetinae ; *Energy Metabolism/drug effects ; Fatty Acids/metabolism ; In Vitro Techniques ; Mitochondria/metabolism ; Norepinephrine/pharmacology ; Oxygen Consumption/drug effects ; }, abstract = {Heat evolution in isolated brown fat cells has been measured by microcalorimetry. Thermogenesis (= oxygen consumption) is enhanced in the presence of CO2. This effect is probably due to pyruvate carboxylase activity which will increase the mitochondrial concentration of oxaloacetate. Oxaloacetate serves as condensing partner for acetyl-CoA coming from fatty acid oxidation. The high rate of oxygen consumption is impossible in cells when mitochondrial respiration is coupled to ATP synthesis, due to low amounts of ATP synthetase enzyme. A loosening of coupling is therefore required. This is possibly facilitated by acyl-CoA.}, } @article {pmid1041247, year = {1975}, author = {}, title = {Mitochondria, chloroplasts, and energy transfer: a discussion.}, journal = {Ciba Foundation symposium}, volume = {}, number = {31}, pages = {63-68}, pmid = {1041247}, issn = {0300-5208}, mesh = {Adenosine Triphosphate/metabolism ; Bacteria/metabolism ; Biological Evolution ; Biological Transport, Active ; Chloroplasts/*metabolism ; Cytosol/metabolism ; Energy Metabolism ; Energy Transfer ; Enzyme Induction ; Ions/metabolism ; Membranes/metabolism ; Mitochondria/*metabolism ; Oxidative Phosphorylation ; Oxygen/pharmacology ; Photosynthesis ; }, } @article {pmid125189, year = {1975}, author = {Lipmann, F}, title = {The roots of bioenergetics.}, journal = {Ciba Foundation symposium}, volume = {}, number = {31}, pages = {3-22}, doi = {10.1002/9780470720134.ch2}, pmid = {125189}, issn = {0300-5208}, mesh = {Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Biochemistry/*history ; Biological Evolution ; Creatine/metabolism ; Cytochromes/metabolism ; *Energy Metabolism ; Fermentation ; Flavoproteins/metabolism ; Fructosephosphates/metabolism ; Glyceric Acids/metabolism ; Glycolysis ; History, 20th Century ; Membrane Potentials ; Microscopy, Electron ; Mitochondria/ultrastructure ; Muscle Contraction ; Myosin Subfragments/metabolism ; Nucleotides/metabolism ; Oxidative Phosphorylation ; Phosphates/metabolism ; Photophosphorylation ; Pyridines/metabolism ; Pyruvates/metabolism ; Thermodynamics ; }, abstract = {Understanding metabolic energy transformation began with the realization of an 'intrusion' of phosphate into the mechanism of alcoholic fermentation. The discovery of an analogous participation of phosphate in muscle glycolysis connected the metabolic generation of energy-rich phosphate bonds fed into a common transmitter, adenosine triphosphate (ATP), with the production of mechanical energy through the finding that the phosphoryl group of creatine phosphate transferred to ATP could supply the energy for muscle contraction. In this way, a functional applicability of the energy of the phosphate bond was first shown. This observation was soon followed by the recognition that the phosphoanhydride bond of ATP provided the driving force in biosynthetic reactions; in this type of bond, metabolic energy apparently collects before it is transmitted for functional and biosynthetic use. The storage of energy in ATP was first detected in anaerobic energy-yielding reactions but soon was also found in respiratory and photosynthetic energy production. However, the mechanism by which energy derived from metabolites was converted into phosphate-bond energy in the latter processes appeared to differ from that of anaerobic energy transmission. Whereas phosphorylated compounds mediate the latter in homogeneous solutions, aerobic phosphorylation and photophosphorylation in prokaryotes seem to require special submembranous structures; and in eukaryotes, energy conversion is a function of special organelles, the mitochondria and chloroplasts. The evolutionary aspects of the transition from prokaryotes to eukaryotes are of considerable interest. In conclusion, the relevance of an apparent prokaryotic origin of the energy-transforming organelles in the eukaryotes will be commented on.}, }