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Bibliography on: Energetics and Mitochondrial Evolution

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ESP: PubMed Auto Bibliography 17 Sep 2020 at 01:55 Created: 

Energetics and Mitochondrial Evolution

Mitochondria are the energy-producing "engines" that provide the power to drive eukaryotic cells. The energy output of hundreds, or thousands, of mitochondria allowed eukaryotic cells to increase in size 1000-fold, or more, over the size of prokaryotics cells. This increase in size allowed an escape from the constraints of low Reynolds numbers and, for the first time, life could function in a way where mechanism, and thus morphology, mattered. Evolution began to shape morphology, allowing the emergence of the multicellular eukaryotic biosphere — the visible living world.

Created with PubMed® Query: mitochondria AND evolution AND (energetics OR "energy metabolism") NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2020-07-25

Cunnane SC, Trushina E, Morland C, et al (2020)

Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.

Nature reviews. Drug discovery pii:10.1038/s41573-020-0072-x [Epub ahead of print].

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.

RevDate: 2020-06-16
CmpDate: 2020-06-16

Aw WC, Garvin MR, JWO Ballard (2019)

Exogenous Factors May Differentially Influence the Selective Costs of mtDNA Mutations.

Advances in anatomy, embryology, and cell biology, 231:51-74.

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.

RevDate: 2020-05-25
CmpDate: 2020-05-25

Guièze R, Liu VM, Rosebrock D, et al (2019)

Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies.

Cancer cell, 36(4):369-384.e13.

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.

RevDate: 2020-05-12

Seebacher F (2020)

Is Endothermy an Evolutionary By-Product?.

Trends in ecology & evolution, 35(6):503-511.

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.

RevDate: 2020-05-10

Gangloff EJ, Schwartz TS, Klabacka R, et al (2020)

Mitochondria as central characters in a complex narrative: Linking genomics, energetics, and pace-of-life in natural populations of garter snakes.

Experimental gerontology pii:S0531-5565(20)30315-6 [Epub ahead of print].

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 divergent 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.

RevDate: 2020-05-06

Scorziello A, Borzacchiello D, Sisalli MJ, et al (2020)

Mitochondrial Homeostasis and Signaling in Parkinson's Disease.

Frontiers in aging neuroscience, 12:100.

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.

RevDate: 2020-04-20
CmpDate: 2020-04-20

Arnedo M, Latorre-Pellicer A, Lucia-Campos C, et al (2019)

More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones.

International journal of molecular sciences, 20(24):.

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.

RevDate: 2020-03-30
CmpDate: 2020-03-30

Tsakiri EN, Gumeni S, Iliaki KK, et al (2019)

Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation.

Aging cell, 18(1):e12845.

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.

RevDate: 2020-03-26
CmpDate: 2020-03-26

Poljsak B, Kovac V, Dahmane R, et al (2019)

Cancer Etiology: A Metabolic Disease Originating from Life's Major Evolutionary Transition?.

Oxidative medicine and cellular longevity, 2019:7831952.

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.

RevDate: 2020-03-12
CmpDate: 2020-03-12

Liu Y, Qu J, Zhang L, et al (2019)

Identification and characterization of the TCA cycle genes in maize.

BMC plant biology, 19(1):592.

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.

RevDate: 2020-02-27
CmpDate: 2020-02-27

Broddrick JT, Du N, Smith SR, et al (2019)

Cross-compartment metabolic coupling enables flexible photoprotective mechanisms in the diatom Phaeodactylum tricornutum.

The New phytologist, 222(3):1364-1379.

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.

RevDate: 2020-02-10
CmpDate: 2020-02-10

Montooth KL, Dhawanjewar AS, CD Meiklejohn (2019)

Temperature-Sensitive Reproduction and the Physiological and Evolutionary Potential for Mother's Curse.

Integrative and comparative biology, 59(4):890-899.

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.

RevDate: 2020-01-17

Chevigny N, Schatz-Daas D, Lotfi F, et al (2020)

DNA Repair and the Stability of the Plant Mitochondrial Genome.

International journal of molecular sciences, 21(1): pii:ijms21010328.

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.

RevDate: 2019-12-17
CmpDate: 2019-12-16

Hampl V, Čepička I, M Eliáš (2019)

Was the Mitochondrion Necessary to Start Eukaryogenesis?.

Trends in microbiology, 27(2):96-104.

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.

RevDate: 2019-12-02

Camus MF, O'Leary M, Reuter M, et al (2020)

Impact of mitonuclear interactions on life-history responses to diet.

Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 375(1790):20190416.

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 (w1118 (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'.

RevDate: 2019-09-29

Yang M, Gong L, Sui J, et al (2019)

The complete mitochondrial genome of Calyptogena marissinica (Heterodonta: Veneroida: Vesicomyidae): Insight into the deep-sea adaptive evolution of vesicomyids.

PloS one, 14(9):e0217952 pii:PONE-D-19-14328.

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.

RevDate: 2019-09-17
CmpDate: 2019-09-17

Soggiu A, Roncada P, Bonizzi L, et al (2019)

Role of Mitochondria in Host-Pathogen Interaction.

Advances in experimental medicine and biology, 1158:45-57.

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.

RevDate: 2019-09-10

Gould SB, Garg SG, Handrich M, et al (2019)

Adaptation to life on land at high O2 via transition from ferredoxin-to NADH-dependent redox balance.

Proceedings. Biological sciences, 286(1909):20191491.

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.

RevDate: 2019-08-08

Ngatia JN, Lan TM, Dinh TD, et al (2019)

Signals of positive selection in mitochondrial protein-coding genes of woolly mammoth: Adaptation to extreme environments?.

Ecology and evolution, 9(12):6821-6832 pii:ECE35250.

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.

RevDate: 2019-10-08
CmpDate: 2019-10-08

Gerlitz M, Knopp M, Kapust N, et al (2018)

Elusive data underlying debate at the prokaryote-eukaryote divide.

Biology direct, 13(1):21 pii:10.1186/s13062-018-0221-x.

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.

RevDate: 2019-06-25

Reis LMD, Adamoski D, Ornitz Oliveira Souza R, et al (2019)

Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells.

The Journal of biological chemistry, 294(24):9342-9357.

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.

RevDate: 2019-11-22

Zimorski V, Mentel M, Tielens AGM, et al (2019)

Energy metabolism in anaerobic eukaryotes and Earth's late oxygenation.

Free radical biology & medicine, 140:279-294.

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.

RevDate: 2019-04-23
CmpDate: 2019-04-23

Vays VB, Vangeli IM, Eldarov CM, et al (2019)

Mitochondria in Obliquely Striated Muscles of the Horsehair Worm Gordionus alpestris (Nematomorpha, Gordioidea) with Structural Organization Typical of Cells with Energy-Intensive Processes.

Biochemistry. Biokhimiia, 84(1):56-61.

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.

RevDate: 2019-06-13
CmpDate: 2019-06-13

Shin MK, JH Cheong (2019)

Mitochondria-centric bioenergetic characteristics in cancer stem-like cells.

Archives of pharmacal research, 42(2):113-127.

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.

RevDate: 2019-11-08
CmpDate: 2019-07-17

Lynch M, GK Marinov (2018)

Response to Martin and colleagues: mitochondria do not boost the bioenergetic capacity of eukaryotic cells.

Biology direct, 13(1):26.

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.

RevDate: 2019-11-08
CmpDate: 2019-11-08

Xie B, Wang S, Jiang N, et al (2019)

Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance.

Cancer letters, 443:56-66.

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.

RevDate: 2019-03-11
CmpDate: 2019-03-11

Hood WR, Austad SN, Bize P, et al (2018)

The Mitochondrial Contribution to Animal Performance, Adaptation, and Life-History Variation.

Integrative and comparative biology, 58(3):480-485.

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.

RevDate: 2019-05-01
CmpDate: 2019-02-25

Pustylnikov S, Costabile F, Beghi S, et al (2018)

Targeting mitochondria in cancer: current concepts and immunotherapy approaches.

Translational research : the journal of laboratory and clinical medicine, 202:35-51.

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.

RevDate: 2019-02-15
CmpDate: 2019-02-04

Río Bártulos C, Rogers MB, Williams TA, et al (2018)

Mitochondrial Glycolysis in a Major Lineage of Eukaryotes.

Genome biology and evolution, 10(9):2310-2325.

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.

RevDate: 2019-05-06
CmpDate: 2019-05-06

Salunke R, Mourier T, Banerjee M, et al (2018)

Highly diverged novel subunit composition of apicomplexan F-type ATP synthase identified from Toxoplasma gondii.

PLoS biology, 16(7):e2006128.

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.

RevDate: 2019-05-13
CmpDate: 2019-05-13

Kasperski A, R Kasperska (2018)

Bioenergetics of life, disease and death phenomena.

Theory in biosciences = Theorie in den Biowissenschaften, 137(2):155-168.

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.

RevDate: 2019-04-01
CmpDate: 2019-04-01

Rolland N, Bouchnak I, Moyet L, et al (2018)

The Main Functions of Plastids.

Methods in molecular biology (Clifton, N.J.), 1829:73-85.

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.

RevDate: 2019-02-16
CmpDate: 2018-08-24

Bilz NC, Jahn K, Lorenz M, et al (2018)

Rubella Viruses Shift Cellular Bioenergetics to a More Oxidative and Glycolytic Phenotype with a Strain-Specific Requirement for Glutamine.

Journal of virology, 92(17):.

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.

RevDate: 2019-03-11
CmpDate: 2019-03-11

Buchanan JL, Meiklejohn CD, KL Montooth (2018)

Mitochondrial Dysfunction and Infection Generate Immunity-Fecundity Tradeoffs in Drosophila.

Integrative and comparative biology, 58(3):591-603.

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.

RevDate: 2018-11-14
CmpDate: 2018-10-30

Liu W, Hu C, Xie W, et al (2018)

The mitochondrial genome of red-necked phalarope Phalaropus lobatus (Charadriiformes: Scolopacidae) and phylogeny analysis among Scolopacidae.

Genes & genomics, 40(5):455-463.

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.

RevDate: 2019-03-11
CmpDate: 2019-03-11

Scott GR, Guo KH, NJ Dawson (2018)

The Mitochondrial Basis for Adaptive Variation in Aerobic Performance in High-Altitude Deer Mice.

Integrative and comparative biology, 58(3):506-518.

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.

RevDate: 2018-12-18
CmpDate: 2018-12-18

Darbani B, Kell DB, I Borodina (2018)

Energetic evolution of cellular Transportomes.

BMC genomics, 19(1):418.

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.

RevDate: 2018-12-11
CmpDate: 2018-12-11

van der Hoek MD, Madsen O, Keijer J, et al (2018)

Evolutionary analysis of the carnitine- and choline acyltransferases suggests distinct evolution of CPT2 versus CPT1 and related variants.

Biochimica et biophysica acta. Molecular and cell biology of lipids, 1863(8):909-918.

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.

RevDate: 2019-01-24
CmpDate: 2018-08-27

Mansilla N, Racca S, Gras DE, et al (2018)

The Complexity of Mitochondrial Complex IV: An Update of Cytochrome c Oxidase Biogenesis in Plants.

International journal of molecular sciences, 19(3):.

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.

RevDate: 2019-06-26
CmpDate: 2019-06-26

Yu H, Wang D, Zou L, et al (2018)

Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: implication for Alzheimer's disease.

Archives of toxicology, 92(4):1363-1382.

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.

RevDate: 2019-02-15
CmpDate: 2019-02-15

Lane N (2018)

Hot mitochondria?.

PLoS biology, 16(1):e2005113.

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.

RevDate: 2018-03-08
CmpDate: 2017-12-25

Dickerson T, Jauregui CE, Y Teng (2017)

Friend or foe? Mitochondria as a pharmacological target in cancer treatment.

Future medicinal chemistry, 9(18):2197-2210.

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.

RevDate: 2018-08-15
CmpDate: 2018-08-15

McDonald AE, Pichaud N, CA Darveau (2018)

"Alternative" fuels contributing to mitochondrial electron transport: Importance of non-classical pathways in the diversity of animal metabolism.

Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology, 224:185-194.

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.

RevDate: 2019-01-24
CmpDate: 2019-01-24

Sun S, Hui M, Wang M, et al (2018)

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.

Comparative biochemistry and physiology. Part D, Genomics & proteomics, 25:42-52.

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.

RevDate: 2019-11-20

Dobson GP, Arsyad A, HL Letson (2017)

The Adenosine Hypothesis Revisited: Modulation of Coupling between Myocardial Perfusion and Arterial Compliance.

Frontiers in physiology, 8:824.

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.

RevDate: 2018-10-10
CmpDate: 2018-07-05

Bombaça ACS, Dias FA, Ennes-Vidal V, et al (2017)

Hydrogen peroxide resistance in Strigomonas culicis: Effects on mitochondrial functionality and Aedes aegypti interaction.

Free radical biology & medicine, 113:255-266.

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.

RevDate: 2019-11-20

Wiens L, Banh S, Sotiri E, et al (2017)

Comparison of Mitochondrial Reactive Oxygen Species Production of Ectothermic and Endothermic Fish Muscle.

Frontiers in physiology, 8:704.

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.

RevDate: 2018-09-17
CmpDate: 2018-02-08

Chaturvedi D, R Mahalakshmi (2017)

Transmembrane β-barrels: Evolution, folding and energetics.

Biochimica et biophysica acta. Biomembranes, 1859(12):2467-2482.

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.

RevDate: 2019-01-18
CmpDate: 2017-12-22

Dunn CD (2017)

Some Liked It Hot: A Hypothesis Regarding Establishment of the Proto-Mitochondrial Endosymbiont During Eukaryogenesis.

Journal of molecular evolution, 85(3-4):99-106.

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.

RevDate: 2018-11-13
CmpDate: 2017-12-21

Rauch C, Christa G, de Vries J, et al (2017)

Mitochondrial Genome Assemblies of Elysia timida and Elysia cornigera and the Response of Mitochondrion-Associated Metabolism during Starvation.

Genome biology and evolution, 9(7):1873-1879.

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.

RevDate: 2018-11-13
CmpDate: 2018-05-03

Hikmat O, Eichele T, Tzoulis C, et al (2017)

Understanding the Epilepsy in POLG Related Disease.

International journal of molecular sciences, 18(9):.

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.

RevDate: 2018-11-13
CmpDate: 2018-01-31

Zachar I, E Szathmáry (2017)

Breath-giving cooperation: critical review of origin of mitochondria hypotheses : Major unanswered questions point to the importance of early ecology.

Biology direct, 12(1):19.

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.

RevDate: 2018-11-13
CmpDate: 2018-04-17

Lai YC, Baker JS, Donti T, et al (2017)

Mitochondrial Dysfunction Mediated by Poly(ADP-Ribose) Polymerase-1 Activation Contributes to Hippocampal Neuronal Damage Following Status Epilepticus.

International journal of molecular sciences, 18(7):.

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.

RevDate: 2018-11-13
CmpDate: 2018-05-07

Brandt T, Mourier A, Tain LS, et al (2017)

Changes of mitochondrial ultrastructure and function during ageing in mice and Drosophila.

eLife, 6:.

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.

RevDate: 2019-11-20

Zhang B, Zhang YH, Wang X, et al (2017)

The mitochondrial genome of a sea anemone Bolocera sp. exhibits novel genetic structures potentially involved in adaptation to the deep-sea environment.

Ecology and evolution, 7(13):4951-4962.

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.

RevDate: 2019-01-18
CmpDate: 2019-01-18

Wang J, Xiang H, Liu L, et al (2017)

Mitochondrial haplotypes influence metabolic traits across bovine inter- and intra-species cybrids.

Scientific reports, 7(1):4179.

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.

RevDate: 2019-01-16
CmpDate: 2018-04-05

Martin WF, Tielens AGM, Mentel M, et al (2017)

The Physiology of Phagocytosis in the Context of Mitochondrial Origin.

Microbiology and molecular biology reviews : MMBR, 81(3):.

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.

RevDate: 2017-09-12
CmpDate: 2017-09-12

Sharma K (2017)

Mitochondrial Dysfunction in the Diabetic Kidney.

Advances in experimental medicine and biology, 982:553-562.

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.

RevDate: 2019-03-29
CmpDate: 2018-05-14

Horscroft JA, Kotwica AO, Laner V, et al (2017)

Metabolic basis to Sherpa altitude adaptation.

Proceedings of the National Academy of Sciences of the United States of America, 114(24):6382-6387.

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.

RevDate: 2019-01-02
CmpDate: 2018-06-13

Lane N (2017)

Serial endosymbiosis or singular event at the origin of eukaryotes?.

Journal of theoretical biology, 434:58-67.

'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.

RevDate: 2018-09-17
CmpDate: 2017-09-26

Yin Q, Zhang Y, Dong D, et al (2017)

Maintenance of neural activities in torpid Rhinolophus ferrumequinum bats revealed by 2D gel-based proteome analysis.

Biochimica et biophysica acta. Proteins and proteomics, 1865(8):1004-1019.

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.

RevDate: 2018-12-02
CmpDate: 2017-12-29

Du SNN, Khajali F, Dawson NJ, et al (2017)

Hybridization increases mitochondrial production of reactive oxygen species in sunfish.

Evolution; international journal of organic evolution, 71(6):1643-1652.

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.

RevDate: 2017-10-24
CmpDate: 2017-10-24

Zimorski V, Rauch C, van Hellemond JJ, et al (2017)

The Mitochondrion of Euglena gracilis.

Advances in experimental medicine and biology, 979:19-37.

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.

RevDate: 2018-11-13
CmpDate: 2017-06-29

Devarshi PP, McNabney SM, TM Henagan (2017)

Skeletal Muscle Nucleo-Mitochondrial Crosstalk in Obesity and Type 2 Diabetes.

International journal of molecular sciences, 18(4):.

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.

RevDate: 2018-06-13
CmpDate: 2018-06-13

Schönfeld P, G Reiser (2017)

Brain energy metabolism spurns fatty acids as fuel due to their inherent mitotoxicity and potential capacity to unleash neurodegeneration.

Neurochemistry international, 109:68-77.

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.

RevDate: 2018-11-13
CmpDate: 2018-09-21

Roberts RG (2017)

Mitochondria-A billion years of cohabitation.

PLoS biology, 15(3):e2002338.

RevDate: 2019-11-20

Karnkowska A, V Hampl (2016)

The curious case of vanishing mitochondria.

Microbial cell (Graz, Austria), 3(10):491-494.

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.

RevDate: 2018-11-13
CmpDate: 2018-01-08

Lynch M, GK Marinov (2017)

Membranes, energetics, and evolution across the prokaryote-eukaryote divide.

eLife, 6:.

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.

RevDate: 2018-11-13
CmpDate: 2017-08-11

Krishnan A, Abdullah TS, Mounajjed T, et al (2017)

A longitudinal study of whole body, tissue, and cellular physiology in a mouse model of fibrosing NASH with high fidelity to the human condition.

American journal of physiology. Gastrointestinal and liver physiology, 312(6):G666-G680.

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.

RevDate: 2017-03-16
CmpDate: 2017-03-16

Ling SS, Zhu Y, Lan D, et al (2017)

Analysis of the cytochrome c oxidase subunit II (COX2) gene in giant panda, Ailuropoda melanoleuca.

Genetics and molecular research : GMR, 16(1): pii:gmr-16-01-gmr.16019158.

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.

RevDate: 2018-09-17
CmpDate: 2017-10-24

Baffy G (2017)

Mitochondrial uncoupling in cancer cells: Liabilities and opportunities.

Biochimica et biophysica acta. Bioenergetics, 1858(8):655-664.

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.

RevDate: 2018-03-09
CmpDate: 2017-11-22

Speijer D (2017)

Alternating terminal electron-acceptors at the basis of symbiogenesis: How oxygen ignited eukaryotic evolution.

BioEssays : news and reviews in molecular, cellular and developmental biology, 39(2):.

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.

RevDate: 2019-11-20

Faktorová D, Dobáková E, Peña-Diaz P, et al (2016)

From simple to supercomplex: mitochondrial genomes of euglenozoan protists.

F1000Research, 5:.

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.

RevDate: 2018-11-13
CmpDate: 2017-06-14

Liu S, Roellig DM, Guo Y, et al (2016)

Evolution of mitosome metabolism and invasion-related proteins in Cryptosporidium.

BMC genomics, 17(1):1006.

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.

RevDate: 2019-11-20

Malecki M, J Bähler (2016)

Identifying genes required for respiratory growth of fission yeast.

Wellcome open research, 1:12.

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.

RevDate: 2019-10-08
CmpDate: 2017-12-13

Raefsky SM, MP Mattson (2017)

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance.

Free radical biology & medicine, 102:203-216.

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., Ca2+, 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.

RevDate: 2018-02-16
CmpDate: 2018-02-16

Sanchez-Puerta MV, García LE, Wohlfeiler J, et al (2017)

Unparalleled replacement of native mitochondrial genes by foreign homologs in a holoparasitic plant.

The New phytologist, 214(1):376-387.

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.

RevDate: 2018-11-13
CmpDate: 2017-07-10

Malecki M, Bitton DA, Rodríguez-López M, et al (2016)

Functional and regulatory profiling of energy metabolism in fission yeast.

Genome biology, 17(1):240.

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.

RevDate: 2018-04-09
CmpDate: 2017-09-22

Đorđević M, Stojković B, Savković U, et al (2017)

Sex-specific mitonuclear epistasis and the evolution of mitochondrial bioenergetics, ageing, and life history in seed beetles.

Evolution; international journal of organic evolution, 71(2):274-288.

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.

RevDate: 2018-09-17
CmpDate: 2017-11-03

Kadam AA, Jubin T, Mir HA, et al (2017)

Potential role of Apoptosis Inducing Factor in evolutionarily significant eukaryote, Dictyostelium discoideum survival.

Biochimica et biophysica acta. General subjects, 1861(1 Pt A):2942-2955.

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.

RevDate: 2017-11-30
CmpDate: 2017-05-09

Sookoian S, Flichman D, Scian R, et al (2016)

Mitochondrial genome architecture in non-alcoholic fatty liver disease.

The Journal of pathology, 240(4):437-449.

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.

RevDate: 2018-11-13
CmpDate: 2017-07-14

Nunn AV, Guy GW, JD Bell (2016)

The quantum mitochondrion and optimal health.

Biochemical Society transactions, 44(4):1101-1110.

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.

RevDate: 2016-07-28
CmpDate: 2016-08-11

Pennisi E (2016)

EVOLUTIONARY BIOLOGY. Do genomic conflicts drive evolution?.

Science (New York, N.Y.), 353(6297):334-335.

RevDate: 2018-03-08
CmpDate: 2017-10-26

Martin WF, Neukirchen S, Zimorski V, et al (2016)

Energy for two: New archaeal lineages and the origin of mitochondria.

BioEssays : news and reviews in molecular, cellular and developmental biology, 38(9):850-856.

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.

RevDate: 2018-03-16
CmpDate: 2018-01-17

Cardoso S, Carvalho C, Correia SC, et al (2016)

Alzheimer's Disease: From Mitochondrial Perturbations to Mitochondrial Medicine.

Brain pathology (Zurich, Switzerland), 26(5):632-647.

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.

RevDate: 2017-10-04
CmpDate: 2017-10-04

Mesa-Torres N, Calvo AC, Oppici E, et al (2016)

Caenorhabditis elegans AGXT-1 is a mitochondrial and temperature-adapted ortholog of peroxisomal human AGT1: New insights into between-species divergence in glyoxylate metabolism.

Biochimica et biophysica acta, 1864(9):1195-1205.

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.

RevDate: 2016-02-26
CmpDate: 2016-03-14

Hamers L (2016)

EVOLUTION. Why do cells' power plants hang on to their own genomes?.

Science (New York, N.Y.), 351(6276):903.

RevDate: 2016-05-27
CmpDate: 2016-03-03

Ball SG, Bhattacharya D, AP Weber (2016)

EVOLUTION. Pathogen to powerhouse.

Science (New York, N.Y.), 351(6274):659-660.

RevDate: 2018-11-13
CmpDate: 2017-07-12

Kelley JL, Arias-Rodriguez L, Patacsil Martin D, et al (2016)

Mechanisms Underlying Adaptation to Life in Hydrogen Sulfide-Rich Environments.

Molecular biology and evolution, 33(6):1419-1434.

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.

RevDate: 2018-12-02
CmpDate: 2016-06-16

Lane N, WF Martin (2016)

Mitochondria, complexity, and evolutionary deficit spending.

Proceedings of the National Academy of Sciences of the United States of America, 113(6):E666.

RevDate: 2018-11-13
CmpDate: 2016-06-06

Ray S, Kassan A, Busija AR, et al (2016)

The plasma membrane as a capacitor for energy and metabolism.

American journal of physiology. Cell physiology, 310(3):C181-92.

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.

RevDate: 2017-02-17
CmpDate: 2017-02-17

Jaromin E, Wyszkowska J, Labecka AM, et al (2016)

Hindlimb muscle fibre size and glycogen stores in bank voles with increased aerobic exercise metabolism.

The Journal of experimental biology, 219(Pt 4):470-473.

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.

RevDate: 2018-11-13
CmpDate: 2016-08-30

Roussel E, Drolet MC, Walsh-Wilkinson E, et al (2015)

Transcriptional Changes Associated with Long-Term Left Ventricle Volume Overload in Rats: Impact on Enzymes Related to Myocardial Energy Metabolism.

BioMed research international, 2015:949624.

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.

RevDate: 2018-03-13
CmpDate: 2018-01-23

He S, Lu J, Jiang W, et al (2016)

The complete mitochondrial genome sequence of a cavefish Sinocyclocheilus anshuiensis (Cypriniformes: Cyprinidae).

Mitochondrial DNA. Part A, DNA mapping, sequencing, and analysis, 27(6):4256-4258.

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.

RevDate: 2018-12-02
CmpDate: 2017-09-12

Long Z, Zhang X, Sun Q, et al (2017)

Evolution of metabolic disorder in rats fed high sucrose or high fat diet: Focus on redox state and mitochondrial function.

General and comparative endocrinology, 242:92-100.

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.

RevDate: 2018-11-13
CmpDate: 2016-09-26

Garcia-Heredia JM, A Carnero (2015)

Decoding Warburg's hypothesis: tumor-related mutations in the mitochondrial respiratory chain.

Oncotarget, 6(39):41582-41599.

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.

RevDate: 2018-11-13
CmpDate: 2016-05-27

Lopes-Marques M, Delgado IL, Ruivo R, et al (2015)

The Origin and Diversity of Cpt1 Genes in Vertebrate Species.

PloS one, 10(9):e0138447.

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.

RevDate: 2018-11-13
CmpDate: 2016-03-07

Kassa T, Jana S, Strader MB, et al (2015)

Sickle Cell Hemoglobin in the Ferryl State Promotes βCys-93 Oxidation and Mitochondrial Dysfunction in Epithelial Lung Cells (E10).

The Journal of biological chemistry, 290(46):27939-27958.

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.

RevDate: 2019-03-29
CmpDate: 2017-02-01

Bremer K, Kocha KM, Snider T, et al (2016)

Sensing and responding to energetic stress: The role of the AMPK-PGC1α-NRF1 axis in control of mitochondrial biogenesis in fish.

Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology, 199:4-12.

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.

RevDate: 2018-11-13
CmpDate: 2016-08-01

Stefano GB, Mantione KJ, Capellan L, et al (2015)

Morphine stimulates nitric oxide release in human mitochondria.

Journal of bioenergetics and biomembranes, 47(5):409-417.

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.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

Electronic Scholarly Publishing
961 Red Tail Lane
Bellingham, WA 98226

E-mail: RJR8222 @

Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).


ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.


Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )