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Recent studies suggest that carbohydrate restriction can improve the training-induced adaptation of muscle oxidative capacity. However, the importance of low muscle glycogen on the molecular signaling of mitochondrial biogenesis remains unclear. Here, we compare the effects of exercise with low (LG) and normal (NG) glycogen on different molecular factors involved in the regulation of mitochondrial biogenesis. Ten highly trained cyclists ( V O 2max 65 ± 1 ml/kg/min, W max 387 ± 8 W) exercised for 60 min at approximately 64 % V O 2max with either low [166 ± 21 mmol/kg dry weight (dw)] or normal (478 ± 33 mmol/kg dw) muscle glycogen levels achieved by prior exercise/diet intervention. Muscle biopsies were taken before, and 3 h after, exercise. The mRNA of peroxisome proliferator-activated receptor-γ coactivator-1 was enhanced to a greater extent when exercise was performed with low compared with normal glycogen levels (8.1-fold vs. 2.5-fold increase). Cytochrome c oxidase subunit I and pyruvate dehydrogenase kinase isozyme 4 mRNA were increased after LG (1.3- and 114-fold increase, respectively), but not after NG. Phosphorylation of AMP-activated protein kinase, p38 mitogen-activated protein kinases and acetyl-CoA carboxylase was not changed 3 h post-exercise. Mitochondrial reactive oxygen species production and glutathione oxidative status tended to be reduced 3 h post-exercise. We conclude that exercise with low glycogen levels amplifies the expression of the major genetic marker for mitochondrial biogenesis in highly trained cyclists. The results suggest that low glycogen exercise may be beneficial for improving muscle oxidative capacity.

Animal classification is primarily based on morphological characters, even though these may not be the first to diverge during speciation. In many cases, closely related taxa are actually difficult to distinguish based on morphological characters alone, especially when there is no substantial niche separation. As a consequence, the diversity of certain groups is likely to be underestimated. Lepidoptera –moths and butterflies– represent the largest group of herbivorous insects. The extensive diversification in the group is generally assumed to have its origin in the spectacular radiation of flowering plants and the resulting abundance of ecological niches. However, speciation can also occur without strong ecological divergence. For example, reproductive isolation can evolve as the result of divergence in mate preference and the associated pheromone communication system. We combined pheromone trapping and genetic analysis to elucidate the evolutionary relationships within a complex of primitive moth species (Lepidoptera: Eriocraniidae). Mitochondrial and nuclear DNA markers provided evidence that Eriocrania semipurpurella, as currently defined by morphological characters, includes three cryptic species in Northern and Western Europe. Male moths of these cryptic species, as well as of the closely related E. sangii, exhibited relative specificity in terms of their attraction to specific ratios of two major pheromone components, (2S,6Z)-nonen-2-ol and (2R,6Z)-nonen-2-ol. Our data suggest strong assortative mating in these species in the absence of apparent niche separation, indicating that Eriocrania moths may represent an example of non-ecological speciation. Finally, our study argues in favour of combining pheromone investigations and DNA barcoding as powerful tools for identifying and delimitating species boundaries.

The textbook description of mitochondrial respiratory complexes (RCs) views them as free-moving entities linked by the mobile carriers coenzyme Q (CoQ) and cytochrome c (cyt c). This model (known as the fluid model) is challenged by the proposal that all RCs except complex II can associate in supercomplexes (SCs). The proposed SCs are the respirasome (complexes I, III, and IV), complexes I and III, and complexes III and IV. The role of SCs is unclear, and their existence is debated. By genetic modulation of interactions between complexes I and III and III and IV, we show that these associations define dedicated CoQ and cyt c pools and that SC assembly is dynamic and organizes electron flux to optimize the use of available substrates.

The origin of oxygenic photosynthesis in Cyanobacteria led to the rise of oxygen on Earth ~2.3 billion years ago, profoundly altering the course of evolution by facilitating the development of aerobic respiration and complex multicellular life. Here we report the genomes of 41 uncultured organisms related to the photosynthetic Cyanobacteria (class Oxyphotobacteria), including members of the class Melainabacteria and a new class of Cyanobacteria (class Sericytochromatia) that is basal to the Melainabacteria and Oxyphotobacteria. All members of the Melainabacteria and Sericytochromatia lack photosynthetic machinery, indicating that phototrophy was not an ancestral feature of the Cyanobacteria and that Oxyphotobacteria acquired the genes for photosynthesis relatively late in cyanobacterial evolution. We show that all three classes independently acquired aerobic respiratory complexes, supporting the hypothesis that aerobic respiration evolved after oxygenic photosynthesis.

Cytochrome c oxidase (complex IV, CIV) is known in mammals to exist independently or in association with other respiratory proteins to form supercomplexes (SCs). In Saccharomyces cerevisiae, CIV is found solely in an SC with cytochrome bc1 (complex III, CIII). Here, we present the cryogenic electron microscopy (cryo-EM) structure of S. cerevisiae CIV in a III2IV2 SC at 3.3 Å resolution. While overall similarity to mammalian homologs is high, we found notable differences in the supernumerary subunits Cox26 and Cox13; the latter exhibits a unique arrangement that precludes CIV dimerization as seen in bovine. A conformational shift in the matrix domain of Cox5A—involved in allosteric inhibition by ATP—may arise from its association with CIII. The CIII–CIV arrangement highlights a conserved interaction interface of CIII, albeit one occupied by complex I in mammalian respirasomes. We discuss our findings in the context of the potential impact of SC formation on CIV regulation.

The pathogenesis of declining bone mineral density, a universal feature of ageing, is not fully understood. Somatic mitochondrial DNA (mtDNA) mutations accumulate with age in human tissues and mounting evidence suggests that they may be integral to the ageing process. To explore the potential effects of mtDNA mutations on bone biology, we compared bone microarchitecture and turnover in an ageing series of wild type mice with that of the PolgA mut/mut mitochondrial DNA ‘mutator’ mouse. In vivo analyses showed an age-related loss of bone in both groups of mice; however, it was significantly accelerated in the PolgA mut/mut mice. This accelerated rate of bone loss is associated with significantly reduced bone formation rate, reduced osteoblast population densities, increased osteoclast population densities, and mitochondrial respiratory chain deficiency in osteoblasts and osteoclasts in PolgA mut/mut mice compared with wild-type mice. In vitro assays demonstrated severely impaired mineralised matrix formation and increased osteoclast resorption by PolgA mut/mut cells. Finally, application of an exercise intervention to a subset of PolgA mut/mut mice showed no effect on bone mass or mineralised matrix formation in vitro. Our data demonstrate that mitochondrial dysfunction, a universal feature of human ageing, impairs osteogenesis and is associated with accelerated bone loss.

The viability of Mycobacterium tuberculosis ( Mtb ) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of Mtb -infected marmosets with a cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (Δ ndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δ ndh-2 mutant is only mildly attenuated in mice and not differently susceptible to clofazimine, a drug in clinical use proposed to engage NDH-2. These results demonstrate the intrinsic plasticity of Mtb ’s respiratory chain, and highlight the challenges associated with targeting the pathogen’s respiratory enzymes for tuberculosis drug development. New tuberculosis therapies, targeting respiratory chain components of Mycobacterium tuberculosis , are under development. Here the authors show that, contrary to common belief, some of these components are not essential for pathogen viability and/or virulence in animal models of infection.

The mitochondrial respiratory chain is essential for oxidative phosphorylation and comprises multiple complexes, including cytochrome c oxidase, assembled in macromolecular supercomplexes. Little is known about factors that contribute to supercomplex organization. Here we identify COX7RP as a factor that promotes supercomplex assembly. Cox7rp -knockout mice exhibit decreased muscular activity and heat production failure in the cold due to reduced COX activity. In contrast, COX7RP -transgenic mice exhibit increased exercise performance with increased cytochrome c oxidase activity. Two-dimensional blue native electrophoresis reveals that COX7RP is a key molecule that promotes assembly of the III 2 /IV n supercomplex with complex I. Our study identified COX7RP as a protein that functions in I/III 2 /IV n supercomplex assembly and is required for full activity of mitochondrial respiration. Interactions between mitochondrial respiratory chain complexes control electron transfer and oxidative phosphorylation. Here, the authors find that COX7RP regulates supercomplex assembly, and show that decreasing or increasing COX7RP expression, respectively, reduces and enhances muscular performance in mice.

After myelination, oligodendrocytes are able to survive without mitochondrial respiration, suggesting that they can switch to aerobic glycolysis and release lactate. Extra support for myelinated axons In the central nervous system, the myelin sheath that insulates and protects the axon is produced by glial cells known as oligodendrocytes. A study of conditional mutant mice in which myelin-producing cells fail to assemble mitochondrial cytochrome c oxidase complex IV shows, surprisingly, that the oligodendrocytes continued to support myelination in the absence of mitochondrial respiration. They seem to be able to switch to lactate-producing aerobic glycolysis. And because myelinated axons can utilize lactate when energy-deprived, this may be an extra means by which the oligodendrocytes support functioning axons. Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity 1 , 2 , 3 . However, the underlying support mechanisms are not understood 4 . Here we identify a metabolic component of axon–glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors 5 , post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived 6 , our findings suggest a model in which axon–glia metabolic coupling serves a physiological function.

Combined analysis of large data sets characterizing genes, transcripts, and proteins can elucidate biological functions and disease processes. Williams et al. report an exceptionally detailed characterization of mitochondrial function in a genetic reference panel of recombinant inbred mice. They measured the metabolic function of nearly 400 mice under various environmental conditions and collected detailed quantitative information from livers of the animals on over 25,000 transcripts. These data were integrated with quantitation of over 2500 proteins and nearly 1000 metabolites. Such analysis showed a frequent lack of correlation of transcript and protein abundance, enabled the identification of genomic variants of mitochondrial enzymes that caused inborn errors in metabolism, and revealed two genes that appear to function in cholesterol metabolism. Science , this issue p. 10.1126/science.aad0189 Advances in mass spectrometry yield insights into mitochondrial function. Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein’s activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics—a combination moving us forward in complex trait analysis.