Skeletal muscle regeneration depends on the correct expansion of resident quiescent stem cells (satellite cells), a process that becomes less efficient with aging. Here, we show that mitochondrial ...dynamics are essential for the successful regenerative capacity of satellite cells. The loss of mitochondrial fission in satellite cells—due to aging or genetic impairment—deregulates the mitochondrial electron transport chain (ETC), leading to inefficient oxidative phosphorylation (OXPHOS) metabolism and mitophagy and increased oxidative stress. This state results in muscle regenerative failure, which is caused by the reduced proliferation and functional loss of satellite cells. Regenerative functions can be restored in fission-impaired or aged satellite cells by the re-establishment of mitochondrial dynamics (by activating fission or preventing fusion), OXPHOS, or mitophagy. Thus, mitochondrial shape and physical networking controls stem cell regenerative functions by regulating metabolism and proteostasis. As mitochondrial fission occurs less frequently in the satellite cells in older humans, our findings have implications for regeneration therapies in sarcopenia.
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•Mitochondrial fission increases in satellite cells (SCs) after muscle injury•Mitochondrial fission boosts SC proliferation by inducing OXPHOS and proteostasis•DRP1 loss in SCs (genetically or during aging) impairs muscle regeneration•Normalizing mitochondrial dynamics in aged SCs restores muscle regeneration
Hong et al. illustrate that mitochondrial dynamics are required for tissue regeneration. Mitochondrial fission facilitates stem cell function via OXPHOS and mitophagy regulation. The genetic (or aging-related) loss of the mitochondrial fission regulator DRP1 in muscle stem cells blunts their proliferation and regenerative capacity, whereas DRP1 re-establishment rescues these defects.
Mitochondria are dynamic subcellular organelles that convert nutrient intermediates into readily available energy equivalents. Optimal mitochondrial function is ensured by a highly evolved quality ...control system, coordinated by protein machinery that regulates a process of continual fusion and fission. In this work, we provide in vivo evidence that the ATP‐independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin‐related GTPase OPA1 (optic atrophy 1). We also show that OMA1 deficiency causes a profound perturbation of the mitochondrial fusion–fission equilibrium that has important implications for metabolic homeostasis. Thus, ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters. Additionally, Oma1‐mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis. These alterations are especially significant under metabolic stress conditions, indicating that an intact OMA1‐OPA1 system is essential for developing the appropriate adaptive response to different metabolic stressors such as a high‐fat diet or cold‐shock. This study provides the first description of an unexpected role in energy metabolism for the metalloprotease OMA1 and reinforces the importance of mitochondrial quality control for normal metabolic function.
The metalloprotease OMA1 is involved in the proteolytic inactivation of the dynaminrelated GTPase OPA1, a key regulator of mitochondrial dynamics. OMA1 knockout mice indicate that mitochondrial quality control and dynamics impact energy metabolism, in particular under metabolic stress.
Fundamental biological processes hinge on coordinated interactions between genes spanning two obligate genomes—mitochondrial and nuclear. These interactions are key to complex life, and allelic ...variation that accumulates and persists at the loci embroiled in such intergenomic interactions should therefore be subjected to intense selection to maintain integrity of the mitochondrial electron transport system. Here, we compile evidence that suggests that mitochondrial–nuclear (mitonuclear) allelic interactions are evolutionarily significant modulators of the expression of key health-related and life-history phenotypes, across several biological scales—within species (intra- and interpopulational) and between species. We then introduce a new frontier for the study of mitonuclear interactions—those that occur within individuals, and are fuelled by the mtDNA heteroplasmy and the existence of nuclear-encoded mitochondrial gene duplicates and isoforms. Empirical evidence supports the idea of high-resolution tissue- and environment-specific modulation of intraindividual mitonuclear interactions. Predicting the penetrance, severity and expression patterns of mtDNA-induced mitochondrial diseases remains a conundrum. We contend that a deeper understanding of the dynamics and ramifications of mitonuclear interactions, across all biological levels, will provide key insights that tangibly advance our understanding, not only of core evolutionary processes, but also of the complex genetics underlying human mitochondrial disease.
'Mencía'/'Jaen' it's an important red grape variety, exclusive of the Iberian Peninsula, used in wine production namely in Bierzo D.O. and Dão D.O., respectively. This work evaluates the effect of ...the two different "terroirs" on the phenolic composition and chromatic characteristics of 'Mencía'/'Jaen' monovarietal wines produced at an industrial scale in the same vintage. Using Principal Component Analysis (PCA), Partial Least Squares-Discrimination Analysis (PLS-DA), and Orthogonal PLS-DA (OPLS-DA) it was found that peonidin-3-coumaroylglucoside, petunidin-3-glucoside, malvidin-3-coumaroylglucoside, peonidin-3-glucoside, malvidin-3-acetylglucoside, malvidin-3-glucoside, and ferulic acid were the phenolic compounds with the highest differences between the two regions. PLS regression allowed to correlate the differences in lightness (L*) and redness (a*) of wines from 'Jaen' and 'Mencía' to differences in colored anthocyanins, polymeric pigments, total pigments, total anthocyanins, cyanidin-3-acetylglucoside, delphinidin-3-acetylglucoside, delphinidin-3-glucoside, peonidin-3-coumaroylglucoside, petunidin-3-glucoside and malvidin-3-glucoside in wines, and the colorless ferulic, caffeic, and coutaric acids, and ethyl caffeate. The wines a* values were more affected by colored anthocyanins, ferulic acid, total anthocyanins, delphinidin-3-acetylglucoside, delphinidin-3-glucoside and petunidin-3-acetylglucoside, and catechin. The positive influence of ferulic acid in the a* values and ferulic, caffeic, coutaric acids, and ethyl caffeate on the L* values can be due to the co-pigmentation phenomena. The higher dryness and lower temperatures during the September nights in this vintage might explain the differences observed in the anthocyanin content and chromatic characteristics of the wines.
Macrophages tightly scale their core metabolism after being activated, but the precise regulation of the mitochondrial electron-transport chain (ETC) and its functional implications are currently ...unknown. Here we found that recognition of live bacteria by macrophages transiently decreased assembly of the ETC complex I (CI) and CI-containing super-complexes and switched the relative contributions of CI and CII to mitochondrial respiration. This was mediated by phagosomal NADPH oxidase and the reactive oxygen species (ROS)-dependent tyrosine kinase Fgr. It required Toll-like receptor signaling and the NLRP3 inflammasome, which were both connected to bacterial viability-specific immune responses. Inhibition of CII during infection with Escherichia coli normalized serum concentrations of interleukin 1β (IL-1β) and IL-10 to those in mice treated with dead bacteria and impaired control of bacteria. We have thus identified ETC adaptations as an early immunological-metabolic checkpoint that adjusts innate immune responses to bacterial infection.
Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs in pathophysiological contexts such as wound healing, cancer, and chronic inflammatory disease. During sprouting ...angiogenesis, endothelial tip and stalk cells coordinately remodel their cell-cell junctions to allow collective migration and extension of the sprout while maintaining barrier integrity. All these processes require energy, and the predominant ATP generation route in endothelial cells is glycolysis. However, it remains unclear how ATP reaches the plasma membrane and intercellular junctions. In this study, we demonstrate that the glycolytic enzyme pyruvate kinase 2 (PKM2) is required for sprouting angiogenesis in vitro and in vivo through the regulation of endothelial cell-junction dynamics and collective migration. We show that PKM2-silencing decreases ATP required for proper VE-cadherin internalization/traffic at endothelial cell-cell junctions. Our study provides fresh insight into the role of ATP subcellular compartmentalization in endothelial cells during angiogenesis. Since manipulation of EC glycolysis constitutes a potential therapeutic intervention route, particularly in tumors and chronic inflammatory disease, these findings may help to refine the targeting of endothelial glycolytic activity in disease.
Tumor cells rewire their metabolism to fulfill the demands of highly proliferative cells. This changes cellular metabolism to adapt to fuel and oxygen availability for energy production and to ...increase the synthesis capacity of building blocks for cell division and growth. In addition, the metabolic shift also modulates the immunogenicity of the tumor cells. Recently, Mahmood and colleagues reported a connection between mitochondrial DNA mutations in cancer cells and their response to immunotherapy in a mouse model of melanoma.
is an endemic species in northwestern Mexico. It produces colorful fruits called pitayas that have an edible pulp. They have phytochemical compounds associated with biological activities. ...Ultrafiltration is a widely used method for the clarification of fruit juices and the recovery of phytochemicals. However, its effect has not been extensively studied in extracts. Therefore, the objective of this work is to study the effect of the ultrafiltration of pitaya extract (
) on its phytochemical content, antioxidant capacity, and identification of phenolic compounds by UPLC-DAD-MS, providing greater knowledge about the pitaya. In this study, two extracts were analyzed, the unclarified extract (UE) and the clarified extract (CE). The antioxidant capacity was higher in the CE with 15.93 ± 0.42 mM TE/g, DPPH and 18.37 ± 0.016 mM TE/g, ABTS. The UPLC-MS analysis indicated the decrease in phenolic compounds in the CE and the presence of gallic acid and resorcinol, compounds that had not been identified in other species of
spp. The correlation analysis indicated that all the phytochemicals present in the pitaya contribute significantly to the antioxidant capacity. The ultrafiltration process could be a viable option to improve the biological activity of the natural extracts.
Electrons feed into the mitochondrial electron transport chain (mETC) from NAD- or FAD-dependent enzymes. A shift from glucose to fatty acids increases electron flux through FAD, which can saturate ...the oxidation capacity of the dedicated coenzyme Q (CoQ) pool and result in the generation of reactive oxygen species. To prevent this, the mETC superstructure can be reconfigured through the degradation of respiratory complex I, liberating associated complex III to increase electron flux via FAD at the expense of NAD. Here, we demonstrate that this adaptation is driven by the ratio of reduced to oxidized CoQ. Saturation of CoQ oxidation capacity induces reverse electron transport from reduced CoQ to complex I, and the resulting local generation of superoxide oxidizes specific complex I proteins, triggering their degradation and the disintegration of the complex. Thus, CoQ redox status acts as a metabolic sensor that fine-tunes mETC configuration in order to match the prevailing substrate profile.
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•High CoQH2/CoQ ratio induces reverse electron transport under physiological conditions•RET-generated ROS induces partial complex I degradation•Increase in the CIII fraction detached of CI optimizes mETC to consume fatty acids•The CoQH2/CoQ ratio serves as a sensor of respiratory chain efficiency
Guarás et al. show how the mitochondrial electron transport chain (mtETC) is optimized to better oxidize different nutrients or fuels using the reducing status of ubiquinone as a metabolic sensor and ROS generated by complex I by reverse electron transport as an executor.
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