bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2021‒03‒21
fourteen papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Nat Chem Biol. 2021 Mar 15.
      The protein complexes of the mitochondrial electron transport chain exist in isolation and in higher order assemblies termed supercomplexes (SCs) or respirasomes (SC I+III2+IV). The association of complexes I, III and IV into the respirasome is regulated by unknown mechanisms. Here, we designed a nanoluciferase complementation reporter for complex III and IV proximity to determine in vivo respirasome levels. In a chemical screen, we found that inhibitors of the de novo pyrimidine synthesis enzyme dihydroorotate dehydrogenase (DHODH) potently increased respirasome assembly and activity. By-passing DHODH inhibition via uridine supplementation decreases SC assembly by altering mitochondrial phospholipid composition, specifically elevated peroxisomal-derived ether phospholipids. Cell growth rates upon DHODH inhibition depend on ether lipid synthesis and SC assembly. These data reveal that nucleotide pools signal to peroxisomes to modulate synthesis and transport of ether phospholipids to mitochondria for SC assembly, which are necessary for optimal cell growth in conditions of nucleotide limitation.
  2. Cell Metab. 2021 Mar 13. pii: S1550-4131(21)00102-9. [Epub ahead of print]
      Exercise training positively affects metabolic health through increased mitochondrial oxidative capacity and improved glucose regulation and is the first line of treatment in several metabolic diseases. However, the upper limit of the amount of exercise associated with beneficial therapeutic effects has not been clearly identified. Here, we used a training model with a progressively increasing exercise load during an intervention over 4 weeks. We closely followed changes in glucose tolerance, mitochondrial function and dynamics, physical exercise capacity, and whole-body metabolism. Following the week with the highest exercise load, we found a striking reduction in intrinsic mitochondrial function that coincided with a disturbance in glucose tolerance and insulin secretion. We also assessed continuous blood glucose profiles in world-class endurance athletes and found that they had impaired glucose control compared with a matched control group.
    Keywords:  athletes; continuous glucose monitoring; exercise; exercise adaptations; glucose tolerance; high-intensity interval training; insulin resistance; metabolic dysfunction; mitochondria; mitochondrial dynamics; mitochondrial dysfunction
  3. Free Radic Biol Med. 2021 Mar 12. pii: S0891-5849(21)00162-3. [Epub ahead of print]
      Electron transfer between respiratory complexes is an essential step for the efficiency of the mitochondrial oxidative phosphorylation. Until recently, it was stablished that ubiquinone and cytochrome c formed homogenous single pools in the inner mitochondrial membrane which were not influenced by the presence of respiratory supercomplexes. However, this idea was challenged by the fact that bottlenecks in electron transfer appeared after disruption of supercomplexes into their individual complexes. The postulation of the plasticity model embraced all these observations and concluded that complexes and supercomplexes co-exist and are dedicated to a spectrum of metabolic requirements. Here, we review the involvement of superassembly in complex I stability, the role of supercomplexes in ROS production and the segmentation of the CoQ and cyt c pools, together with their involvement in signaling and disease. Taking apparently conflicting literature we have built up a comprehensive model for the segmentation of CoQ and cyt c mediated by supercomplexes, discuss the current limitations and provide a prospect of the current knowledge in the field.
    Keywords:  CoQ; cyt c; pools; respirasomes; supercomplexes
  4. Biochim Biophys Acta Bioenerg. 2021 Mar 10. pii: S0005-2728(21)00042-6. [Epub ahead of print] 148409
      The ratio of ADP and ATP is a natural indicator of cellular bioenergetic state and thus a prominent analyte in metabolism research. Beyond adenylate interconversion via oxidative phosphorylation and ATPase activities, ADP and ATP act as steric regulators of enzymes, e.g. cytochrome C oxidase, and are major factors in mitochondrial calcium storage potential. Consideration of all routes of adenylate conversion is critical to successfully predict their abundance in an experimental system and to correctly interpret many aspects of mitochondrial function. We showcase here how adenylate kinases elicit considerable impact on the outcome of a variety of mitochondrial assays through their drastic manipulation of the adenylate profile. Parameters affected include cytochrome c oxidase activity, P/O ratio, and mitochondrial calcium dynamics. Study of the latter revealed that the presence of ATP is required for mitochondrial calcium to be shaped into a particularly dense form of mitochondrial amorphous calcium phosphate.
    Keywords:  Adenylate kinase; P/O ratio; amorphous calcium phosphate; calcium capacity; cytochrome C oxidase; mitochondria
  5. Free Radic Biol Med. 2021 Mar 11. pii: S0891-5849(21)00141-6. [Epub ahead of print]
      Excessive mitochondrial ROS production has been causally linked to the pathophysiology of aging in the heart and other organs, and plays a deleterious role in several age-related cardiac pathologies, including myocardial ischemia-reperfusion injury and heart failure, the two worldwide leading causes of death and disability in the elderly. However, ROS generation is also a fundamental mitochondrial function that orchestrates several signaling pathways, some of them exerting cardioprotective effects. In cardiac myocytes, mitochondria are particularly abundant and are specialized in subcellular populations, in part determined by their relationships with other organelles and their cyclic calcium handling activity necessary for adequate myocardial contraction/relaxation and redox balance. Depending on their subcellular location, mitochondria can themselves be differentially targeted by ROS and display distinct age-dependent functional decline. Thus, precise mitochondria-targeted therapies aimed at counteracting unregulated ROS production are expected to have therapeutic benefits in certain aging-related heart conditions. However, for an adequate design of such therapies, it is necessary to unravel the complex and dynamic interactions between mitochondria and other cellular processes.
    Keywords:  AGEs; Aging; cardiomyocytes; cardioprotection; sarcoplasmic reticulum
  6. FEBS Lett. 2021 Mar 20.
      In animals, mitochondria are mainly organised into an interconnected tubular network extending across the cell along a cytoskeletal scaffold. Mitochondrial fission and fusion, as well as distribution along cytoskeletal tracks, are counterbalancing mechanisms acting in concert to maintain a mitochondrial network tuned to cellular function. Balanced mitochondrial dynamics permits quality control of the network including biogenesis and turnover, distribution of mtDNA, and are tuned to metabolic status. Cellular and organismal health relies on a delicate balance between fission and fusion and large rearrangements in the mitochondrial network can be seen in response to cellular insults and disease. Indeed, dysfunction in the major components of the fission and fusion machineries including Dynamin-related protein 1 (DRP1), Mitofusins 1 and 2 (MFN1, MFN2) and Optic atrophy protein 1 (OPA1) and ensuing imbalance of mitochondrial dynamics can lead to neurodegenerative disease. Altered mitochondrial dynamics is also seen in more common diseases. In this review, the machinery involved in mitochondrial dynamics and their dysfunction in disease will be discussed.
    Keywords:  membrane dynamics; mitochondria; mitochondrial disease; mitochondrial fission; mitochondrial fusion; organelles; oxidative phosphorylation
  7. Life Sci. 2021 Mar 11. pii: S0024-3205(21)00325-8. [Epub ahead of print] 119340
      AIMS: Hypoxic training promotes human cardiopulmonary function and exercise performance efficiently, but the myocellular mechanism has been less studied. We aimed to examine the effects of hypoxic trainings on mitochondrial turnover and vascular remodeling of skeletal muscle.MAIN METHODS: C57BL/6 J mice were divided into control, hypoxic exposure, exercise training, "live high-train low" (LHTL), and "live low-train high" (LLTH) groups (n = 8/group). Western blot and immunohistochemistry were used to evaluate mitochondrial turnover of gastrocnemius and angiogenesis of quadriceps after six weeks interventions.
    KEY FINDINGS: Compared with control group, both LHTL and LLTH increased phosphorylation levels of p38 MAPK markedly (p < 0.05). LLTH also elevated PGC-1α protein expression significantly (p < 0.05). All interventions did not influence Bnip3 and Drp-1 proteins levels (p > 0.05), while LLTH enhanced Parkin and Mff protein contents significantly (p < 0.05). Immunohistochemical analysis showed both LHTL and LLTH promoted CD31 and VEGF expressions (p < 0.05). ATP content, citrate synthase activities of gastrocnemius were robustly elevated in LHTL and LLTH groups (p < 0.01). The exercise training increased Mff protein and ATP content in gastrocnemius as well as VEGF expression in quadriceps (p < 0.05). The hypoxic exposure also increased ATP content, citrate synthase, and ATP synthase activities in gastrocnemius as well as VEGF expression in quadriceps (p < 0.01).
    SIGNIFICANCE: Our results suggested that hypoxic trainings, especially LLTH, promoted mitochondrial turnover and angiogenesis of skeletal muscle, which may be an underlying mechanism of hypoxic training-induced exercise capacity.
    Keywords:  Exercise; Hypoxic training; Mitochondrial biogenesis; Mitophagy
  8. Exerc Sport Sci Rev. 2021 Apr 01. 49(2): 67-76
      Exercise stimulates the biogenesis of mitochondria in muscle. Some literature supports the use of pharmaceuticals to enhance mitochondria as a substitute for exercise. We provide evidence that exercise rejuvenates mitochondrial function, thereby augmenting muscle health with age, in disease, and in the absence of cellular regulators. This illustrates the power of exercise to act as mitochondrial medicine in muscle.
  9. Biochim Biophys Acta Mol Basis Dis. 2021 Mar 10. pii: S0925-4439(21)00053-3. [Epub ahead of print] 166120
      Lipodystrophy syndromes are a group of rare diseases related to the pathological impairment of adipose tissue and metabolic comorbidities, including dyslipidemia, diabetes, insulin resistance, hypoleptinemia, and hypoadiponectinemia. They can be categorized as partial or generalized according to the degree of fat loss, and inherited or acquired disorders, if they are associated with genetic mutations or are related to autoimmunity, respectively. Some types of lipodystrophies have been associated with changes in both redox and endoplasmic reticulum (ER) homeostasis as well as muscle dysfunction (MD). Although ER stress (ERS) has been related to muscle dysfunction (MD) in many diseases, there is no data concerning its role in lipodystrophies' muscle physiopathology. Here we focused on congenital lipodystrophies associated with ERS and MD. We also described recent advances in our understanding of the relationships among ERS, MD, and genetic lipodystrophies, highlighting the adiponectin-protective roles.
    Keywords:  ER stress; Inherited lipodystrophies; Muscle dysfunctions
  10. Am J Physiol Endocrinol Metab. 2021 Mar 15.
      Dache et al. (2020, FASEB J. 15, e2002338-15) recently reported the presence of respiratory-competent cell-free mitochondria in human blood (up to 3.7 x 106 per mL of blood), providing exciting perspectives on the potential role of these extra-cellular mitochondria. While their evidence for the presence of cell-free mitochondria in human blood is compelling, their conclusion that these cell-free mitochondria are respiratory-competent or functional has to be re-evaluated. To this end, we evaluated the functionality of cell-free mitochondria in human blood using high-resolution respirometry and mitochondria extracted from platelets of the same blood samples as positive controls. While cell-free mitochondria were present in human plasma (i.e. significant MitoTracker Green Fluorescence and complex IV activity), there was no evidence suggesting that their mitochondrial electron transport system (ETS) was functional (i.e. respiration rate not significantly different from 0; no significant responses to ADP, uncoupler or mitochondrial inhibitors oligomycin and antimycin A). Yet, in vitro complex IV activity was detectable and even slightly higher than levels found in mitochondria extracted from platelets, suggesting that cell-free mitochondria in human blood are likely to only retain a non-functional part of the electron transport system. Despite being unlikely to be fully functional in the narrow-sense (i.e. capable of oxidative phosphorylation), circulating cell-free mitochondria may have significant physiological roles that remain to be elucidated.
    Keywords:  bioenergetics; blood cells; extra-cellular mitochondria; mitochondrial function; platelet
  11. Nat Aging. 2021 Feb;1(2): 165-178
      Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how UPRmt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPRmt, as well as mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.
  12. Int J Cardiol. 2021 Mar 16. pii: S0167-5273(21)00485-X. [Epub ahead of print]
    Keywords:  Heart failure; MCU; Mitochondrial calcium uniporter
  13. Med Sci Sports Exerc. 2021 Feb 19.
      PURPOSE: To determine the role of mammalian target of rapamycin (mTORC1) activation and catabolic markers in resistance training's (RT) anti-atrophy effect during cachexia-induced muscle loss.METHODS: Myofiber atrophy was induced by injecting Walker 256 tumor cells into rats exposed or not exposed to the RT protocol of ladder climbing. The role of RT-induced anabolic stimulation was investigated in tumor-bearing rats with the mTORC1 inhibitor rapamycin, and cross-sectional areas of skeletal muscle were evaluated to identify atrophy or hypertrophy. Components of the mTORC1 and ubiquitin-proteasome pathways were assessed by real-time PCR or immunoblotting.
    RESULTS: While RT prevented myofiber atrophy and impaired the strength of tumor-bearing rats, in healthy rats it promoted activated mTORC1, as demonstrated by p70S6K's increased phosphorylation and myofiber's enlarged cross-sectional area. However, RT promoted no changes in the ratio of p70S6K to phospho-p70S6K protein expression while prevented myofiber atrophy in tumor-bearing rats. Beyond that, treatment with rapamycin did not preclude RT's preventive effect on myofiber atrophy in tumor-bearing rats. Thus, RT's ability to prevent cancer-induced myofiber atrophy seems to be independent of mTORC1's and p70S6K's activation. Indeed, RT's preventive effect on cancer-induced myofiber atrophy was associated with its capacity to attenuate elevated TNF-α and IL-6 as well as to prevent oxidative damage in muscles and an elevated abundance of atrogin-1.
    CONCLUSION: By inducing attenuated myofiber atrophy independent of mTORC1's signaling activation, RT prevents muscle atrophy during cancer by reducing inflammation, oxidative damage, and atrogin-1 expression.
  14. Physiol Rev. 2021 Mar 18.
      The design of the energy metabolism system in striated muscle remains a major area of investigation. Here, we review our current understanding and emerging hypotheses regarding the metabolic support of muscle contraction. Maintenance of ATP free energy, so called energy homeostasis, via mitochondrial oxidative phosphorylation is critical to sustained contractile activity and this major design criterion is the focus of this review. Cell volume invested in mitochondria reduces the space available for generating contractile force, and this spatial balance between mitochondria and contractile elements to meet the varying sustained power demands across muscle types is another important design criterion. This is accomplished with remarkably similar mass-specific mitochondrial protein composition across muscle types, implying that it is the organization of mitochondria within the muscle cell that is critical to supporting sustained muscle function. Beyond the production of ATP, ubiquitous distribution of ATPases throughout the muscle requires rapid distribution of potential energy across these large cells. Distribution of potential energy has long been thought to occur primarily through facilitated metabolite diffusion but recent analysis has questioned the importance of this process under normal physiological conditions. Recent structural and functional studies have supported the hypothesis that the mitochondrial reticulum provides a rapid energy distribution system via the conduction of the mitochondrial membrane potential to maintain metabolic homeostasis during contractile activity. We extensively review this aspect of the energy metabolism design contrasting it with metabolite diffusion models and how mitochondrial structure can play a role in the delivery of energy in the striated muscle.
    Keywords:  cellular energy distribution; mitochondria; mitochondrial networks; mitochondrial reticulum; oxidative phosphorylation