bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒06‒07
ten papers selected by
Rafael Antonio Casuso Pérez
University of Granada


  1. Nature. 2020 Jun;582(7810): 129-133
    Fan M, Zhang J, Tsai CW, Orlando BJ, Rodriguez M, Xu Y, Liao M, Tsai MF, Feng L.
      Mitochondria take up Ca2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca2+ signalling and cell death1,2. In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU protein, the gatekeepers MICU1 and MICU2, and an auxiliary subunit, EMRE, essential for Ca2+ transport3-8. To prevent detrimental Ca2+ overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic Ca2+ concentrations to switch MCU on and off9,10. Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca2+-activated states. These structures define the architecture of this multicomponent Ca2+-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated Ca2+ uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial Ca2+ overload.
    DOI:  https://doi.org/10.1038/s41586-020-2309-6
  2. Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(20)30010-1. [Epub ahead of print]354 1-61
    Gibellini L, De Gaetano A, Mandrioli M, Van Tongeren E, Bortolotti CA, Cossarizza A, Pinti M.
      Initially discovered as a protease responsible for degradation of misfolded or damaged proteins, the mitochondrial Lon protease (Lonp1) turned out to be a multifaceted enzyme, that displays at least three different functions (proteolysis, chaperone activity, binding of mtDNA) and that finely regulates several cellular processes, within and without mitochondria. Indeed, LONP1 in humans is ubiquitously expressed, and is involved in regulation of response to oxidative stress and, heat shock, in the maintenance of mtDNA, in the regulation of mitophagy. Furthermore, its proteolytic activity can regulate several biochemical pathways occurring totally or partially within mitochondria, such as TCA cycle, oxidative phosphorylation, steroid and heme biosynthesis and glutamine production. Because of these multiple activities, Lon protease is highly conserved throughout evolution, and mutations occurring in its gene determines severe diseases in humans, including a rare syndrome characterized by Cerebral, Ocular, Dental, Auricular and Skeletal anomalies (CODAS). Finally, alterations of LONP1 regulation in humans can favor tumor progression and aggressiveness, further highlighting the crucial role of this enzyme in mitochondrial and cellular homeostasis.
    Keywords:  CODAS; Colon cancer; LONP1; Lon protease; Mitochondria; Proteotoxic stress; mtDNA
    DOI:  https://doi.org/10.1016/bs.ircmb.2020.02.005
  3. Int J Mol Sci. 2020 May 30. pii: E3923. [Epub ahead of print]21(11):
    Giacomello E, Crea E, Torelli L, Bergamo A, Reggiani C, Sava G, Toniolo L.
      Skeletal muscle aging is accompanied by mass reduction and functional decline, as a result of multiple factors, such as protein expression, morphology of organelles, metabolic equilibria, and neural communication. Skeletal muscles are formed by multiple fibers that express different Myosin Heavy Chains (MyHCs) and have different metabolic properties and different blood supply, with the purpose to adapt their contraction to the functional need. The fine interplay between the different fibers composing a muscle and its architectural organization determine its functional properties. Immunohistochemical and histochemical analyses of the skeletal muscle tissue, besides evidencing morphological characteristics, allow for the precise determination of protein expression and metabolic properties, providing essential information at the single-fiber level. Aiming to gain further knowledge on the influence of aging on skeletal muscles, we investigated the expression of the MyHCs, the Succinate Dehydrogenase (SDH) activity, and the presence of capillaries and Tubular Aggregates (TAs) in the tibialis anterior muscles of physiologically aging C57BL/6J mice aged 8 (adult), 18 (middle aged), and 24 months (old). We observed an increase of type-IIB fast-contracting fibers, an increase of the oxidative capacity of type-IIX and -IIA fibers, a general decrease of the capillarization, and the onset of TAs in type-IIB fibers. These data suggest that aging entails a selective modification of the muscle fiber profiles.
    Keywords:  Myosin Heavy Chain; capillaries; metabolic profile; muscle fiber; skeletal muscle aging
    DOI:  https://doi.org/10.3390/ijms21113923
  4. Antioxidants (Basel). 2020 Jun 02. pii: E472. [Epub ahead of print]9(6):
    Mailloux RJ.
      Mitochondria are quantifiably the most important sources of superoxide (O2●-) and hydrogen peroxide (H2O2) in mammalian cells. The overproduction of these molecules has been studied mostly in the contexts of the pathogenesis of human diseases and aging. However, controlled bursts in mitochondrial ROS production, most notably H2O2, also plays a vital role in the transmission of cellular information. Striking a balance between utilizing H2O2 in second messaging whilst avoiding its deleterious effects requires the use of sophisticated feedback control and H2O2 degrading mechanisms. Mitochondria are enriched with H2O2 degrading enzymes to desensitize redox signals. These organelles also use a series of negative feedback loops, such as proton leaks or protein S-glutathionylation, to inhibit H2O2 production. Understanding how mitochondria produce ROS is also important for comprehending how these organelles use H2O2 in eustress signaling. Indeed, twelve different enzymes associated with nutrient metabolism and oxidative phosphorylation (OXPHOS) can serve as important ROS sources. This includes several flavoproteins and respiratory complexes I-III. Progress in understanding how mitochondria generate H2O2 for signaling must also account for critical physiological factors that strongly influence ROS production, such as sex differences and genetic variances in genes encoding antioxidants and proteins involved in mitochondrial bioenergetics. In the present review, I provide an updated view on how mitochondria budget cellular H2O2 production. These discussions will focus on the potential addition of two acyl-CoA dehydrogenases to the list of ROS generators and the impact of important phenotypic and physiological factors such as tissue type, mouse strain, and sex on production by these individual sites.
    Keywords:  bioenergetics; hydrogen peroxide; isopotential groups; mitochondria; reactive oxygen species; sex differences; substrate preferences
    DOI:  https://doi.org/10.3390/antiox9060472
  5. Cell Metab. 2020 Jun 02. pii: S1550-4131(20)30249-7. [Epub ahead of print]31(6): 1047-1049
    Rasmussen ML, Robertson GL, Gama V.
      Mitochondrial fission is sustained through contact with several organelles, including the endoplasmic reticulum, lysosomes, and the actin cytoskeleton. Nagashima et al. (2020) now demonstrate that PI(4)P-containing Golgi-derived vesicles also modulate mitochondrial fission, driven by Arf1 and PI(4)KIIIβ activity, identifying a new organelle contact involved in maintaining mitochondrial homeostasis.
    DOI:  https://doi.org/10.1016/j.cmet.2020.05.010
  6. EMBO J. 2020 Jun 03. e103812
    Sánchez-González C, Nuevo-Tapioles C, Herrero Martín JC, Pereira MP, Serrano Sanz S, Ramírez de Molina A, Cuezva JM, Formentini L.
      It is controversial whether mitochondrial dysfunction in skeletal muscle is the cause or consequence of metabolic disorders. Herein, we demonstrate that in vivo inhibition of mitochondrial ATP synthase in muscle alters whole-body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl-glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This mitochondrial energy crisis increases lactate production, prevents fatty acid β-oxidation, and forces the catabolism of branched-chain amino acids (BCAA) to provide acetyl-CoA for de novo lipid synthesis. In turn, muscle accumulation of acetyl-CoA leads to acetylation-dependent inhibition of mitochondrial respiratory complex II enhancing oxidative phosphorylation dysfunction which results in augmented ROS production. By screening 702 FDA-approved drugs, we identified edaravone as a potent mitochondrial antioxidant and enhancer. Edaravone administration restored ROS and lipid homeostasis in skeletal muscle and reinstated insulin sensitivity. Our results suggest that muscular mitochondrial perturbations are causative of metabolic disorders and that edaravone is a potential treatment for these diseases.
    Keywords:  ATP synthase; Acetyl-CoA; edaravone; insulin resistance; mitochondria
    DOI:  https://doi.org/10.15252/embj.2019103812
  7. Clin Sci (Lond). 2020 Jun 12. 134(11): 1255-1258
    Zhu Q.
      Unfolded protein response (UPR) often coordinates with autophagy to maintain cellular proteostasis. Disturbance of proteostasis correlates with diseases including diabetes and neurological complications. In a recent article in Clinical Science, Kong et al. highlighted the critical role of endoplasmic reticulum (ER) stress-autophagy axis in maintaining cognitive functions and provided pharmacological evidence with respect to cognitive improvements in a diabetic mouse model. These novel findings present new insights into the pathological mechanisms and therapeutic implications with the ER stress modulators in diabetes-related cognitive dysfunction.
    Keywords:  ER stress; autophagy; cognitive dysfunction; diabetes
    DOI:  https://doi.org/10.1042/CS20200235
  8. Mitochondrion. 2020 Jun 02. pii: S1567-7249(20)30032-5. [Epub ahead of print]
    Cuong Tran H, Van Aken O.
      Mitochondria are key components of eukaryotic cells, so their proper functioning is monitored via different mitochondrial signalling responses. One of these mitochondria-to-nuclear 'retrograde' responses to maintain mitochondrial homeostasis is the mitochondrial unfolded protein response (UPRmt), which can be activated by a variety of defects including blocking mitochondrial translation, respiration, protein import or transmembrane potential. Although UPRmt was first reported in cultured mammalian cells, this signalling pathway has also been extensively studied in the nematode Caenorhabditis elegans. In yeast, there are no published studies focusing on UPRmt in a strict sense, but other unfolded protein responses (UPR) that appear related to UPRmt have been described, such as the UPR activated by protein mistargeting (UPRam) and mitochondrial compromised protein import response (mitoCPR). In plants, very little is known about UPRmt and only recently some of the regulators have been identified. In this paper, we summarise and compare the current knowledge of the UPRmt and related responses across eukaryotic kingdoms: animals, fungi and plants. Our comparison suggests that each kingdom has evolved its own specific set of regulators, however, the functional categories represented among UPRmt-related target genes appear to be largely overlapping. This indicates that the strategies for preserving proper mitochondrial functions are partially conserved, targeting mitochondrial chaperones, proteases, import components, dynamics and stress response, but likely also non-mitochondrial functions including growth regulators/hormone balance and amino acid metabolism. We also identify homologs of known UPRmt regulators and responsive genes across kingdoms, which may be interesting targets for future research.
    Keywords:  Mitochondria; UPR(am); UPR(mt); mitoCPR; retrograde signalling; unfolded protein response
    DOI:  https://doi.org/10.1016/j.mito.2020.05.009
  9. Cell Metab. 2020 Jun 02. pii: S1550-4131(20)30252-7. [Epub ahead of print]31(6): 1041-1043
    Chini EN.
      In this issue of Cell Metabolism, Pirinen et al. (2020) show that disruption in NAD+ homeostasis is a key component of the pathogenesis of mitochondrial myopathy in humans that can be targeted by the administration of the NAD+ precursor niacin, identifying NAD+ boosting as a potential treatment for this devastating disease.
    DOI:  https://doi.org/10.1016/j.cmet.2020.05.013
  10. Nat Commun. 2020 Jun 01. 11(1): 2714
    Balsa E, Perry EA, Bennett CF, Jedrychowski M, Gygi SP, Doench JG, Puigserver P.
      Electron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise ATP synthesis and render cells vulnerable to nutrient and oxidative stress conditions. This bioenergetic failure is thought to underlie pathologies associated with mitochondrial diseases. However, the precise metabolic processes resulting from a defective mitochondrial ETC that compromise cell viability under stress conditions are not entirely understood. We design a whole genome gain-of-function CRISPR activation screen using human mitochondrial disease complex I (CI) mutant cells to identify genes whose increased function rescue glucose restriction-induced cell death. The top hit of the screen is the cytosolic Malic Enzyme (ME1), that is sufficient to enable survival and proliferation of CI mutant cells under nutrient stress conditions. Unexpectedly, this metabolic rescue is independent of increased ATP synthesis through glycolysis or oxidative phosphorylation, but dependent on ME1-produced NADPH and glutathione (GSH). Survival upon nutrient stress or pentose phosphate pathway (PPP) inhibition depends on compensatory NADPH production through the mitochondrial one-carbon metabolism that is severely compromised in CI mutant cells. Importantly, this defective CI-dependent decrease in mitochondrial NADPH production pathway or genetic ablation of SHMT2 causes strong increases in inflammatory cytokine signatures associated with redox dependent induction of ASK1 and activation of stress kinases p38 and JNK. These studies find that a major defect of CI deficiencies is decreased mitochondrial one-carbon NADPH production that is associated with increased inflammation and cell death.
    DOI:  https://doi.org/10.1038/s41467-020-16423-1