bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒06‒14
seven papers selected by
Rafael Antonio Casuso Pérez
University of Granada


  1. Front Physiol. 2020 ;11 515
    Quiles JM, Gustafsson ÅB.
      Mitochondrial dysfunction is a hallmark of cardiac pathophysiology. Defects in mitochondrial performance disrupt contractile function, overwhelm myocytes with reactive oxygen species (ROS), and transform these cellular powerhouses into pro-death organelles. Thus, quality control (QC) pathways aimed at identifying and removing damaged mitochondrial proteins, components, or entire mitochondria are crucial processes in post-mitotic cells such as cardiac myocytes. Almost all of the mitochondrial proteins are encoded by the nuclear genome and the trafficking of these nuclear-encoded proteins necessitates significant cross-talk with the cytosolic protein QC machinery to ensure that only functional proteins are delivered to the mitochondria. Within the organelle, mitochondria contain their own protein QC system consisting of chaperones and proteases. This system represents another level of QC to promote mitochondrial protein folding and prevent aggregation. If this system is overwhelmed, a conserved transcriptional response known as the mitochondrial unfolded protein response is activated to increase the expression of proteins involved in restoring mitochondrial proteostasis. If the mitochondrion is beyond repair, the entire organelle must be removed before it becomes cytotoxic and causes cellular damage. Recent evidence has also uncovered mitochondria as participants in cytosolic protein QC where misfolded cytosolic proteins can be imported and degraded inside mitochondria. However, this process also places increased pressure on mitochondrial QC pathways to ensure that the imported proteins do not cause mitochondrial dysfunction. This review is focused on discussing the pathways involved in regulating mitochondrial QC and their relationship to cellular proteostasis and mitochondrial health in the heart.
    Keywords:  Parkin; UPR; UPS; import; mitochondria; mitophagy; proteasome; proteotoxicity
    DOI:  https://doi.org/10.3389/fphys.2020.00515
  2. Redox Biol. 2020 May 26. pii: S2213-2317(20)30416-X. [Epub ahead of print]36 101557
    Cully TR, Rodney GG.
      The ability for skeletal muscle to perform optimally can be affected by the regulation of Ca2+ within the triadic junctional space at rest. Reactive oxygen species impact muscle performance due to changes in oxidative stress, damage and redox regulation of signaling cascades. The interplay between ROS and Ca2+ signaling at the triad of skeletal muscle is therefore important to understand as it can impact the performance of healthy and diseased muscle. Here, we aimed to examine how changes in Ca2+ and redox signaling within the junctional space micro-domain of the mouse skeletal muscle fibre alters the homeostasis of these complexes. The dystrophic mdx mouse model displays increased RyR1 Ca2+ leak and increased NAD(P)H Oxidase 2 ROS. These alterations make the mdx mouse an ideal model for understanding how ROS and Ca2+ handling impact each other. We hypothesised that elevated t-tubular Nox2 ROS increases RyR1 Ca2+ leak contributing to an increase in cytoplasmic Ca2+, which could then initiate protein degradation and impaired cellular functions such as autophagy and ER stress. We found that inhibiting Nox2 ROS did not decrease RyR1 Ca2+ leak observed in dystrophin-deficient skeletal muscle. Intriguingly, another NAD(P)H isoform, Nox4, is upregulated in mice unable to produce Nox2 ROS and when inhibited reduced RyR1 Ca2+ leak. Our findings support a model in which Nox4 ROS induces RyR1 Ca2+ leak and the increased junctional space [Ca2+] exacerbates Nox2 ROS; with the cumulative effect of disruption of downstream cellular processes that would ultimately contribute to reduced muscle or cellular performance.
    Keywords:  Calcium; DMD; Dystrophy; Mdx; NAD(P)H oxidase; Nox2; Nox4; RyR1; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.redox.2020.101557
  3. Front Physiol. 2020 ;11 469
    Ato S, Kido K, Sase K, Fujita S.
      Skeletal muscle disuse rapidly decreases muscle mass. Resistance training (RT) is believed as the most effective way to gain muscle mass via an increase in mTORC1 activity and muscle protein synthesis (MPS). However, it remains unclear whether muscle atrophy by disuse alters the mTORC1 activation and MPS response to an acute resistance exercise (RE) and chronic RT-mediated skeletal muscle hypertrophy. This study investigated the influence of disuse muscle atrophy on the response of mTORC1 activation and MPS to an acute RE. We also evaluated whether disuse muscle atrophy affects the response of RT-induced muscle mass gain. Thirty male Sprague-Dawley rats were randomly divided into control (CON) or hindlimb suspension (HS) groups. A 14-day HS via the tail was used as the model for gastrocnemius muscle disuse in the HS group. Unilateral lower limb muscle contraction using by percutaneous electrical stimulation was used to mimic the stimuli of RE. Ten bouts of RE were performed in 3-week as chronic RT. Our results showed that MPS and mTORC1 activity was unchanged after HS at basal state. However, the ribosomal RNA (rRNA) level was reduced in HS rats compared to that in CON rats at basal state. MPS and rRNA increased in both HS and CON rats in response to acute RE to the same extent. However, the level of mTORC1 activation in response to an acute RE was significantly higher in HS than that in the CON group at 12 h after exercise, even though no difference was observed at 3 h after exercise. The 10-bout RT significantly increased gastrocnemius muscle mass in both CON and HS rats. The response of muscle hypertrophy did not differ between the groups. Therefore, MPS in response to acute RE and muscle hypertrophy in response to chronic RT were unaltered after disuse muscle atrophy.
    Keywords:  disuse atrophy; mTORC1; muscle protein synthesis; resistance training; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2020.00469
  4. Antioxid Redox Signal. 2020 Jun 11.
    Pothion H, Jehan C, Tostivint H, Cartier D, Bucharles C, Falluel-Morel A, Boukhzar L, Anouar Y, Lihrmann I.
      Selenoproteins incorporate the 21st amino acid selenocysteine into their polypeptide chain. Seven members of this family reside in the endoplasmic reticulum (ER), controlling the redox and ionic environment to maintain proteostasis. Noteworthy, selenoprotein T (SELENOT) is the only ER-resident selenoprotein whose gene disruption induces embryonic lethality. As expected for essential genes, its structure is remarkably conserved across eukaryotes. Its thioredoxin-like domain supports selenosulfide/disulfide reactions, an oxidoreductase activity which is essential to maintain ER redox homeostasis. Reduction of SELENOT expression in transgenic cell and animal models leads to an accumulation of reactive oxygen and nitrogen species, depletion of Ca2+ stores, and activation of the unfolded protein response (UPR). Expectedly, hormone secretion is impaired in endocrine and neuroendocrine cells due to ER stress. When ER stress could not be alleviated, cell viability is compromised. Mechanistically, SELENOT is anchored to the ER membrane and is able to bind the STT3A-type oligosaccharyltransferase complex in order to regulate N-glycan occupancy of specific substrates including glycohormones and GPI-anchored proteins which have key roles in cell adhesion and communication. Given the importance of limiting the ER stress that occurs in different pathologies such as neurodegenerative, cardiovascular, metabolic and immune diseases, further work should be performed to better understand the role of SELENOT, and to design small mimetics such as selenopeptides to improve ER proteostasis and to prevent ER stress. In this review, we present the current state-of-art on the role of SELENOT in ER homeostasis, based on our observations that SELENOT is essential to alleviate ER stress.
    DOI:  https://doi.org/10.1089/ars.2019.7931
  5. Cell Metab. 2020 Jun 02. pii: S1550-4131(20)30257-6. [Epub ahead of print]
    Ibrahim A, Yucel N, Kim B, Arany Z.
      Most organs use fatty acids (FAs) as a key nutrient, but little is known of how blood-borne FAs traverse the endothelium to reach underlying tissues. We conducted a small-molecule screen and identified niclosamide as a suppressor of endothelial FA uptake and transport. Structure/activity relationship studies demonstrated that niclosamide acts through mitochondrial uncoupling. Inhibitors of oxidative phosphorylation and the ATP/ADP translocase also suppressed FA uptake, pointing principally to ATP production. Decreasing total cellular ATP by blocking glycolysis did not decrease uptake, indicating that specifically mitochondrial ATP is required. Endothelial FA uptake is promoted by fatty acid transport protein 4 (FATP4) via its ATP-dependent acyl-CoA synthetase activity. Confocal microscopy revealed that FATP4 resides in the endoplasmic reticulum (ER), and that endothelial ER is intimately juxtaposed with mitochondria. Together, these data indicate that mitochondrial ATP production, but not total ATP levels, drives endothelial FA uptake and transport via acyl-CoA formation in mitochondrial/ER microdomains.
    Keywords:  ATP; FATP4; endothelial; fatty acid; mitochondria; niclosamide; vectorial acylation
    DOI:  https://doi.org/10.1016/j.cmet.2020.05.018
  6. Pulm Circ. 2020 Apr-Jun;10(2):10(2): 2045894020925762
    McCullough DJ, Kue N, Mancini T, Vang A, Clements RT, Choudhary G.
      Pulmonary hypertension is associated with pronounced exercise intolerance (decreased V ċ O2 max) that can significantly impact quality of life. The cause of exercise intolerance in pulmonary hypertension remains unclear. Mitochondrial supercomplexes are large respiratory assemblies of individual electron transport chain complexes which can promote more efficient respiration. In this study, we examined pulmonary hypertension and exercise-induced changes in skeletal muscle electron transport chain protein expression and supercomplex assembly. Pulmonary arterial hypertension was induced in rats with the Sugen/Hypoxia model (10% FiO2, three weeks). Pulmonary arterial hypertension and control rats were assigned to an exercise training protocol group or kept sedentary for one month. Cardiac function and V ċ O2 max were assessed at the beginning and end of exercise training. Red (Type 1-oxidative muscle) and white (Type 2-glycolytic muscle) gastrocnemius were assessed for changes in electron transport chain complex protein expression and supercomplex assembly via SDS- and Blue Native-PAGE. Results showed that pulmonary arterial hypertension caused a significant decrease in V ċ O2 max via treadmill testing that was improved with exercise (P < 0.01). Decreases in cardiac output and pulmonary acceleration time due to pulmonary arterial hypertension were not improved with exercise. Pulmonary arterial hypertension reduced expression in individual electron transport chain complex protein expression (NDUFB8 (CI), SDHB (CII), Cox IV (CIV), but not UQCRC2 (CIII), or ATP5a (CV)) in red gastrocnemius muscle. Both red gastrocnemius and white gastrocnemius electron transport chain expression was unaffected by exercise. However, non-denaturing Blue Native-PAGE analysis of mitochondrial supercomplexes demonstrated increases with exercise training in pulmonary arterial hypertension in the red gastrocnemius but not white gastrocnemius muscle. Pulmonary arterial hypertension-induced exercise intolerance is improved with exercise and is associated with muscle type specific alteration in mitochondrial supercomplex assembly and expression of mitochondrial electron transport chain proteins.
    Keywords:  exercise intolerance; respirasome; right heart failure; supercomplexes
    DOI:  https://doi.org/10.1177/2045894020925762
  7. Redox Biol. 2020 May 26. pii: S2213-2317(20)30358-X. [Epub ahead of print]36 101568
    Brown JA, Sammy MJ, Ballinger SW.
      The incidence of common, metabolic diseases (e.g. obesity, cardiovascular disease, diabetes) with complex genetic etiology has been steadily increasing nationally and globally. While identification of a genetic model that explains susceptibility and risk for these diseases has been pursued over several decades, no clear paradigm has yet been found to disentangle the genetic basis of polygenic/complex disease development. Since the evolution of the eukaryotic cell involved a symbiotic interaction between the antecedents of the mitochondrion and nucleus (which itself is a genetic hybrid), we suggest that this history provides a rational basis for investigating whether genetic interaction and co-evolution of these genomes still exists. We propose that both mitochondrial and Mendelian, or "mito-Mendelian" genetics play a significant role in cell function, and thus disease risk. This paradigm contemplates the natural variation and co-evolution of both mitochondrial and nuclear DNA backgrounds on multiple mitochondrial functions that are discussed herein, including energy production, cell signaling and immune response, which collectively can influence disease development. At the nexus of these processes is the economy of mitochondrial metabolism, programmed by both mitochondrial and nuclear genomes.
    DOI:  https://doi.org/10.1016/j.redox.2020.101568