bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒03‒29
23 papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Antioxid Redox Signal. 2020 Mar 25.
    Ji L, Yeo D, Kang C.
      SIGNIFICANCE: Regular contractile activity plays a critical role in maintaining skeletal muscle morphological integrity and physiological function. If the muscle is forced to stop contraction, such as during limb immobilization (IM), the IGF/Akt/mTOR signaling pathway that normally stimulates protein synthesis and inhibits proteolysis will be suppressed, whereas the FoxO-controlled catabolic pathways such as ubiquitin-proteolysis and autophagy/mitophagy will be activated and dominate, resulting in muscle fiber atrophy. Recent Advances. Mitochondria occupy a central position in regulating both protein synthesis and degradation via several redox-sensitive pathways including PGC-1α, mitochondrial fusion/fission proteins, mitophagy, and sirtuins. Prolonged IM downregulates PGC-1α due to AMPK and FoxO activation thus decreasing mitochondrial biogenesis and causing oxidative damage. Decline of mitochondrial inner membrane potential and increased mitochondrial fission can trigger cascades of mitophagy leading to loss of mitochondrial homeostasis (mitostasis), inflammation, and apoptosis. The phenotypic outcomes of these disorders are compromised muscle function and fiber atrophy.CRITICAL ISSUES: Given the molecular mechanism of the pathogenesis, it is imperative that the integrity of intracellular signaling be restored to prevent the deterioration. So far, overexpression of PGC-1α via transgene and in vivo DNA transfection has been found to be effective in ameliorating mitostasis and reduces IM-induced muscle atrophy. Nutritional supplementation of select amino acids and phytochemicals also provides mechanistic and practical insights into the prevention of muscle disuse atrophy.
    FUTURE DIRECTIONS: In light of the importance of mitochondria in regulating the various critical signaling pathways, future work should focus on exploring new epigenetic strategies to restore mitostasis and redox balance.
  2. Skelet Muscle. 2020 ;10 7
    Kallabis S, Abraham L, Müller S, Dzialas V, Türk C, Wiederstein JL, Bock T, Nolte H, Nogara L, Blaauw B, Braun T, Krüger M.
      Background: Skeletal muscles are composed of a heterogeneous collection of fiber types with different physiological adaption in response to a stimulus and disease-related conditions. Each fiber has a specific molecular expression of myosin heavy chain molecules (MyHC). So far, MyHCs are currently the best marker proteins for characterization of individual fiber types, and several proteome profiling studies have helped to dissect the molecular signature of whole muscles and individual fibers.Methods: Herein, we describe a mass spectrometric workflow to measure skeletal muscle fiber type-specific proteomes. To bypass the limited quantities of protein in single fibers, we developed a Proteomics high-throughput fiber typing (ProFiT) approach enabling profiling of MyHC in single fibers. Aliquots of protein extracts from separated muscle fibers were subjected to capillary LC-MS gradients to profile MyHC isoforms in a 96-well format. Muscle fibers with the same MyHC protein expression were pooled and subjected to proteomic, pulsed-SILAC, and phosphoproteomic analysis.
    Results: Our fiber type-specific quantitative proteome analysis confirmed the distribution of fiber types in the soleus muscle, substantiates metabolic adaptions in oxidative and glycolytic fibers, and highlighted significant differences between the proteomes of type IIb fibers from different muscle groups, including a differential expression of desmin and actinin-3. A detailed map of the Lys-6 incorporation rates in muscle fibers showed an increased turnover of slow fibers compared to fast fibers. In addition, labeling of mitochondrial respiratory chain complexes revealed a broad range of Lys-6 incorporation rates, depending on the localization of the subunits within distinct complexes.
    Conclusion: Overall, the ProFiT approach provides a versatile tool to rapidly characterize muscle fibers and obtain fiber-specific proteomes for different muscle groups.
    Keywords:  Muscle fiber proteomics; MyHC profiling; Phosphoproteomics; Protein turnover
  3. Curr Opin Cell Biol. 2020 Mar 19. pii: S0955-0674(20)30030-2. [Epub ahead of print]65 42-49
    Vassilopoulos S.
      In skeletal muscle fibers, ubiquitous membrane trafficking pathways responsible for transporting newly synthesized proteins, recycling cell surface receptors, and organizing membrane compartmentation have adapted to the high needs of an extremely specialized cell under constant mechanical stress. Membrane remodeling proteins involved in ubiquitous mechanisms such as clathrin-mediated endocytosis, caveolae formation, and membrane fusion have evolved to produce new pathways with sometimes completely different functions such as adhesion and mechanoprotection. In this review, I discuss recent advances in understanding the specialized features of skeletal muscle clathrin-coated plaques, caveolae, and dysferlin-mediated membrane repair. A special emphasis is given on recent findings suggesting that membrane trafficking pathways have evolved to participate into the mechanisms responsible for sarcolemma resistance to mechanical stress and discuss how defects in these pathways result in muscle disease.
    Keywords:  Caveolae; Clathrin; Costameres; Dynamin; Mechanoprotection; Membrane repair; Membrane stress; Myopathy; Skeletal muscle
  4. Curr Opin Cell Biol. 2020 Mar 21. pii: S0955-0674(20)30033-8. [Epub ahead of print]65 58-65
    Harper CS, White AJ, Lackner LL.
      Mitochondria make physical contact with nearly every other membrane in the cell, and these contacts have a wide variety of functions that are carried out by proteins that reside at the sites of contact. Over the past decade, tremendous insight into the identity and functions of proteins localized to mitochondrial contact sites has been gained. In doing so, it has become clear that one protein or protein complex can contribute to contact site formation and function in a wide variety of ways. Thus, complex and often surprising relationships between the roles of a mitochondrial contact site and its multifunctional resident proteins continue to be unraveled.
    Keywords:  Membrane contact sites; Mitochondria; Mitochondrial contact sites
  5. FASEB J. 2020 Mar 23.
    Leermakers PA, Remels AHV, Zonneveld MI, Rouschop KMA, Schols AMWJ, Gosker HR.
      Iron homeostasis is essential for mitochondrial function, and iron deficiency has been associated with skeletal muscle weakness and decreased exercise capacity in patients with different chronic disorders. We hypothesized that iron deficiency-induced loss of skeletal muscle mitochondria is caused by increased mitochondrial clearance. To study this, C2C12 myotubes were subjected to the iron chelator deferiprone. Mitochondrial parameters and key constituents of mitophagy pathways were studied in presence or absence of pharmacological autophagy inhibition or knockdown of mitophagy-related proteins. Furthermore, it was explored if mitochondria were present in extracellular vesicles (EV). Iron chelation resulted in an increase in BCL2/Adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and BNIP3-like gene and protein levels, and the appearance of mitochondria encapsulated by lysosome-like vesicular structures in myotubes. Moreover, mitochondria were secreted via EV. These changes were associated with cellular mitochondrial impairments. These impairments were unaltered by autophagy inhibition, knockdown of mitophagy-related proteins BNIP3 and BNIP3L, or knockdown of their upstream regulator hypoxia-inducible factor 1 alpha. In conclusion, mitophagy is not essential for development of iron deficiency-induced reductions in mitochondrial proteins or respiratory capacity. The secretion of mitochondria-containing EV could present an additional pathway via which mitochondria can be cleared from iron chelation-exposed myotubes.
    Keywords:  extracellular vesicles; iron depletion; mitochondrial clearance; myotubes
  6. Antioxidants (Basel). 2020 Mar 23. pii: E263. [Epub ahead of print]9(3):
    Doerr V, Montalvo RN, Kwon OS, Talbert EE, Hain BA, Houston FE, Smuder AJ.
      Clinical use of the chemotherapeutic doxorubicin (DOX) promotes skeletal muscle atrophy and weakness, adversely affecting patient mobility and strength. Although the mechanisms responsible for DOX-induced skeletal muscle dysfunction remain unclear, studies implicate the significant production of reactive oxygen species (ROS) in this pathology. Supraphysiological ROS levels can enhance protein degradation via autophagy, and it is established that DOX upregulates autophagic signaling in skeletal muscle. To determine the precise contribution of accelerated autophagy to DOX-induced skeletal muscle dysfunction, we inhibited autophagy in the soleus via transduction of a dominant negative mutation of the autophagy related 5 (ATG5) protein. Targeted inhibition of autophagy prevented soleus muscle atrophy and contractile dysfunction acutely following DOX administration, which was associated with a reduction in mitochondrial ROS and maintenance of mitochondrial respiratory capacity. These beneficial modifications were potentially the result of enhanced transcription of antioxidant response element-related genes and increased antioxidant capacity. Specifically, our results showed significant upregulation of peroxisome proliferator-activated receptor gamma co-activator 1-alpha, nuclear respiratory factor-1, nuclear factor erythroid-2-related factor-2, nicotinamide-adenine dinucleotide phosphate quinone dehydrogenase-1, and catalase in the soleus with DOX treatment when autophagy was inhibited. These findings establish a significant role of autophagy in the development of oxidative stress and skeletal muscle weakness following DOX administration.
    Keywords:  adriamycin; antioxidant; mitochondria; peroxisome proliferator-activated receptor gamma co-activator 1-alpha, chemotherapy
  7. Trends Cell Biol. 2020 Apr;pii: S0962-8924(20)30020-9. [Epub ahead of print]30(4): 317-328
    Lu B, Guo S.
      Maintaining cellular protein homeostasis (proteostasis) is an essential task for all eukaryotes. Proteostasis failure worsens with aging and is considered a cause of and a therapeutic target for age-related diseases including neurodegenerative disorders. The cellular networks regulating proteostasis and the pathogenic events driving proteostasis failure in disease remain poorly understood. Model organism studies in yeast and Drosophila reveal an intriguing link between mitochondrial function and proteostasis. In this review we examine recent findings on mitochondrial outer membrane (MOM)-associated mRNA translation, how this process is sensitive to mitochondrial dysfunction and constantly surveyed by ribosome-associated quality control (RQC), and how defects in this process generate aberrant proteins with unusual C-terminal extensions (CTEs) that promote aggregation and drive proteostasis failure. We also discuss the implications for human diseases.
    Keywords:  CAT-tailing; MISTERMINATE; co-translational mitochondrial import; mitochondrial dysfunction; protein homeostasis (proteostasis); ribosome-associated quality control
  8. J Gerontol A Biol Sci Med Sci. 2020 Mar 23. pii: glaa071. [Epub ahead of print]
    Zampino M, Semba RD, Adelnia F, Spencer RG, Fishbein KW, Schrack JA, Simonsick EM, Ferrucci L.
      BACKGROUND: Resting metabolic rate (RMR) tends to decline with aging. The age-trajectory of decline in RMR is similar to changes that occur in muscle mass, muscle strength and fitness but while the decline in these phenotypes have been related to changes of mitochondrial function and oxidative capacity, whether lower RMR is associated with poorer mitochondrial oxidative capacity is unknown.METHODS: In 619 participants of the Baltimore Longitudinal Study of Aging, we analyzed the cross-sectional association between RMR (kcal/day), assessed by indirect calorimetry, and skeletal muscle maximal oxidative phosphorylation capacity, assessed as post-exercise phosphocreatine recovery time constant (τPCr), by phosphorous magnetic resonance spectroscopy. Linear regression models were used to evaluate the relationship between τPCr and RMR, adjusting for potential confounders.
    RESULTS: Independent of age, sex, lean body mass, muscle density and fat mass, higher RMR was significantly associated with shorter τPCr, indicating greater mitochondrial oxidative capacity.
    CONCLUSION: Higher RMR is associated with a higher mitochondrial oxidative capacity in skeletal muscle. This association may reflect a relationship between better muscle quality and greater mitochondrial health.
  9. Lab Anim (NY). 2020 Apr;49(4): 119-125
    Mousavi SR, Jafari M, Rezaei S, Agha-Alinejad H, Sobhani V.
      Exercise induces different effects on antioxidant status depending on its intensity. The forced running wheel (FRW) model maintains a constant intensity and volume during exercise. The aim of the present study was to investigate the effects of FRW exercise at different running speeds on several serum biochemical parameters of liver and muscle functions and on oxidative stress biomarkers in skeletal muscle, liver and serum in the rat. Thirty-six male Wistar rats were randomly divided into six groups. Five groups participated in constant power tests at intensities of 10, 13, 14.5, 16, and 17.5 m/min, and a non-exercise group was chosen as the control. Serum, muscle and liver tissues were collected after the tests and analyzed. At speeds >16 m/min, exercise on an FRW significantly increased several serum biochemical parameters, malondialdehyde level and superoxide dismutase activity in all tissues of exercise rats compared with control rats; FRW exercise also increased catalase activity in the liver and glutathione S-transferase activity in muscle, whereas it decreased glutathione level in all tissues and catalase activity in muscle and serum. These data suggest that FRW exercise in rats activates an adaptation of the antioxidant system response in skeletal muscle at speeds <16 m/min, whereas it induces oxidative stress at higher speeds in muscle, liver and serum. In addition, we observed a correlation between the systematic and local oxidative stress status in rats after exercise on FRW.
  10. J Appl Physiol (1985). 2020 Mar 26.
    Eshima H, Tamura Y, Kakehi S, Kakigi R, Hashimoto R, Funai K, Kawamori R, Watada H.
      Obesity and aging reduce skeletal muscle contractile function. However, it remains unclear whether obesity additively promotes muscle contractile dysfunction in the setting of aging. In this study, we investigated skeletal muscle contractile function ex vivo and intracellular Ca2+ release in male C57BL/6 mice fed a low-fat diet (LFD) or a high-fat diet (HFD) for 4 or 20 months. Tetanic force production in the extensor digitorum longus muscle was decreased by aging or HFD-feeding, and the further reduction was observed in aged HFD mice. The 20-month HFD-fed mice, not the 20-month LFD-fed mice nor 4-month HFD-fed mice showed reduced intracellular Ca2+ peak levels by high-concentration of caffeine (25 mM) compared with 4-month LFD mice. Aging and HFD feeding additively increased intracellular lipid (IMCL) levels and was associated with the degree of impaired muscle contractile force and peak Ca2+ level. These data suggest that impairment in the contractile force in aged muscle is aggravated by HFD, which may be due at least in part to dysfunction in intracellular Ca2+ release. The IMCL level may be a marker for impaired muscle contractile force caused by aging and HFD.
    Keywords:  aging; calcium; high-fat diet; muscle contraction; obesity
  11. Redox Biol. 2020 Mar 16. pii: S2213-2317(20)30125-7. [Epub ahead of print]32 101507
    Fernando R, Wardelmann K, Deubel S, Kehm R, Jung T, Mariotti M, Vasilaki A, Gladyshev VN, Kleinridders A, Grune T, Castro JP.
      Adipogenesis is a fundamental process of white adipose tissue function, supporting lipid storage and release, while avoiding its spillover and ectopic accumulation in tissues and organs. During aging adipogenesis is impaired and among other factors, oxidative stress contributes to this process. Adipogenesis requires functional and dynamic mitochondria; however, this organelle itself becomes dysfunctional during aging and accounts for most of reactive oxygen species (ROS) production. Here, we evaluated whether oxidative stress impairs adipogenesis through functional impairment of mitodynamics by utilizing hyperoxia as a continuous source of oxidative stress while maintaining cellular viability. This negatively impacted mitochondrial function, including respiration and dynamics and ultimately blocked adipogenesis. Interestingly, this state was reversible by using the antidiabetic drug, Rosiglitazone, which reduced oxidative stress, restored mitochondrial dynamics and respiration and augmented adipogenesis. Moreover, in vitro results were in agreement with in vivo models of oxidative stress and aging, in which mice depleted of the superoxide dismutase enzyme 1 (SOD1) and old wild-type C57BL/6JRj mice demonstrated the same trend of adipogenic potential. Importantly, in humans the results follow the same pattern, showing a downregulation of adipogenic markers during aging. Since the levels of oxidative stress and peripheral insulin resistance increase with age, while adipogenesis decreases during aging, our model helps to understand a possible way to overcome physiologically low, steady stress conditions and restore adipogenesis, avoiding accumulation of deleterious hypertrophic adipocytes in favor of beneficial hyperplasia.
    Keywords:  Adipogenesis; Hyperoxia; Mitochondrial dysfunction; Oxidative stress; Rosiglitazone
  12. Nat Commun. 2020 Mar 25. 11(1): 1560
    Raun SH, Henriquez-Olguín C, Karavaeva I, Ali M, Møller LLV, Kot W, Castro-Mejía JL, Nielsen DS, Gerhart-Hines Z, Richter EA, Sylow L.
      Exercise training is a powerful means to combat metabolic diseases. Mice are extensively used to investigate the benefits of exercise, but mild cold stress induced by ambient housing temperatures may confound translation to humans. Thermoneutral housing is a strategy to make mice more metabolically similar to humans but its effects on exercise adaptations are unknown. Here we show that thermoneutral housing blunts exercise-induced improvements in insulin action in muscle and adipose tissue and reduces the effects of training on energy expenditure, body composition, and muscle and adipose tissue protein expressions. Thus, many reported effects of exercise training in mice are likely secondary to metabolic stress of ambient housing temperature, making it challenging to translate to humans. We conclude that adaptations to exercise training in mice critically depend upon housing temperature. Our findings underscore housing temperature as a critical parameter in the design and interpretation of murine exercise training studies.
  13. Pharmacol Res. 2020 Mar 18. pii: S1043-6618(19)32049-3. [Epub ahead of print] 104758
    Silva-Palacios A, Zazueta C, Pedraza-Chaverri J.
      Cardiovascular system cell biology is tightly regulated and mitochondria play a relevant role in maintaining heart function. In recent decades, associations between such organelles and the sarco/endoplasmic reticulum (SR) have been raised great interest. Formally identified as mitochondria-associated SR membranes (MAMs), these structures regulate different cellular functions, including calcium management, lipid metabolism, autophagy, oxidative stress, and management of unfolded proteins. In this review, we highlight MAMs' alterations mainly in cardiomyocytes, linked with cardiovascular diseases, such as cardiac ischemia-reperfusion, heart failure, and dilated cardiomyopathy. We also describe proteins that are part of the MAMs' machinery, as the FUN14 domain containing 1 (FUNDC1), the sigma 1 receptor (Sig-1R) and others, which might be new molecular targets to preserve the function and structure of the heart in such diseases. Understanding the machinery of MAMs and its function demands our attention, as such knowledge might contribute to strengthen the role of these relative novel structures in heart diseases.
    Keywords:  MAMs; cardiomyocytes; cardiovascular diseases; endoplasmic reticulum; mitochondria
  14. Endocrinol Metab (Seoul). 2020 Mar;35(1): 1-6
    Kim G, Kim JH.
      Skeletal muscle is regarded as an endocrine and paracrine organ. Muscle-derived secretory proteins, referred to as myokines, mediate interactions between skeletal muscle mass and other organs such as the liver, adipose tissue, pancreas, bone, and the cardiovascular system. As individuals age, reduced levels of physical activity and sarcopenia (loss of skeletal muscle mass and strength) are associated with physical frailty and disability. Recently, several studies have suggested that the loss of skeletal muscle mass may contribute to metabolic disease. Therefore, herein, we focus on the relationships between skeletal muscle mass and metabolic diseases, including metabolic syndrome and non-alcoholic fatty liver disease.
    Keywords:  Metabolic syndrome; Muscle, skeletal; Non-alcoholic fatty liver disease; Sarcopenia
  15. Circ Res. 2020 Mar 27. 126(7): 926-941
    Wallace KB, Sardão VA, Oliveira PJ.
      Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes a historic record of past drug treatments (mitochondrial memory) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of doxorubicin-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation, and permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes and increased apoptosis. We also suggest some possible pharmacological and nonpharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in doxorubicin-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.
    Keywords:  cardiomyopathy; cardiotoxicity; doxorubicin; mitochondria; oxidative stress
  16. Cell Mol Life Sci. 2020 Mar 21.
    Pascoe AL, Johnston AJ, Murphy RM.
      Skeletal muscle is one of the largest functional tissues in the human body; it is highly plastic and responds dramatically to anabolic and catabolic stimuli, including weight training and malnutrition, respectively. Excessive loss of muscle mass, or atrophy, is a common symptom of many disease states with severe impacts on prognosis and quality of life. TNF-like weak inducer of apoptosis (TWEAK) and its cognate receptor, fibroblast growth factor-inducible 14 (Fn14) are an emerging cytokine signaling pathway in the pathogenesis of muscle atrophy. Upregulation of TWEAK and Fn14 has been described in a number of atrophic and injured muscle states; however, it remains unclear whether they are contributing to the degenerative or regenerative aspect of muscle insults. The current review focuses on the expression and apparent downstream outcomes of both TWEAK and Fn14 in a range of catabolic and anabolic muscle models. Apparent changes in the signaling outcomes of TWEAK-Fn14 activation dependent on the relative expression of both the ligand and the receptor are discussed as a potential source of divergent TWEAK-Fn14 downstream effects. This review proposes both a physiological and pathological model of TWEAK-Fn14 signaling. Further research is needed on the switch between these states to develop therapeutic interventions for this pathway.
    Keywords:  Cachexia; Differentiation; Muscle loss; Myogenesis; NFκb; Proliferation
  17. Med Sci Sports Exerc. 2020 Mar 20.
    Hentilä J, Hulmi JJ, Laakkonen EK, Ahtiainen JP, Suominen H, Korhonen MT.
      PURPOSE: Exercise and aging may modulate muscle protein homeostasis and autophagy, but few studies examine highly-trained middle-aged or older individuals. This study elucidated the effects of a new long-term training stimulus on markers of muscle autophagy and unfolded protein response (UPR) and on sprint running performance in masters sprinters.METHODS: Thirty-two male competitive sprinters (aged 40-76 years) were randomly divided into experimental (EX) and control (CTRL) groups. The EX training program was a combination of heavy and explosive strength and sprint exercises aimed at improving sprint performance. Fifteen and thirteen participants completed the 20-week intervention period in EX and CTRL, respectively. The latter were told to continue their routine exercises. Key protein markers were analyzed by western blotting from vastus lateralis (VL) muscle biopsies. Muscle thickness of VL was analyzed by ultrasonography and sprint performance by a 60-meter running test.
    RESULTS: EX induced improvement in 60-meter sprint performance when compared to controls (time x group, P = 0.003) without changes in VL muscle thickness. Content of lipidated microtubule-associated protein 1A/1B-light chain 3 (LC3-II) increased in EX (P = 0.022) suggesting increased autophagosome content. Additionally, an autophagosome clearance marker sequestosome 1 (p62) decreased in EX (P = 0.006). Markers of UPR selectively modulated with decreases (e.g. ATF4, P = 0.003) and increases (e.g. EIF2α, P = 0.019) observed in EX.
    CONCLUSIONS: These findings suggest that a new intensive training stimulus that combines strength training with sprint training may increase muscle autophagosome content in a basal state without any evidence of impaired autophagosome clearance in masters sprinters. Simultaneously, the combined training may have a selective effect on the content of UPR signaling components.
  18. Mol Metab. 2020 Feb 15. pii: S2212-8778(20)30008-9. [Epub ahead of print] 100942
    Wiese M, Bannister AJ.
      BACKGROUND: Virtually all eukaryotic cells contain spatially distinct genomes, a single nuclear genome that harbours the vast majority of genes and much smaller genomes found in mitochondria present at thousands of copies per cell. To generate a coordinated gene response to various environmental cues, the genomes must communicate with each another. Much of this bi-directional crosstalk relies on epigenetic processes, including DNA, RNA, and histone modification pathways. Crucially, these pathways, in turn depend on many metabolites generated in specific pools throughout the cell, including the mitochondria. They also involve the transport of metabolites as well as the enzymes that catalyse these modifications between nuclear and mitochondrial genomes.SCOPE OF REVIEW: This study examines some of the molecular mechanisms by which metabolites influence the activity of epigenetic enzymes, ultimately affecting gene regulation in response to metabolic cues. We particularly focus on the subcellular localisation of metabolite pools and the crosstalk between mitochondrial and nuclear proteins and RNAs. We consider aspects of mitochondrial-nuclear communication involving histone proteins, and potentially their epigenetic marks, and discuss how nuclear-encoded enzymes regulate mitochondrial function through epitranscriptomic pathways involving various classes of RNA molecules within mitochondria.
    MAJOR CONCLUSIONS: Epigenetic communication between nuclear and mitochondrial genomes occurs at multiple levels, ultimately ensuring a coordinated gene expression response between different genetic environments. Metabolic changes stimulated, for example, by environmental factors, such as diet or physical activity, alter the relative abundances of various metabolites, thereby directly affecting the epigenetic machinery. These pathways, coupled to regulated protein and RNA transport mechanisms, underpin the coordinated gene expression response. Their overall importance to the fitness of a cell is highlighted by the identification of many mutations in the pathways we discuss that have been linked to human disease including cancer.
    Keywords:  Chromatin; Enzymes; Epigenetics; Histones; Metabolites; Mitochondria; RNA modification
  19. Biochem Soc Trans. 2020 Mar 27. pii: BST20190987. [Epub ahead of print]
    Das R, Chakrabarti O.
      The cellular mitochondrial population undergoes repeated cycles of fission and fusion to maintain its integrity, as well as overall cellular homeostasis. While equilibrium usually exists between the fission-fusion dynamics, their rates are influenced by organellar and cellular metabolic and pathogenic conditions. Under conditions of cellular stress, there is a disruption of this fission and fusion balance and mitochondria undergo either increased fusion, forming a hyperfused meshwork or excessive fission to counteract stress and remove damaged mitochondria via mitophagy. While some previous reports suggest that hyperfusion is initiated to ameliorate cellular stress, recent studies show its negative impact on cellular health in disease conditions. The exact mechanism of mitochondrial hyperfusion and its role in maintaining cellular health and homeostasis, however, remain unclear. In this review, we aim to highlight the different aspects of mitochondrial hyperfusion in either promoting or mitigating stress and also its role in immunity and diseases.
    Keywords:  ER-mitochondria cross-talk; fission–fusion dynamics; hyperfusion; mitochondria
  20. J Biol Methods. 2020 ;7(1): e127
    Roberts MD, Young KC, Fox CD, Vann CG, Roberson PA, Osburn SC, Moore JH, Mumford PW, Romero MA, Beck DT, Haun CT, Badisa VLD, Mwashote BM, Ibeanusi V, Kavazis AN.
      Several published protocols exist for isolating contractile or myofibrillar (MF) proteins from skeletal muscle, however, achieving complete resuspension of the myofibril pellet can be technically challenging. We performed several previously published MF isolation methods with the intent of determining which method was most suitable for MF protein isolation and solubilization. Here, we provide an optimized protocol to isolate sarcoplasmic and solubilized MF protein fractions from mammalian skeletal muscle suitable for several downstream assays.
    Keywords:  MF protein; actin; muscle; myosin; protein isolation
  21. Biochim Biophys Acta Bioenerg. 2020 Mar 19. pii: S0005-2728(20)30043-8. [Epub ahead of print] 148193
    Stuchebrukhov A, Schäfer J, Berg J, Brzezinski P.
      Components of respiratory chains in mitochondria and some aerobic bacteria assemble into larger, multiprotein membrane-bound supercomplexes. Here, we address the functional significance of supercomplexes composed of respiratory-chain complexes III and IV. Complex III catalyzes oxidation of quinol and reduction of water-soluble cytochrome c (cyt c), while complex IV catalyzes oxidation of the reduced cyt c and reduction of dioxygen to water. We focus on two questions: (i) under which conditions does diffusion of cyt c become rate limiting for electron transfer between these two complexes? (ii) is there a kinetic advantage of forming a supercomplex composed of complexes III and IV? To answer these questions, we use a theoretical approach and assume that cyt c diffuses in the water phase while complexes III and IV either diffuse independently in the two dimensions of the membrane or form supercomplexes. The analysis shows that the electron flux between complexes III and IV is determined by the equilibration time of cyt c within the volume of the intermembrane space, rather than the cyt c diffusion time constant. Assuming realistic relative concentrations of membrane-bound components and cyt c and that all components diffuse independently, the data indicate that electron transfer between complexes III and IV can become rate limiting. Hence, there is a kinetic advantage of bringing complexes III and IV together in the membrane to form supercomplexes.
    Keywords:  Cytochrome aa(3); Electron transfer; Kinetics; Ligand; Mechanism; Membrane protein; Proton transfer
  22. Cell Death Dis. 2020 Mar 23. 11(3): 204
    Lee DG, Kam MK, Lee SR, Lee HJ, Lee DS.
      Iron is an essential element for cellular functions, including those of neuronal cells. However, an imbalance of iron homeostasis, such as iron overload, has been observed in several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Iron overload causes neuronal toxicity through mitochondrial fission, dysregulation of Ca2+, ER-stress, and ROS production. Nevertheless, the precise mechanisms between iron-induced oxidative stress and iron toxicity related to mitochondria and endoplasmic reticulum (ER) in vivo are not fully understood. Here, we demonstrate the role of peroxiredoxin 5 (Prx5) in iron overload-induced neurotoxicity using Prx5-deficient mice. Iron concentrations and ROS levels in mice fed a high iron diet were significantly higher in Prx5-/- mice than wildtype (WT) mice. Prx5 deficiency also exacerbated ER-stress and ER-mediated mitochondrial fission via Ca2+/calcineurin-mediated dephosphorylation of Drp1 at Serine 637. Moreover, immunoreactive levels of cleaved caspase3 in the CA3 region of the hippocampus were higher in iron-loaded Prx5-/- mice than WT mice. Furthermore, treatment with N-acetyl-cysteine, a reactive oxygen species (ROS) scavenger, attenuated iron overload-induced hippocampal damage by inhibiting ROS production, ER-stress, and mitochondrial fission in iron-loaded Prx5-/- mice. Therefore, we suggest that iron overload-induced oxidative stress and ER-mediated mitochondrial fission may be essential for understanding iron-mediated neuronal cell death in the hippocampus and that Prx5 may be useful as a novel therapeutic target in the treatment of iron overload-mediated diseases and neurodegenerative diseases.
  23. J Gerontol A Biol Sci Med Sci. 2020 Mar 26. pii: glaa072. [Epub ahead of print]
    Petrocelli JJ, McKenzie AI, Mahmassani ZS, Reidy PT, Stoddard GJ, Poss AM, Holland WL, Summers SA, Drummond MJ.
      Acute bed rest places older adults at risk for health complications by disrupting homeostasis in many organ systems, including the cardiovascular system. Circulating ceramides are emerging biomarkers predictive of cardiovascular and metabolic health and have recently been shown to be sensitive indices of cardiovascular (CV) risk. Therefore, the purpose of this study was to characterize the time course of changes in circulating ceramides in healthy younger and older adults after 5d of bed rest and to determine whether short-term bed rest alters CV-related circulating ceramides. We hypothesized that circulating ceramides predictive of poor cardiometabolic outcomes would increase following 5-days of bed rest. Thirty-five healthy younger and older men and women (young: n=13, old: n=22) underwent 5-days of controlled bed rest. Fasting blood samples collected daily during the course of bed rest were used to measure circulating ceramides, lipoproteins, adiponectin, and fibroblast growth factor 21 (FGF21) levels. The primary findings were that circulating ceramides decreased while ceramide ratios and the cardiac event risk rest 1 (CERT1) score were increased primarily in older adults, and these findings were independent of changes in circulating lipoprotein levels. Additionally, we found that changes in circulating adiponectin, FGF21 and the six-minute walk test (6MW) inversely correlated with CV-related circulating ceramides after bed rest. The results of this study highlight the sensitivity of circulating ceramides to detect potential CV dysfunction that may occur with acute physical disuse in aging.
    Keywords:  CV risk factors; Sphingolipids; blood lipids; disuse; inactivity