bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒05‒17
seventeen papers selected by
Rafael Antonio Casuso Pérez
University of Granada


  1. Trends Cell Biol. 2020 Jun;pii: S0962-8924(20)30055-6. [Epub ahead of print]30(6): 428-439
    Anderson NS, Haynes CM.
      Eukaryotic cells must accurately monitor the integrity of the mitochondrial network to overcome environmental insults and respond to physiological cues. The mitochondrial unfolded protein response (UPRmt) is a mitochondrial-to-nuclear signaling pathway that maintains mitochondrial proteostasis, mediates signaling between tissues, and regulates organismal aging. Aberrant UPRmt signaling is associated with a wide spectrum of disorders, including congenital diseases as well as cancers and neurodegenerative diseases. Here, we review recent research into the mechanisms underlying UPRmt signaling in Caenorhabditis elegans and discuss emerging connections between the UPRmt signaling and a translational regulation program called the 'integrated stress response'. Further study of the UPRmt will potentially enable development of new therapeutic strategies for inherited metabolic disorders and diseases of aging.
    Keywords:  integrated stress response; mitochondria; mitochondrial unfolded protein response; stress signaling
    DOI:  https://doi.org/10.1016/j.tcb.2020.03.001
  2. Scand J Med Sci Sports. 2020 May 13.
    Skattebo Ø, Capelli C, B Rud , Auensen M, Calbet JAL, Hallén J.
      When exercising with a small muscle mass, the mass-specific O2 delivery exceeds the muscle oxidative capacity resulting in a lower O2 extraction compared to whole-body exercise. We elevated the muscle oxidative capacity and tested its impact on O2 extraction during small muscle mass exercise. Nine individuals conducted six weeks of one-legged knee extension (1L-KE) endurance training. After training, the trained leg (TL) displayed 45% higher citrate synthase and COX-IV protein content in vastus lateralis and 15-22% higher pulmonary oxygen uptake ( V ˙ O2peak ) and peak power output ( W ˙ peak ) during 1L-KE than the control leg (CON; all P<0.05). Leg O2 extraction (catheters) and blood flow (ultrasound Doppler) were measured while both legs exercised simultaneously during 2L-KE at the same submaximal power outputs (real-time feedback-controlled). TL displayed higher O2 extraction than CON (main effect: 1.7±1.6%-points; P=0.010; 40-83% of W ˙ peak ) with the largest between-leg difference at 83% of W ˙ peak (O2 extraction: 3.2±2.2%-points; arteriovenous O2 difference: 7.1±4.8 mL·L-1 ; P<0.001). At 83% of W ˙ peak , muscle O2 conductance (DM O2 ; Fick law of diffusion) and the equilibration index Y were higher in TL (P<0.01), indicating reduced diffusion limitations. The between-leg difference in O2 extraction correlated with the between-leg ratio of citrate synthase and COX-IV (r=72-0.73; P=0.03), but not with the difference in the capillary-to-fibre ratio (P=0.965). In conclusion, endurance training improves O2 extraction during small muscle mass exercise by elevating the muscle oxidative capacity and the recruitment of DM O2 ; especially evident during high-intensity exercise exploiting a larger fraction of the muscle oxidative capacity.
    Keywords:  Arteriovenous oxygen difference; Blood flow; Endurance training; Fick method; Limitations; Maximal oxygen uptake; Muscle oxygen diffusion; Peripheral adaptations
    DOI:  https://doi.org/10.1111/sms.13707
  3. Front Cell Dev Biol. 2020 ;8 270
    Ravanelli S, den Brave F, Hoppe T.
      Mitochondria are essential organelles important for energy production, proliferation, and cell death. Biogenesis, homeostasis, and degradation of this organelle are tightly controlled to match cellular needs and counteract chronic stress conditions. Despite providing their own DNA, the vast majority of mitochondrial proteins are encoded in the nucleus, synthesized by cytosolic ribosomes, and subsequently imported into different mitochondrial compartments. The integrity of the mitochondrial proteome is permanently challenged by defects in folding, transport, and turnover of mitochondrial proteins. Therefore, damaged proteins are constantly sequestered from the outer mitochondrial membrane and targeted for proteasomal degradation in the cytosol via mitochondrial-associated degradation (MAD). Recent studies identified specialized quality control mechanisms important to decrease mislocalized proteins, which affect the mitochondrial import machinery. Interestingly, central factors of these ubiquitin-dependent pathways are shared with the ER-associated degradation (ERAD) machinery, indicating close collaboration between both tubular organelles. Here, we summarize recently described cellular stress response mechanisms, which are triggered by defects in mitochondrial protein import and quality control. Moreover, we discuss how ubiquitin-dependent degradation is integrated with cytosolic stress responses, particularly focused on the crosstalk between MAD and ERAD.
    Keywords:  C. elegans; Cdc48; Msp1; mitochondria; mitochondria-associated degradation (MAD); p97; proteostasis; ubiquitin
    DOI:  https://doi.org/10.3389/fcell.2020.00270
  4. J Appl Physiol (1985). 2020 May 14.
    Roberson PA, Shimkus KL, Welles JE, Xu D, Whitsell AL, Kimball EM, Jefferson LS, Kimball SR.
      INTRODUCTION: Skeletal muscle atrophy is associated with disease, aging, and disuse. Hindlimb unloading (HU) in animals provides an experimental model to study muscle atrophy. A comprehensive time course for how HU affects biomarkers of protein synthesis and degradation acutely and chronically, and the associated resistance to an anabolic stimulus following disuse, remains undocumented.METHODS: 16-week old C57BL/6 mice underwent 0, 1, 12, 24, 72, 168, or 336h of HU. Following 336h of HU, mice were reloaded for 1, 24, or 72h. Another group of mice underwent 120h of HU, were fasted or refed, and then compared to similar condition control animals (CTL). Protein content and phosphorylation of biomarkers of protein synthesis, degradation, and autophagy were assessed in the soleus muscle.
    RESULTS: Gastrocnemius, soleus, and plantaris muscles atrophied within 120h of HU. Protein synthesis trended to decrease following 24h of HU. p70S6K phosphorylation and protein synthesis increased with reloading. Following HU, changes in MAFbx and DEPTOR expression and DEPTOR phosphorylation were consistent with development of a catabolic state. DEPTOR expression recovered following reloading. Animals that underwent 120h of HU exhibited attenuation of refeeding-induced p70S6K phosphorylation compared to CTL counterparts. Following 120h of HU, protein synthesis, 4E-BP1 phosphorylation, and DEPTOR, MAFbx, and Sestrin1 expression indicated a catabolic state. Following 120h of HU, autophagy markers including p62 expression, REDD1 expression, LC3 ratio, and ULK-1 phosphorylation indicated impaired autophagy.
    CONCLUSIONS: HU promotes a deleterious balance between protein synthesis and degradation. The time course herein provides scientists information about when the associated biomarkers become affected.
    Keywords:  Hindlimb unloading; anabolic resistance; disuse atrophy; hindlimb suspension; skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00155.2020
  5. Nat Metab. 2019 Sep;1(9): 876-885
    Verkerke ARP, Ferrara PJ, Lin CT, Johnson JM, Ryan TE, Maschek JA, Eshima H, Paran CW, Laing BT, Siripoksup P, Tippetts TS, Wentzler EJ, Huang H, Spangenburg EE, Brault JJ, Villanueva CJ, Summers SA, Holland WL, Cox JE, Vance DE, Neufer PD, Funai K.
      The biophysical environment of membrane phospholipids affects structure, function, and stability of membrane-bound proteins.1,2 Obesity can disrupt membrane lipids, and in particular, alter the activity of sarco/endoplasmic reticulum (ER/SR) Ca2+-ATPase (SERCA) to affect cellular metabolism.3-5 Recent evidence suggests that transport efficiency (Ca2+ uptake / ATP hydrolysis) of skeletal muscle SERCA can be uncoupled to increase energy expenditure and protect mice from diet-induced obesity.6,7 In isolated SR vesicles, membrane phospholipid composition is known to modulate SERCA efficiency.8-11 Here we show that skeletal muscle SR phospholipids can be altered to decrease SERCA efficiency and increase whole-body metabolic rate. The absence of skeletal muscle phosphatidylethanolamine (PE) methyltransferase (PEMT) promotes an increase in skeletal muscle and whole-body metabolic rate to protect mice from diet-induced obesity. The elevation in metabolic rate is caused by a decrease in SERCA Ca2+-transport efficiency, whereas mitochondrial uncoupling is unaffected. Our findings support the hypothesis that skeletal muscle energy efficiency can be reduced to promote protection from obesity.
    DOI:  https://doi.org/10.1038/s42255-019-0111-2
  6. Endocr Rev. 2020 May 11. pii: bnaa016. [Epub ahead of print]
    Severinsen MCK, Pedersen BK.
      Physical activity decreases the risk of a network of diseases and exercise may be prescribed as medicine for lifestyle-related disorders such as type 2 diabetes, dementia, cardiovascular diseases and cancer. During the past couple of decades, it has been apparent that skeletal muscle works as an endocrine organ, which can produce and secrete hundreds of myokines that exert their effects in either autocrine, paracrine or endocrine manners. Recent advances show that skeletal muscle produces myokines in response to exercise, which allow for crosstalk between the muscle and other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed and skin, as well as communication within the muscle itself. Although only few myokines have been allocated to a specific function in humans, it has been identified that the biological roles of myokines include effects on e.g. cognition, lipid and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure and tumor growth. This suggests that myokines may be useful biomarkers for monitoring exercise prescription for people with e.g. cancer, diabetes or neurodegenerative diseases.
    Keywords:  Metabolism; cancer; cytokines; diabetes; exercise; physical activity
    DOI:  https://doi.org/10.1210/endrev/bnaa016
  7. J Clin Med. 2020 May 12. pii: E1440. [Epub ahead of print]9(5):
    Picca A, Guerra F, Calvani R, Coelho-Junior HJ, Bossola M, Landi F, Bernabei R, Bucci C, Marzetti E.
      Mitochondria are intracellular organelles involved in a myriad of activities. To safeguard their vital functions, mitochondrial quality control (MQC) systems are in place to support organelle plasticity as well as physical and functional connections with other cellular compartments. In particular, mitochondrial interactions with the endosomal compartment support the shuttle of ions and metabolites across organelles, while those with lysosomes ensure the recycling of obsolete materials. The extrusion of mitochondrial components via the generation and release of mitochondrial-derived vesicles (MDVs) has recently been described. MDV trafficking is now included among MQC pathways, possibly operating via mitochondrial-lysosomal contacts. Since mitochondrial dysfunction is acknowledged as a hallmark of aging and a major pathogenic factor of multiple age-associated conditions, the analysis of MDVs and, more generally, of extracellular vesicles (EVs) is recognized as a valuable research tool. The dissection of EV trafficking may help unravel new pathophysiological pathways of aging and diseases as well as novel biomarkers to be used in research and clinical settings. Here, we discuss (1) MQC pathways with a focus on mitophagy and MDV generation; (2) changes of MQC pathways during aging and their contribution to inflamm-aging and progeroid conditions; and (3) the relevance of MQC failure to several disorders, including neurodegenerative conditions (i.e., Parkinson's disease, Alzheimer's disease) and cardiovascular disease.
    Keywords:  biomarkers; exosomes; extracellular vesicles; geroprotective interventions; mitochondrial damage; mitochondrial dynamics; mitochondrial-derived vesicles (MDVs); mitochondrial-lysosomal axis; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3390/jcm9051440
  8. J Appl Physiol (1985). 2020 May 14.
    Hardee JP, Fix DK, Koh HJ, Wang X, Goldsmith EC, Carson JA.
      Cancer-induced wasting is accompanied by disruptions to muscle oxidative metabolism and protein turnover that have been associated with systemic inflammation, whereas exercise and stimulated muscle contractions can positively regulate muscle protein synthesis and mitochondrial homeostasis. In preclinical cancer cachexia models a single bout of eccentric contractions (ECC) can induce protein synthesis while repeated ECC bouts prevent myofiber atrophy. The cellular mechanisms providing this protection from atrophy have not been resolved. Therefore, the purpose of this study was to determine if repeated stimulated eccentric contraction bouts effect basal muscle oxidative metabolism and protein synthesis during cancer cachexia, and if these changes were associated with plasma IL-6 levels. Male ApcMin/+ (MIN; N=10) mice initiating cachexia and healthy C57BL/6 (B6; N=11) controls performed repeated ECC bouts over 2 weeks. MIN mice exhibited body weight loss and elevated plasma IL-6 prior to and during repeated ECC bouts. Control MIN muscle demonstrated disrupted signaling related to inflammation, oxidative capacity and protein synthesis regulation, which were all improved by repeated ECC bouts. With cachexia plasma IL-6 levels were negatively correlated with myofiber cross-sectional area, oxidative capacity and protein synthesis. Interestingly, ECC improvements in these outcomes were positively correlated with plasma IL-6 levels in MIN mice. There was also a positive relationship between muscle oxidative capacity and protein synthesis following repeated ECC bouts in MIN mice. Collectively, repeated ECC bouts altered the cachectic muscle phenotype independent to systemic wasting, and there was a strong association between muscle oxidative capacity and protein synthesis in this adaptive response.
    Keywords:  ApcMin/+; Cancer cachexia; Eccentric contractions; Protein synthesis; oxidative metabolism
    DOI:  https://doi.org/10.1152/japplphysiol.00908.2019
  9. Exp Gerontol. 2020 May 10. pii: S0531-5565(20)30312-0. [Epub ahead of print] 110964
    Dalle S, Koppo K.
      Muscle loss is an important feature that occurs in multiple pathologies including osteoarthritis (OA), chronic obstructive pulmonary disease (COPD) and type II diabetes (T2D). Despite differences in pathogenesis and disease-related complications, there are reasons to believe that some fundamental underlying mechanisms are inherent to the muscle wasting process, irrespective of the pathology. Recent evidence shows that inflammation, either local or systemic, contributes to the modulation of muscle mass and/or muscle strength, via an altered molecular profile in muscle tissue. However, it remains ambiguous to which extent and via which mechanisms inflammatory signaling affects muscle mass in disease. Therefore, the objective of the present review is to discuss the role of inflammation on skeletal muscle anabolism, catabolism and functionality in three pathologies that are characterized by an eventual loss in muscle mass (and muscle strength), i.e. OA, COPD and T2D. In OA and COPD, most rodent models confirmed that systemic (COPD) or muscle (OA) inflammation directly induces muscle loss or muscle dysfunctionality. However, in a patient population, the association between inflammation and muscular maladaptations are more ambiguous. For example, in T2D patients, systemic inflammation is associated with muscle loss whereas in OA patients this link has not consistently been established. T2D rodent models revealed that increased levels of advanced glycation end-products (AGEs) and a decreased mTORC1 activation play a key role in muscle atrophy, but it remains to be elucidated whether AGEs and mTORC1 are interconnected and contribute to muscle loss in T2D patients. Generally, if any, associations between inflammation and muscle are mainly based on observational and cross-sectional data. There is definitely a need for longitudinal evidence through well-powered randomized control trials that take into account confounders such as age, disease-phenotypes, comorbidities, physical (in) activity etc. This will allow to improve our understanding of the complex interaction between inflammatory signaling and muscle mass loss and hence contribute to the development of therapeutic strategies to combat muscle wasting in these diseases.
    Keywords:  Inflammation; Muscle anabolism; Muscle catabolism; Muscle protein metabolism; Muscle wasting; Sarcopenia
    DOI:  https://doi.org/10.1016/j.exger.2020.110964
  10. Front Cell Dev Biol. 2020 ;8 274
    Su Y, Huang X, Huang Z, Huang T, Xu Y, Yi C.
      Signal transducer and activator of transcription 3 (STAT3) is a transcription factor (TF) that regulates a variety of biological processes, including a key role in mediating mitochondrial metabolism. It has been shown that STAT3 performs this function by translocating in minute amounts into mitochondria and interacting with mitochondrial proteins and genome. However, whether STAT3 localizes in mitochondria is still up for debate. To decipher the role of mitochondrial STAT3 requires a detailed understanding of its cellular localization. Using Percoll density gradient centrifugation, we surprisingly found that STAT3 is not located in the mitochondrial fraction, but instead, in the mitochondria-associated endoplasmic reticulum membrane (MAM) fraction. This was confirmed by sub-diffraction image analysis of labeled mitochondria in embryonic astrocytes. Also, we find that other TFs that have been previously found to localize in mitochondria are also found instead in the MAM fraction. Our results suggest that STAT3 and other transcriptional factors are, contrary to prior studies, consolidated specifically at MAMs, and further efforts to understand mitochondrial STAT3 function must take into consideration this localization, as the associated functional consequences offer a different interpretation to the questions of STAT3 trafficking and signaling in the mitochondria.
    Keywords:  ER; MAM; STAT3; mitochondrial localization; transcription factors
    DOI:  https://doi.org/10.3389/fcell.2020.00274
  11. J Cell Mol Med. 2020 May 14.
    Hernandez-Resendiz S, Prunier F, Girao H, Dorn G, Hausenloy DJ, .
      New treatments are needed to protect the myocardium against the detrimental effects of acute ischaemia/reperfusion (IR) injury following an acute myocardial infarction (AMI), in order to limit myocardial infarct (MI) size, preserve cardiac function and prevent the onset of heart failure (HF). Given the critical role of mitochondria in energy production for cardiac contractile function, prevention of mitochondrial dysfunction during acute myocardial IRI may provide novel cardioprotective strategies. In this regard, the mitochondrial fusion and fissions proteins, which regulate changes in mitochondrial morphology, are known to impact on mitochondrial quality control by modulating mitochondrial biogenesis, mitophagy and the mitochondrial unfolded protein response. In this article, we review how targeting these inter-related processes may provide novel treatment targets and new therapeutic strategies for reducing MI size, preventing the onset of HF following AMI.
    Keywords:  acute myocardial ischaemia/reperfusion injury; cardioprotection; mitochondrial morphology; mitochondrial unfolded protein response; mitophagy cardioprotection
    DOI:  https://doi.org/10.1111/jcmm.15384
  12. J Mol Cell Cardiol. 2020 May 07. pii: S0022-2828(20)30120-6. [Epub ahead of print]
    Liu JC.
      The uptake of Ca2+ into mitochondria is thought to be an important signal communicating the need for increased energy production. However, dysregulated uptake leading to mitochondrial Ca2+ overload can trigger opening of the mitochondrial permeability transition pore and potentially cell death. Thus mitochondrial Ca2+ entry is regulated via the activity of a Ca2+-selective channel known as the mitochondrial calcium uniporter. The last decade has seen enormous momentum in the discovery of the molecular identities of the multiple proteins comprising the uniporter. Increasing numbers of studies in cultured cells and animal models have provided insight into how disruption of uniporter proteins affects mitochondrial Ca2+ regulation and impacts tissue function and physiology. This review aims to summarize some of these recent findings, particularly in the context of the heart.
    DOI:  https://doi.org/10.1016/j.yjmcc.2020.04.028
  13. Proc Natl Acad Sci U S A. 2020 May 15. pii: 201916584. [Epub ahead of print]
    Kwak C, Shin S, Park JS, Jung M, Nhung TTM, Kang MG, Lee C, Kwon TH, Park SK, Mun JY, Kim JS, Rhee HW.
      The mitochondria-associated membrane (MAM) has emerged as a cellular signaling hub regulating various cellular processes. However, its molecular components remain unclear owing to lack of reliable methods to purify the intact MAM proteome in a physiological context. Here, we introduce Contact-ID, a split-pair system of BioID with strong activity, for identification of the MAM proteome in live cells. Contact-ID specifically labeled proteins proximal to the contact sites of the endoplasmic reticulum (ER) and mitochondria, and thereby identified 115 MAM-specific proteins. The identified MAM proteins were largely annotated with the outer mitochondrial membrane (OMM) and ER membrane proteins with MAM-related functions: e.g., FKBP8, an OMM protein, facilitated MAM formation and local calcium transport at the MAM. Furthermore, the definitive identification of biotinylation sites revealed membrane topologies of 85 integral membrane proteins. Contact-ID revealed regulatory proteins for MAM formation and could be reliably utilized to profile the proteome at any organelle-membrane contact sites in live cells.
    Keywords:  FKBP8; membrane contact site; membrane protein topology; mitochondria-associated membrane (MAM); proximity labeling
    DOI:  https://doi.org/10.1073/pnas.1916584117
  14. Exp Mol Med. 2020 May 12.
    Cho HM, Sun W.
      Mitochondrial dysfunction critically impairs cellular health and often causes or affects the progression of several diseases, including neurodegenerative diseases and cancer. Thus, cells must have several ways to monitor the condition of mitochondrial quality and maintain mitochondrial health. Accumulating evidence suggests that the molecular machinery responding to spontaneous changes in mitochondrial morphology is associated with the routine mitochondrial quality control system. In this short review, we discuss recent progress made in linking mitochondrial structural dynamics and the quality control system.
    DOI:  https://doi.org/10.1038/s12276-020-0434-9
  15. Cell Metab. 2020 May 05. pii: S1550-4131(20)30197-2. [Epub ahead of print]
    Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, Liu J, Jiang K, Liu R, Guo Z, Deeney J, Apovian CM, Snyder-Cappione J, Hawk GS, Fleeman RM, Pihl RMF, Thompson K, Belkina AC, Cui L, Proctor EA, Kern PA, Nikolajczyk BS.
      Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 profile by activating the Th17 master regulator, STAT3, which in turn bound IL-17A and F promoters. Mitophagy-targeting siRNA failed to activate the Th17 profile. We conclude that metformin improves autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes.
    Keywords:  T cells; autophagy; inflammaging; metformin; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2020.04.015
  16. Methods Mol Biol. 2020 ;2144 57-65
    Reynolds JC, Lee C.
      Endurance testing simultaneously assesses a wide variety of physiological systems including the cardiovascular, respiratory, metabolic, and neuromuscular systems (Gabriel and Zierath, Cell Metab 25:1000-1011, 2017). Treadmill running is a noninvasive method to evaluate fitness capacity in a longitudinal or cross-sectional manner. High-intensity exercise tests can be used to determine peak physical capacity in mice. However, because aging is associated with a progressive loss of physical capacity the running protocols can be adapted and optimized for aged mice.
    Keywords:  Aging; Fitness; Mice; Running; Treadmill
    DOI:  https://doi.org/10.1007/978-1-0716-0592-9_5
  17. J Clin Endocrinol Metab. 2020 May 15. pii: dgaa258. [Epub ahead of print]
    Jackisch L, Murphy AM, Kumar S, Randeva H, Tripathi G, McTernan PG.
      CONTEXT: Dysfunctional ER and mitochondria are known to contribute to the pathology of metabolic disease. This damage may occur, in part, as a consequence of ER-mitochondria cross-talk in conditions of nutrient excess such as obesity. To date insight into this dynamic relationship has not been characterised in adipose tissue. Therefore, this study investigated whether ER stress contributes to the development of mitochondrial inefficiency in human adipocytes from lean and obese participants.METHODS: Human differentiated adipocytes from Chub-S7 cell line and primary abdominal subcutaneous adipocytes from lean and obese participants were treated with tunicamycin to induce ER stress. Key parameters of mitochondrial function were assessed, including mitochondrial respiration, membrane potential (MMP) and dynamics.
    RESULTS: ER stress led to increased respiratory capacity in a model adipocyte system (Chub-S7 adipocytes) in a concentration and time dependent manner (24hr: 23%↑; 48hr: 68%↑, (p<0.001); 72hr: 136%↑, (p<0.001)). This corresponded with mitochondrial inefficiency and diminished MMP, highlighting the formation of dysfunctional mitochondria. Morphological analysis revealed reorganisation of mitochondrial network, specifically mitochondrial fragmentation. Furthermore, p-DRP1, a key protein in fission, significantly increased (p<0.001). Additionally, adipocytes from obese subjects displayed lower basal respiration (49%↓, p<0.01) and were unresponsive to tunicamycin in contrast to their lean counterparts, demonstrating inefficient mitochondrial oxidative capacity.
    CONCLUSION: These human data suggest that adipocyte mitochondrial inefficiency is driven by ER stress and exacerbated in obesity. Nutrient excess induced ER stress leads to mitochondrial dysfunction that may therefore shift lipid deposition ectopically and thus have further implications on the development of related metabolic disorders.
    Keywords:  ER stress; Obesity; human adipocytes; mitochondrial dysfunction
    DOI:  https://doi.org/10.1210/clinem/dgaa258