bims-misrem 2020-11-22 papers

bims-misrem

Biomed News

on Mitochondria and sarcoplasmic reticulum in muscle mass

Issue of 2020‒11‒22
nine papers selected by
Rafael Antonio Casuso Pérez
University of Granada

Mitochondrial Safeguard: a stress response that offsets extreme fusion and protects respiratory function via flickering-induced Oma1 activation.
Physiological Ca2+ Transients Versus Pathological Steady-State Ca2+ Elevation, Who Flips the ROS Coin in Skeletal Muscle Mitochondria.
Mitochondrial Ca2+ Dynamics in MCU Knockout C. elegans Worms.
Mitochondrial respiratory supercomplexes in mammalian cells: structural versus functional role.
Accelerated FASTK mRNA degradation induced by oxidative stress is responsible for the destroyed myocardial mitochondrial gene expression and respiratory function in alcoholic cardiomyopathy.
Heat-induced endoplasmic reticulum stress in soleus and gastrocnemius muscles and differential response to UPR pathway in rats.
Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A.
Functions of outer mitochondrial membrane proteins: mediating the crosstalk between mitochondrial dynamics and mitophagy.
OPA1, a new mitochondrial target in cancer therapy.

EMBO J. 2020 Nov 17. e105074

Mitochondrial Safeguard: a stress response that offsets extreme fusion and protects respiratory function via flickering-induced Oma1 activation.

Daisuke Murata, Tatsuya Yamada, Takeshi Tokuyama, Kenta Arai, Pedro M Quirós, Carlos López-Otín, Miho Iijima, Hiromi Sesaki.

  The connectivity of mitochondria is regulated by a balance between fusion and division. Many human diseases are associated with excessive mitochondrial connectivity due to impaired Drp1, a dynamin-related GTPase that mediates division. Here, we report a mitochondrial stress response, named mitochondrial safeguard, that adjusts the balance of fusion and division in response to increased mitochondrial connectivity. In cells lacking Drp1, mitochondria undergo hyperfusion. However, hyperfusion does not completely connect mitochondria because Opa1 and mitofusin 1, two other dynamin-related GTPases that mediate fusion, become proteolytically inactivated. Pharmacological and genetic experiments show that the activity of Oma1, a metalloprotease that cleaves Opa1, is regulated by short pulses of the membrane depolarization without affecting the overall membrane potential in Drp1-knockout cells. Re-activation of Opa1 and Mitofusin 1 in Drp1-knockout cells further connects mitochondria beyond hyperfusion, termed extreme fusion, leading to bioenergetic deficits. These findings reveal an unforeseen safeguard mechanism that prevents extreme fusion of mitochondria, thereby maintaining mitochondrial function when the balance is shifted to excessive connectivity.

Keywords:  Drp1; Oma1; Opa1; mitochondrial fusion; mitofusin

DOI:  https://doi.org/10.15252/embj.2020105074
Front Physiol. 2020 ;11 595800

Physiological Ca2+ Transients Versus Pathological Steady-State Ca2+ Elevation, Who Flips the ROS Coin in Skeletal Muscle Mitochondria.

Ang Li, Jianxun Yi, Xuejun Li, Jingsong Zhou.

  Mitochondria are both the primary provider of ATP and the pivotal regulator of cell death, which are essential for physiological muscle activities. Ca2+ plays a multifaceted role in mitochondrial function. During muscle contraction, Ca2+ influx into mitochondria activates multiple enzymes related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation, resulting in increased ATP synthesis to meet the energy demand. Pathophysiological conditions such as skeletal muscle denervation or unloading also lead to elevated Ca2+ levels inside mitochondria. However, the outcomes of this steady-state elevation of mitochondrial Ca2+ level include exacerbated reactive oxygen species (ROS) generation, sensitized opening of mitochondrial permeability transition pore (mPTP), induction of programmed cell death, and ultimately muscle atrophy. Previously, both acute and long-term endurance exercises have been reported to activate certain signaling pathways to counteract ROS production. Meanwhile, electrical stimulation is known to help prevent apoptosis and alleviate muscle atrophy in denervated animal models and patients with motor impairment. There are various mechanistic studies that focus on the excitation-transcription coupling framework to understand the beneficial role of exercise and electrical stimulation. Interestingly, a recent study has revealed an unexpected role of rapid mitochondrial Ca2+ transients in keeping mPTP at a closed state with reduced mitochondrial ROS production. This discovery motivated us to contribute this review article to inspire further discussion about the potential mechanisms underlying differential outcomes of physiological mitochondrial Ca2+ transients and pathological mitochondrial Ca2+ elevation in skeletal muscle ROS production.

Keywords:  electric field stimulation; mitochondrial Ca2+ homeostasis; mitochondrial ROS; mitoflash; skeletal muscle; transitory mPTP opening

DOI:  https://doi.org/10.3389/fphys.2020.595800
Int J Mol Sci. 2020 Nov 16. pii: E8622. [Epub ahead of print]21(22):

Mitochondrial Ca2+ Dynamics in MCU Knockout C. elegans Worms.

Pilar Álvarez-Illera, Paloma García-Casas, Rosalba I Fonteriz, Mayte Montero, Javier Alvarez.

  Mitochondrial [Ca2+] plays an important role in the regulation of mitochondrial function, controlling ATP production and apoptosis triggered by mitochondrial Ca2+ overload. This regulation depends on Ca2+ entry into the mitochondria during cell activation processes, which is thought to occur through the mitochondrial Ca2+ uniporter (MCU). Here, we have studied the mitochondrial Ca2+ dynamics in control and MCU-defective C. elegans worms in vivo, by using worms expressing mitochondrially-targeted YC3.60 yellow cameleon in pharynx muscle. Our data show that the small mitochondrial Ca2+ oscillations that occur during normal physiological activity of the pharynx were very similar in both control and MCU-defective worms, except for some kinetic differences that could mostly be explained by changes in neuronal stimulation of the pharynx. However, direct pharynx muscle stimulation with carbachol triggered a large and prolonged increase in mitochondrial [Ca2+] that was much larger in control worms than in MCU-defective worms. This suggests that MCU is necessary for the fast mitochondrial Ca2+ uptake induced by large cell stimulations. However, low-amplitude mitochondrial Ca2+ oscillations occurring under more physiological conditions are independent of the MCU and use a different Ca2+ pathway.

Keywords:  C. elegans; MCU; calcium dynamics; knockout; mitochondria; mitochondrial calcium uniporter

DOI:  https://doi.org/10.3390/ijms21228622
J Mol Med (Berl). 2020 Nov 17.

Mitochondrial respiratory supercomplexes in mammalian cells: structural versus functional role.

Sabzali Javadov, Sehwan Jang, Xavier R Chapa-Dubocq, Zaza Khuchua, Amadou Ks Camara.

  Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are transported through the electron transport chain (ETC) complexes and develop the proton motive force across the inner mitochondrial membrane that is used for ATP synthesis. Studies since the 1960s have been concentrated on the two models of structural organization of ETC complexes known as "solid-state" and "fluid-state" models. However, advanced new techniques such as blue-native gel electrophoresis, mass spectroscopy, and cryogenic electron microscopy for analysis of macromolecular protein complexes provided new data in favor of the solid-state model. According to this model, individual ETC complexes are assembled into macromolecular structures known as respiratory supercomplexes (SCs). A large number of studies over the last 20 years proposed the potential role of SCs to facilitate substrate channeling, maintain the integrity of individual ETC complexes, reduce electron leakage and production of reactive oxygen species, and prevent excessive and random aggregation of proteins in the inner mitochondrial membrane. However, many other studies have challenged the proposed functional role of SCs. Recently, a third model known as the "plasticity" model was proposed that partly reconciles both "solid-state" and "fluid-state" models. According to the "plasticity" model, respiratory SCs can co-exist with the individual ETC complexes. To date, the physiological role of SCs remains unknown, although several studies using tissue samples of patients or animal/cell models of human diseases revealed an associative link between functional changes and the disintegration of SC assembly. This review summarizes and discusses previous studies on the mechanisms and regulation of SC assembly under physiological and pathological conditions.

Keywords:  Electron transport chain complexes; Human diseases; Inner mitochondrial membrane; Mitochondria; Respiratory Supercomplexes

DOI:  https://doi.org/10.1007/s00109-020-02004-8
Redox Biol. 2020 Nov 01. pii: S2213-2317(20)30983-6. [Epub ahead of print]38 101778

Accelerated FASTK mRNA degradation induced by oxidative stress is responsible for the destroyed myocardial mitochondrial gene expression and respiratory function in alcoholic cardiomyopathy.

Fuyang Zhang, Kai Wang, Shumiao Zhang, Juan Li, Rong Fan, Xiyao Chen, Jianming Pei.

  Chronic alcoholism disrupts mitochondrial function and often results in alcoholic cardiomyopathy (ACM). Fas-activated serine/threonine kinase (FASTK) is newly recognized as a key post-transcriptional regulator of mitochondrial gene expression. However, the modulatory role of FASTK in cardiovascular pathophysiology remains totally unknown. In experimental ACM models, cardiac FASTK expression markedly declined. Ethanol directly suppressed FASTK expression at post-transcriptional level through NADPH oxidase-derived reactive oxygen species (ROS). Ethanol destabilized FASTK mRNA 3'-untranslated region (3'-UTR) and accelerated its decay, which was blocked by the clearance of ROS. Regnase-1 (Reg1), a ribonuclease regulating mRNA stability, was induced by ROS in ethanol-stimulated cardiomyocytes. Reg1 directly bound to FASTK mRNA 3'-UTR and promoted its degradation, whereas silencing of Reg1 reversed ethanol-induced FASTK downregulation. Compared to wild type control, alcohol-related myocardial morphological (hypertrophy, fibrosis and cardiomyocyte apoptosis) and functional (reduced ejection fraction and compromised cardiomyocyte contraction) anomalies were worsened in FASTK deficient mice. Mechanistically, FASTK ablation repressed NADH dehydrogenase subunit 6 (MTND6, a mitochondrial gene encoding a subunit of complex I) mRNA production and reduced complex I-supported respiration. Importantly, cardiomyocyte-specific upregulation of FASTK through intra-cardiac AAV9-cTNT injection mitigated myocardial mitochondrial dysfunction and restrained ACM progression. In vitro study showed that overexpression of FASTK ameliorated ethanol-induced MTND6 mRNA downregulation, complex I inactivation, and cardiomyocyte death, whereas these beneficial effects were counteracted by rotenone, a complex I inhibitor. Collectively, ROS-accelerated FASTK mRNA degradation via Reg1 underlies chronic ethanol ingestion-associated mitochondrial dysfunction and cardiomyopathy. Restoration of FASTK expression through genetic approaches might be a promising therapeutic strategy for ACM.

Keywords:  Alcoholic cardiomyopathy; Fas-activated serine/threonine kinase; Mitochondrial gene expression; Regnase-1; mRNA stability

DOI:  https://doi.org/10.1016/j.redox.2020.101778
Cell Stress Chaperones. 2020 Nov 18.

Heat-induced endoplasmic reticulum stress in soleus and gastrocnemius muscles and differential response to UPR pathway in rats.

Shivani Sharma, Pooja Chaudhary, Rajat Sandhir, Abhishek Bharadwaj, Rajinder K Gupta, Rahul Khatri, Amir Chand Bajaj, T P Baburaj, Sachin Kumar, M S Pal, Prasanna K Reddy, Bhuvnesh Kumar.

  The present study aimed to investigate the differential response of oxidative (soleus) and glycolytic (gastrocnemius) muscles to heat-induced endoplasmic reticulum (ER) stress. It was hypothesized that due to compositional and functional differences, both muscles respond differently to acute heat stress. To address this, male Sprague Dawley rats (12/group) were subjected to thermoneutral (25 °C) or heat stress (42 °C) conditions for 1 h. Soleus and gastrocnemius muscles were removed for analysis post-exposure. A significant increase in body temperature and free radical generation was observed in both the muscles following heat exposure. This further caused a significant increase in protein carbonyl content, AOPP, and lipid peroxidation in heat-stressed muscles. These changes were more pronounced in heat-stressed soleus compared to the gastrocnemius muscle. Accumulation of unfolded, denatured proteins results in ER stress, causing activation of unfolded protein response (UPR) pathway. The expressions of UPR transducers were significantly higher in soleus as compared to the gastrocnemius muscle. A significant elevation in resting intracellular calcium ion was also observed in heat-stressed soleus muscle. Overloading of cells with misfolded proteins in soleus muscle activated ER-induced apoptosis as indicated by significant upregulation of C/EBP homologous protein and Caspase12. The study provides a detailed mechanistic representation of the differential response of muscles toward UPR under heat stress. Data suggests that soleus majorly being an oxidative muscle is more prone to heat stress-induced insult indicated by enhanced apoptosis. This study may aid in devising mitigation strategies to improve muscle performance under heat stress.

Keywords:  Apoptosis; Gastrocnemius muscle; Heat stress; Oxidative stress; Soleus muscle; Unfolded protein response

DOI:  https://doi.org/10.1007/s12192-020-01178-x
Proc Natl Acad Sci U S A. 2020 Nov 20. pii: 202019263. [Epub ahead of print]

Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A.

Se-Jin Lee, Adam Lehar, Yewei Liu, Chi Hai Ly, Quynh-Mai Pham, Michael Michaud, Renata Rydzik, Daniel W Youngstrom, Michael M Shen, Vesa Kaartinen, Emily L Germain-Lee, Thomas A Rando.

  Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

Keywords:  activin; myostatin; receptors; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2019263117
Cell Death Differ. 2020 Nov 18.

Functions of outer mitochondrial membrane proteins: mediating the crosstalk between mitochondrial dynamics and mitophagy.

Hongxu Xian, Yih-Cherng Liou.

Most cellular stress responses converge on the mitochondria. Consequently, the mitochondria must rapidly respond to maintain cellular homeostasis and physiological demands by fine-tuning a plethora of mitochondria-associated processes. The outer mitochondrial membrane (OMM) proteins are central to mediating mitochondrial dynamics, coupled with continuous fission and fusion. These OMM proteins also have vital roles in controlling mitochondrial quality and serving as mitophagic receptors for autophagosome enclosure during mitophagy. Mitochondrial fission segregates impaired mitochondria in smaller sizes from the mother mitochondria and may favor mitophagy for eliminating damaged mitochondria. Conversely, mitochondrial fusion mixes dysfunctional mitochondria with healthy ones to repair the damage by diluting the impaired components and consequently prevents mitochondrial clearance via mitophagy. Despite extensive research efforts into deciphering the interplay between fission-fusion and mitophagy, it is still not clear whether mitochondrial fission essentially precedes mitophagy. In this review, we summarize recent breakthroughs concerning OMM research, and dissect the functions of these proteins in mitophagy from their traditional roles in fission-fusion dynamics, in response to distinct context, at the intersection of the OMM platform. These insights into the OMM proteins in mechanistic researches would lead to new aspects of mitochondrial quality control and better understanding of mitochondrial homeostasis intimately tied to pathological impacts.

DOI: https://doi.org/10.1038/s41418-020-00657-z
Aging (Albany NY). 2020 Nov 13. 12(21): 20931-20933

OPA1, a new mitochondrial target in cancer therapy.

Stephanie Herkenne, Luca Scorrano.



Keywords:  OPA1; angiogenesis; cancer; mitochondria

DOI:  https://doi.org/10.18632/aging.104207