bims-misrem 2021-01-10 papers

bims-misrem

Biomed News

on Mitochondria and sarcoplasmic reticulum in muscle mass

Issue of 2021–01–10
nine papers selected by
Rafael Antonio Casuso Pérez, University of Granada

Mitochondria Associated Membranes (MAMs): Architecture and physiopathological role.
Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1.
Disturbances in Calcium Homeostasis Promotes Skeletal Muscle Atrophy: Lessons From Ventilator-Induced Diaphragm Wasting.
Mitochondrial Dynamics in Adult Cardiomyocytes and Heart Diseases.
Nox2 signaling and muscle fiber remodeling are attenuated by losartan administration during skeletal muscle unloading.
Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria.
Regulation of lipid metabolism by the unfolded protein response.
Mitochondrial Impairment in Sarcopenia.
Tune instead of destroy: How proteolysis keeps OXPHOS in shape.

Cell Calcium. 2021 Jan 02. pii: S0143-4160(20)30185-8. [Epub ahead of print]94 102343

Mitochondria Associated Membranes (MAMs): Architecture and physiopathological role.

Lucia Barazzuol, Flavia Giamogante, Tito Calì.

  In the last decades, the communication between the Endoplasmic reticulum (ER) and mitochondria has obtained great attention: mitochondria-associated membranes (MAMs), which represent the contact sites between the two organelles, have indeed emerged as central hub involved in different fundamental cell processes, such as calcium signalling, apoptosis, autophagy and lipid biosynthesis. Consistently, dysregulation of ER-mitochondria crosstalk has been associated with different pathological conditions, ranging from diabetes to cancer and neurodegenerative diseases. In this review, we will try to summarize the current knowledge on MAMs' structure and functions in health and their relevance for human diseases.

Keywords:  Calcium signaling; MAMs; Mitochondria; Neurodegeneration; Organelle contact sites

DOI:  https://doi.org/10.1016/j.ceca.2020.102343
Front Cell Dev Biol. 2020 ;8 603688

Regulation of Mitochondrial Respiratory Chain Complex Levels, Organization, and Function by Arginyltransferase 1.

Chunhua Jiang, Balaji T Moorthy, Devang M Patel, Akhilesh Kumar, William M Morgan, Belkis Alfonso, Jingyu Huang, Theodore J Lampidis, Daniel G Isom, Antoni Barrientos, Flavia Fontanesi, Fangliang Zhang.

  Arginyltransferase 1 (ATE1) is an evolutionary-conserved eukaryotic protein that localizes to the cytosol and nucleus. It is the only known enzyme in metazoans and fungi that catalyzes posttranslational arginylation. Lack of arginylation has been linked to an array of human disorders, including cancer, by altering the response to stress and the regulation of metabolism and apoptosis. Although mitochondria play relevant roles in these processes in health and disease, a causal relationship between ATE1 activity and mitochondrial biology has yet to be established. Here, we report a phylogenetic analysis that traces the roots of ATE1 to alpha-proteobacteria, the mitochondrion microbial ancestor. We then demonstrate that a small fraction of ATE1 localizes within mitochondria. Furthermore, the absence of ATE1 influences the levels, organization, and function of respiratory chain complexes in mouse cells. Specifically, ATE1-KO mouse embryonic fibroblasts have increased levels of respiratory supercomplexes I+III2+IVn. However, they have decreased mitochondrial respiration owing to severely lowered complex II levels, which leads to accumulation of succinate and downstream metabolic effects. Taken together, our findings establish a novel pathway for mitochondrial function regulation that might explain ATE1-dependent effects in various disease conditions, including cancer and aging, in which metabolic shifts are part of the pathogenic or deleterious underlying mechanism.

Keywords:  arginylation; arginyltransferase; biogenesis; mitochondria; respiration; respiratory chain complexes

DOI:  https://doi.org/10.3389/fcell.2020.603688
Front Physiol. 2020 ;11 615351

Disturbances in Calcium Homeostasis Promotes Skeletal Muscle Atrophy: Lessons From Ventilator-Induced Diaphragm Wasting.

Hayden W Hyatt, Scott K Powers.

  Mechanical ventilation (MV) is often a life-saving intervention for patients in respiratory failure. Unfortunately, a common and undesired consequence of prolonged MV is the development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is commonly labeled "ventilator-induced diaphragm dysfunction" (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a major risk factor for the failure to wean patients from MV; this inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. Although several processes contribute to the development of VIDD, it is clear that oxidative stress leading to the rapid activation of proteases is a primary contributor. While all major proteolytic systems likely contribute to VIDD, emerging evidence reveals that activation of the calcium-activated protease calpain plays a required role. This review highlights the signaling pathways leading to VIDD with a focus on the cellular events that promote increased cytosolic calcium levels and the subsequent activation of calpain within diaphragm muscle fibers. In particular, we discuss the emerging evidence that increased mitochondrial production of reactive oxygen species promotes oxidation of the ryanodine receptor/calcium release channel, resulting in calcium release from the sarcoplasmic reticulum, accelerated proteolysis, and VIDD. We conclude with a discussion of important and unanswered questions associated with disturbances in calcium homeostasis in diaphragm muscle fibers during prolonged MV.

Keywords:  calpain; muscle atrophy; oxidative stress; proteolysis; reactive oxygen species; ryanodine receptors

DOI:  https://doi.org/10.3389/fphys.2020.615351
Front Cell Dev Biol. 2020 ;8 584800

Mitochondrial Dynamics in Adult Cardiomyocytes and Heart Diseases.

Anqi Li, Meng Gao, Wenting Jiang, Yuan Qin, Guohua Gong.

  Mitochondria are the powerhouse organelles of cells; they participate in ATP generation, calcium homeostasis, oxidative stress response, and apoptosis. Thus, maintenance of mitochondrial function is critical for cellular functions. As highly dynamic organelles, the function of mitochondria is dynamically regulated by their fusion and fission in many cell types, which regulate mitochondrial morphology, number, distribution, metabolism, and biogenesis in cells. Mature rod-shaped cardiomyocytes contain thousands of end-to-end contacted spheroid mitochondria. The movement of mitochondria in these cells is limited, which hinders the impetus for research into mitochondrial dynamics in adult cardiomyocytes. In this review, we discuss the most recent progress in mitochondrial dynamics in mature (adult) cardiomyocytes and the relationship thereof with heart diseases.

Keywords:  dynamics; heart; mature cardiomyocytes; mitochondrial fission; mitochondrial fusion

DOI:  https://doi.org/10.3389/fcell.2020.584800
Physiol Rep. 2021 Jan;9(1): e14606

Nox2 signaling and muscle fiber remodeling are attenuated by losartan administration during skeletal muscle unloading.

Jeffrey M Hord, Marcela M Garcia, Katherine R Farris, Vinicius Guzzoni, Yang Lee, Matthew S Lawler, John M Lawler.

  Reduced mechanical loading results in atrophy of skeletal muscle fibers. Increased reactive oxygen species (ROS) are causal in sarcolemmal dislocation of nNOS and FoxO3a activation. The Nox2 isoform of NADPH oxidase and mitochondria release ROS during disuse in skeletal muscle. Activation of the angiotensin II type 1 receptor (AT1R) can elicit Nox2 complex formation. The AT1R blocker losartan was used to test the hypothesis that AT1R activation drives Nox2 assembly, nNOS dislocation, FoxO3a activation, and thus alterations in morphology in the unloaded rat soleus. Male Fischer 344 rats were divided into four groups: ambulatory control (CON), ambulatory + losartan (40 mg kg-1 day-1 ) (CONL), 7 days of tail-traction hindlimb unloading (HU), and HU + losartan (HUL). Losartan attenuated unloading-induced loss of muscle fiber cross-sectional area (CSA) and fiber-type shift. Losartan mitigated unloading-induced elevation of ROS levels and upregulation of Nox2. Furthermore, AT1R blockade abrogated nNOS dislocation away from the sarcolemma and elevation of nuclear FoxO3a. We conclude that AT1R blockade attenuates disuse remodeling by inhibiting Nox2, thereby lessening nNOS dislocation and activation of FoxO3a.

Keywords:  Angiotensin II type 1 receptor; NADPH oxidase-2; hindlimb unloading; neuronal nitric oxide synthase; skeletal muscle atrophy

DOI:  https://doi.org/10.14814/phy2.14606
Int J Mol Sci. 2020 Dec 31. pii: E363. [Epub ahead of print]22(1):

Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria.

Debanjali Dasgupta, Philippe Delmotte, Gary C Sieck.

  The effects of airway inflammation on airway smooth muscle (ASM) are mediated by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα). In this review article, we will provide a unifying hypothesis for a homeostatic response to airway inflammation that mitigates oxidative stress and thereby provides resilience to ASM. Previous studies have shown that acute exposure to TNFα increases ASM force generation in response to muscarinic stimulation (hyper-reactivity) resulting in increased ATP consumption and increased tension cost. To meet this increased energetic demand, mitochondrial O2 consumption and oxidative phosphorylation increases but at the cost of increased reactive oxygen species (ROS) production (oxidative stress). TNFα-induced oxidative stress results in the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and mitochondria of ASM. In the ER, TNFα selectively phosphorylates inositol-requiring enzyme 1 alpha (pIRE1α) triggering downstream splicing of the transcription factor X-box binding protein 1 (XBP1s); thus, activating the pIRE1α/XBP1s ER stress pathway. Protein unfolding in mitochondria also triggers an unfolded protein response (mtUPR). In our conceptual framework, we hypothesize that activation of these pathways is homeostatically directed towards mitochondrial remodeling via an increase in peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) expression, which in turn triggers: (1) mitochondrial fragmentation (increased dynamin-related protein-1 (Drp1) and reduced mitofusin-2 (Mfn2) expression) and mitophagy (activation of the Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)/Parkin mitophagy pathway) to improve mitochondrial quality; (2) reduced Mfn2 also results in a disruption of mitochondrial tethering to the ER and reduced mitochondrial Ca2+ influx; and (3) mitochondrial biogenesis and increased mitochondrial volume density. The homeostatic remodeling of mitochondria results in more efficient O2 consumption and oxidative phosphorylation and reduced ROS formation by individual mitochondrion, while still meeting the increased ATP demand. Thus, the energetic load of hyper-reactivity is shared across the mitochondrial pool within ASM cells.

Keywords:  Drp1; MCU; Mfn2; asthma; oxidative stress; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/ijms22010363
J Cell Mol Med. 2021 Jan 04.

Regulation of lipid metabolism by the unfolded protein response.

Matthieu Moncan, Katarzyna Mnich, Arnaud Blomme, Aitor Almanza, Afshin Samali, Adrienne M Gorman.

  The endoplasmic reticulum (ER) is the site of protein folding and secretion, Ca2+ storage and lipid synthesis in eukaryotic cells. Disruption to protein folding or Ca2+ homeostasis in the ER leads to the accumulation of unfolded proteins, a condition known as ER stress. This leads to activation of the unfolded protein response (UPR) pathway in order to restore protein homeostasis. Three ER membrane proteins, namely inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6), sense the accumulation of unfolded/misfolded proteins and are activated, initiating an integrated transcriptional programme. Recent literature demonstrates that activation of these sensors can alter lipid enzymes, thus implicating the UPR in the regulation of lipid metabolism. Given the presence of ER stress and UPR activation in several diseases including cancer and neurodegenerative diseases, as well as the growing recognition of altered lipid metabolism in disease, it is timely to consider the role of the UPR in the regulation of lipid metabolism. This review provides an overview of the current knowledge on the impact of the three arms of the UPR on the synthesis, function and regulation of fatty acids, triglycerides, phospholipids and cholesterol.

Keywords:  PRKR-like endoplasmic reticulum kinase; activating transcription factor 6; cholesterol; endoplasmic reticulum; fatty acid; inositol-requiring enzyme 1; lipid metabolism; phospholipid; triglyceride; unfolded protein response

DOI:  https://doi.org/10.1111/jcmm.16255
Biology (Basel). 2021 Jan 06. pii: E31. [Epub ahead of print]10(1):

Mitochondrial Impairment in Sarcopenia.

Francesco Bellanti, Aurelio Lo Buglio, Gianluigi Vendemiale.

  Sarcopenia is defined by the age-related loss of skeletal muscle quality, which relies on mitochondrial homeostasis. During aging, several mitochondrial features such as bioenergetics, dynamics, biogenesis, and selective autophagy (mitophagy) are altered and impinge on protein homeostasis, resulting in loss of muscle mass and function. Thus, mitochondrial dysfunction contributes significantly to the complex pathogenesis of sarcopenia, and mitochondria are indicated as potential targets to prevent and treat this age-related condition. After a concise presentation of the age-related modifications in skeletal muscle quality and mitochondrial homeostasis, the present review summarizes the most relevant findings related to mitochondrial alterations in sarcopenia.

Keywords:  aging skeletal muscle; mitochondrial dysfunction; protein homeostasis

DOI:  https://doi.org/10.3390/biology10010031
Biochim Biophys Acta Bioenerg. 2021 Jan 05. pii: S0005-2728(20)30215-2. [Epub ahead of print] 148365

Tune instead of destroy: How proteolysis keeps OXPHOS in shape.

Karolina Szczepanowska, Aleksandra Trifunovic.

  Mitochondria are highly dynamic and stress-responsive organelles that are renewed, maintained and removed by a number of different mechanisms. Recent findings bring more evidence for the focused, defined, and regulatory function of the intramitochondrial proteases extending far beyond the traditional concepts of damage control and stress responses. Until recently, the macrodegradation processes, such as mitophagy, were promoted as the major regulator of OXPHOS remodelling and turnover. However, the spatiotemporal dynamics of the OXPHOS system can be greatly modulated by the intrinsic mitochondrial mechanisms acting apart from changes in the global mitochondrial dynamics. This, in turn, may substantially contribute to the shaping of the metabolic status of the cell.

Keywords:  Mitochondrial respiratory chain; OXPHOS maintanance; OXPHOS turnover; mitochondrial proteases

DOI:  https://doi.org/10.1016/j.bbabio.2020.148365