bims-misrem 2021-02-07 papers

bims-misrem

Biomed News

on Mitochondria and sarcoplasmic reticulum in muscle mass

Issue of 2021‒02‒07
nine papers selected by
Rafael Antonio Casuso Pérez
University of Granada

The mitochondrial unfolded protein response and its diverse roles in cellular stress.
ER Stress-Sensor Proteins and ER-Mitochondrial Crosstalk-Signaling Beyond (ER) Stress Response.
Molecular Mechanisms of Diaphragm Myopathy in Humans with Severe Heart Failure.
Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes.
Astaxanthin Prevents Atrophy in Slow Muscle Fibers by Inhibiting Mitochondrial Reactive Oxygen Species via a Mitochondria-Mediated Apoptosis Pathway.
Mitochondrial translation deficiency impairs NAD+ -mediated lysosomal acidification.
The Roles of the Ubiquitin-Proteasome System in the Endoplasmic Reticulum Stress Pathway.
Divergent anabolic response to exercise in young and older adult men dependent on time-frame of measurement.
Function and regulation of the divisome for mitochondrial fission.

Int J Biochem Cell Biol. 2021 Jan 30. pii: S1357-2725(21)00018-2. [Epub ahead of print] 105934

The mitochondrial unfolded protein response and its diverse roles in cellular stress.

Ioannis Smyrnias.

  Mitochondrial function is centrally involved in many cellular processes, such as energy production, metabolism of nucleotides, amino acids, and lipids, calcium buffering, and regulation of cell death. Multiple mechanisms are engaged under conditions of mitochondrial dysfunction to restore cellular and, subsequently, systemic functions. The mitochondrial unfolded protein response is a homeostatic mechanism that has attracted a lot of interest recently and has been described in several organisms, including humans. The mitochondrial unfolded protein response serves as a first-line-of-defence mechanism against stress to restore mitochondrial proteostasis and functions. Here, we discuss the canonical mechanisms via which the mitochondrial unfolded protein response is activated under stress and examine recent evidence that links the response with other processes that promote survival and the recovery of the mitochondrial network (i.e. the integrated stress response and mitophagy).

Keywords:  UPR; disease; heart; mitochondria; stress

DOI:  https://doi.org/10.1016/j.biocel.2021.105934
Biomolecules. 2021 Jan 28. pii: 173. [Epub ahead of print]11(2):

ER Stress-Sensor Proteins and ER-Mitochondrial Crosstalk-Signaling Beyond (ER) Stress Response.

Vaishali Kumar, Shuvadeep Maity.

  Recent studies undoubtedly show the importance of inter organellar connections to maintain cellular homeostasis. In normal physiological conditions or in the presence of cellular and environmental stress, each organelle responds alone or in coordination to maintain cellular function. The Endoplasmic reticulum (ER) and mitochondria are two important organelles with very specialized structural and functional properties. These two organelles are physically connected through very specialized proteins in the region called the mitochondria-associated ER membrane (MAM). The molecular foundation of this relationship is complex and involves not only ion homeostasis through the shuttling of calcium but also many structural and apoptotic proteins. IRE1alpha and PERK are known for their canonical function as an ER stress sensor controlling unfolded protein response during ER stress. The presence of these transmembrane proteins at the MAM indicates its potential involvement in other biological functions beyond ER stress signaling. Many recent studies have now focused on the non-canonical function of these sensors. In this review, we will focus on ER mitochondrial interdependence with special emphasis on the non-canonical role of ER stress sensors beyond ER stress.

Keywords:  ER stress; endoplasmic reticulum; mitochondria associated membrane (MAM)

DOI:  https://doi.org/10.3390/biom11020173
Circ Res. 2021 Feb 01.

Molecular Mechanisms of Diaphragm Myopathy in Humans with Severe Heart Failure.

Norman Mangner, Jens Garbade, Estelle Heyne, Marloes van den Berg, Ephraim Bernhard Winzer, Jennifer Hommel, Marcus Sandri, Joanna Jozwiak-Nozdrzykowska, Anna Meyer, Sven Lehmann, Clara Schmitz, Edoardo Malfatti, Michael Schwarzer, Coen Ottenheijm, T Scott Bowen, Axel Linke, Voker Adams.

  Rationale: Diaphragm weakness impairs quality-of-life, exercise capacity, and survival in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. However, the underlying cellular mechanisms responsible in humans remain poorly resolved. Objective: We prospectively evaluated clinical, functional (in vivo/in vitro), histological/ultrastructural and molecular alterations of the diaphragm from CHF patients receiving a left ventricular assist device compared to patients without CHF undergoing elective coronary bypass grafting (control) in the observational LIpsia DiaPhrAgm and MUScle Heart Failure Trial (LIPAMUS-HF). Methods and Results: Participants (Controls=21, CHF=18) underwent cardiopulmonary exercise and spirometry/respiratory muscle testing alongside diaphragm and cardiac imaging. Diaphragm biopsies were phenotyped for mitochondrial respiration, muscle fiber function, histology/ultrastructure, and protein expression. In vivo respiratory muscle function and diaphragm thickness were reduced in CHF by 38% and 23%. Diaphragm biopsies revealed a fiber-type shift and severe fiber atrophy in CHF alongside elevated proteasome-dependent proteolysis (i.e., MuRF1 expression, ubiquitination, ubiquitin proteasome activity) and myofibrillar protein oxidation, which corresponded to upregulated NADPH oxidase (Nox2/Nox4) signaling. Mitochondria demonstrated severe intrinsic functional and ultrastructural abnormalities in CHF characterized by accumulation of small mitochondria and inhibited autophagy/mitophagy. Single muscle fiber contractile function revealed reduced Ca2+ sensitivity in CHF and there was evidence of ryanodine receptor 1 (RyR1) dysfunction indicating Ca2+ leak from the sarcoplasmatic reticulum. Mitochondrial and Ca2+ measures corresponded to upregulated Nox4 isoform NADPH oxidase expression. Molecular markers correlated to whole-body exercise intolerance and diaphragm dysfunction/wasting.Conclusions: CHF patients demonstrate an obvious diaphragm myopathy independent of disuse or other confounding factors such as ageing, obesity, or hypertension. Diaphragm weakness in CHF was associated with intracellular abnormalities characterized by fiber atrophy, oxidative stress, mitochondrial dysfunction, impaired Ca2+ homeostasis, elevated proteasome dependent proteolysis, but inhibited autophagy/mitophagy, which we speculate offers a novel therapeutic molecular target regulated by a Nox-MuRF1/ubiquitin proteasome-mitochondria-RyR1/Ca2+ signaling axis.

Keywords:  MuRF1; diaphragm

DOI:  https://doi.org/10.1161/CIRCRESAHA.120.318060
J Biol Chem. 2020 Jan 03. pii: S0021-9258(17)49552-4. [Epub ahead of print]295(1): 99-110

Mitochondrial oxidants, but not respiration, are sensitive to glucose in adipocytes.

James R Krycer, Sarah D Elkington, Alexis Diaz-Vegas, Kristen C Cooke, James G Burchfield, Kelsey H Fisher-Wellman, Gregory J Cooney, Daniel J Fazakerley, David E James.

  Insulin action in adipose tissue is crucial for whole-body glucose homeostasis, with insulin resistance being a major risk factor for metabolic diseases such as type 2 diabetes. Recent studies have proposed mitochondrial oxidants as a unifying driver of adipose insulin resistance, serving as a signal of nutrient excess. However, neither the substrates for nor sites of oxidant production are known. Because insulin stimulates glucose utilization, we hypothesized that glucose oxidation would fuel respiration, in turn generating mitochondrial oxidants. This would impair insulin action, limiting further glucose uptake in a negative feedback loop of "glucose-dependent" insulin resistance. Using primary rat adipocytes and cultured 3T3-L1 adipocytes, we observed that insulin increased respiration, but notably this occurred independently of glucose supply. In contrast, glucose was required for insulin to increase mitochondrial oxidants. Despite rising to similar levels as when treated with other agents that cause insulin resistance, glucose-dependent mitochondrial oxidants failed to cause insulin resistance. Subsequent studies revealed a temporal relationship whereby mitochondrial oxidants needed to increase before the insulin stimulus to induce insulin resistance. Together, these data reveal that (a) adipocyte respiration is principally fueled from nonglucose sources; (b) there is a disconnect between respiration and oxidative stress, whereby mitochondrial oxidant levels do not rise with increased respiration unless glucose is present; and (c) mitochondrial oxidative stress must precede the insulin stimulus to cause insulin resistance, explaining why short-term, insulin-dependent glucose utilization does not promote insulin resistance. These data provide additional clues to mechanistically link nutrient excess to adipose insulin resistance.

Keywords:  adipocyte; glucose; insulin; insulin resistance; mitochondria; oxidative stress; respiration

DOI:  https://doi.org/10.1074/jbc.RA119.011695
Nutrients. 2021 Jan 26. pii: 379. [Epub ahead of print]13(2):

Astaxanthin Prevents Atrophy in Slow Muscle Fibers by Inhibiting Mitochondrial Reactive Oxygen Species via a Mitochondria-Mediated Apoptosis Pathway.

Luchuanyang Sun, Nobuyuki Miyaji, Min Yang, Edward M Mills, Shigeto Taniyama, Takayuki Uchida, Takeshi Nikawa, Jifeng Li, Jie Shi, Katsuyasu Tachibana, Katsuya Hirasaka.

  Astaxanthin (AX) is a carotenoid that exerts potent antioxidant activity and acts in the lipid bilayer. This study aimed to investigate the effects of AX on muscle-atrophy-mediated disturbance of mitochondria, which have a lipid bilayer. Tail suspension was used to establish a muscle-atrophied mouse model. AX diet fed to tail-suspension mice prevented loss of muscle weight, inhibited the decrease of myofiber size, and restrained the increase of hydrogen peroxide (H2O2) production in the soleus muscle. Additionally, AX improved downregulation of mitochondrial respiratory chain complexes I and III in the soleus muscle after tail suspension. Meanwhile, AX promoted mitochondrial biogenesis by upregulating the expressions of adenosine 5'-monophosphate-activated protein kinase (AMPK) α-1, peroxisome proliferator-activated receptor (PPAR)-γ, and creatine kinase in mitochondrial (Ckmt) 2 in the soleus muscle of tail-suspension mice. To confirm the AX phenotype in the soleus muscle, we examined its effects on mitochondria using Sol8 myotubes derived from the soleus muscle. We found that AX was preferentially detected in the mitochondrial fraction; it significantly suppressed mitochondrial reactive oxygen species (ROS) production in Sol8 myotubes. Moreover, AX inhibited the activation of caspase 3 via inhibiting the release of cytochrome c into the cytosol in antimycin A-treated Sol8 myotubes. These results suggested that AX protected the functional stability of mitochondria, alleviated mitochondrial oxidative stress and mitochondria-mediated apoptosis, and thus, prevented muscle atrophy.

Keywords:  astaxanthin; mitochondria; muscle atrophy; oxidative stress

DOI:  https://doi.org/10.3390/nu13020379
EMBO J. 2021 Feb 02. e105268

Mitochondrial translation deficiency impairs NAD+ -mediated lysosomal acidification.

Mikako Yagi, Takahiro Toshima, Rie Amamoto, Yura Do, Haruka Hirai, Daiki Setoyama, Dongchon Kang, Takeshi Uchiumi.

  Mitochondrial translation dysfunction is associated with neurodegenerative and cardiovascular diseases. Cells eliminate defective mitochondria by the lysosomal machinery via autophagy. The relationship between mitochondrial translation and lysosomal function is unknown. In this study, mitochondrial translation-deficient hearts from p32-knockout mice were found to exhibit enlarged lysosomes containing lipofuscin, suggesting impaired lysosome and autolysosome function. These mice also displayed autophagic abnormalities, such as p62 accumulation and LC3 localization around broken mitochondria. The expression of genes encoding for nicotinamide adenine dinucleotide (NAD+ ) biosynthetic enzymes-Nmnat3 and Nampt-and NAD+ levels were decreased, suggesting that NAD+ is essential for maintaining lysosomal acidification. Conversely, nicotinamide mononucleotide (NMN) administration or Nmnat3 overexpression rescued lysosomal acidification. Nmnat3 gene expression is suppressed by HIF1α, a transcription factor that is stabilized by mitochondrial translation dysfunction, suggesting that HIF1α-Nmnat3-mediated NAD+ production is important for lysosomal function. The glycolytic enzymes GAPDH and PGK1 were found associated with lysosomal vesicles, and NAD+ was required for ATP production around lysosomal vesicles. Thus, we conclude that NAD+ content affected by mitochondrial dysfunction is essential for lysosomal maintenance.

Keywords:  GAPDH; NAD+; Nmnat3; lysosome; mitochondria

DOI:  https://doi.org/10.15252/embj.2020105268
Int J Mol Sci. 2021 Feb 03. pii: 1526. [Epub ahead of print]22(4):

The Roles of the Ubiquitin-Proteasome System in the Endoplasmic Reticulum Stress Pathway.

Junyan Qu, Tingting Zou, Zhenghong Lin.

  The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells, which is essential for synthesis, processing, sorting of protein and lipid metabolism. However, the cells activate a defense mechanism called endoplasmic reticulum stress (ER stress) response and initiate unfolded protein response (UPR) as the unfolded proteins exceed the folding capacity of the ER due to the environmental influences or increased protein synthesis. ER stress can mediate many cellular processes, including autophagy, apoptosis and senescence. The ubiquitin-proteasome system (UPS) is involved in the degradation of more than 80% of proteins in the cells. Today, increasing numbers of studies have shown that the two important components of UPS, E3 ubiquitin ligases and deubiquitinases (DUBs), are tightly related to ER stress. In this review, we summarized the regulation of the E3 ubiquitin ligases and DUBs in ER stress.

Keywords:  E3 ubiquitin ligases; UPR; UPS; deubiquitinases; endoplasmic reticulum stress (ER stress)

DOI:  https://doi.org/10.3390/ijms22041526
J Gerontol A Biol Sci Med Sci. 2021 Feb 04. pii: glab040. [Epub ahead of print]

Divergent anabolic response to exercise in young and older adult men dependent on time-frame of measurement.

Søren Reitelseder, Jacob Bülow, Lars Holm.

  Older adults' skeletal muscle has shown to be less responsive to anabolic stimuli as compared to young both in vitro, in short and controlled in vivo settings and in long-term training studies. However, to translate controlled mechanistic findings to long-term adaptations intermediate measures allowing daily life routines with regard to activity and diet would be useful to evaluate physiological interventions. The purpose of this study was to investigate the exercise effect in young and older adults with two independent methods to measure muscle protein synthesis rate. Healthy young and old men were recruited to the study protocol where myofibrillar fractional synthesis rate (FSR) was measured during 2 d allowing normal activities of daily living (ADL) with D2O labeled alanine and during 4 h in the overnight fasted state with [ 13C6]phenylalanine infusion. During this period one leg completed an exercise session every day (exercise leg) while the contralateral leg was kept inactive (normal leg). Both legs were used for ADL. 2-d myofibrillar FSR was significantly higher in the exercise leg in both young and old as compared to normal leg with no age difference. The 4-h overnight fasted myofibrillar FSR showed that only young exercise leg was significantly higher than normal leg. The present findings support the notion that anabolic resistance exists in the skeletal muscle of healthy older men when evaluated in controlled settings. However, this response is not as clear when measured during daily life where variance is greater, which calls for further investigations in larger cohorts.

Keywords:  Alanine; Daily living; Deuterated water; Muscle protein synthesis; Phenylalanine

DOI:  https://doi.org/10.1093/gerona/glab040
Nature. 2021 Feb;590(7844): 57-66

Function and regulation of the divisome for mitochondrial fission.

Felix Kraus, Krishnendu Roy, Thomas J Pucadyil, Michael T Ryan.

Mitochondria form dynamic networks in the cell that are balanced by the flux of iterative fusion and fission events of the organelles. It is now appreciated that mitochondrial fission also represents an end-point event in a signalling axis that allows cells to sense and respond to external cues. The fission process is orchestrated by membrane-associated adaptors, influenced by organellar and cytoskeletal interactions and ultimately executed by the dynamin-like GTPase DRP1. Here we invoke the framework of the 'mitochondrial divisome', which is conceptually and operationally similar to the bacterial cell-division machinery. We review the functional and regulatory aspects of the mitochondrial divisome and, within this framework, parse the core from the accessory machinery. In so doing, we transition from a phenomenological to a mechanistic understanding of the fission process.

DOI: https://doi.org/10.1038/s41586-021-03214-x