bims-misrem 2021-12-05 papers

Issue of 2021‒12‒05
six papers selected by
Rafael Antonio Casuso Pérez
University of Granada

Cell Death Dis. 2021 Nov 29. 12(12): 1115

MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging.

Yun-Fei Yang, Wu Yang, Zhi-Yin Liao, Yong-Xin Wu, Zhen Fan, Ai Guo, Jing Yu, Qiu-Nan Chen, Jiang-Hao Wu, Jing Zhou, Qian Xiao.

Age-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by D-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca2+ homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.

DOI: https://doi.org/10.1038/s41419-021-04400-5

J Cell Sci. 2021 Dec 02. pii: jcs.259254. [Epub ahead of print]

Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.

Imadeddin Hijazi, Emily Wang, Michelle Orozco, Sarah Pelton, Amy Chang.

Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS response, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation; we now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1▵ cells, defective in peroxisomal ß oxidation of fatty acids, respiratory response to ERS is impaired, and ROS accrues. However, respiratory response to ERS is rescued, and ROS production is mitigated in pox1▵ cells by overexpression of Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the TCA cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation by ERS to remodel respiratory machinery. Several peroxisome-based proteins were also increased, corroborating the peroxisomal role in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.

Keywords: Endoplasmic reticulum; Mitochondria; Stress survival

DOI: https://doi.org/10.1242/jcs.259254

Commun Biol. 2021 Dec 02. 4(1): 1350

ER-misfolded proteins become sequestered with mitochondria and impair mitochondrial function.

Adrián Cortés Sanchón, Harshitha Santhosh Kumar, Matilde Mantovani, Ivan Osinnii, José María Mateos, Andres Kaech, Dimitri Shcherbakov, Rashid Akbergenov, Erik C Böttger.

Proteostasis is a challenge for cellular organisms, as all known protein synthesis machineries are error-prone. Here we show by cell fractionation and microscopy studies that misfolded proteins formed in the endoplasmic reticulum can become associated with and partly transported into mitochondria, resulting in impaired mitochondrial function. Blocking the endoplasmic reticulum-mitochondria encounter structure (ERMES), but not the mitochondrial sorting and assembly machinery (SAM) or the mitochondrial surveillance pathway components Msp1 and Vms1, abrogated mitochondrial sequestration of ER-misfolded proteins. We term this mitochondria-associated proteostatic mechanism for ER-misfolded proteins ERAMS (ER-associated mitochondrial sequestration). We testify to the relevance of this pathway by using mutant α-1-antitrypsin as an example of a human disease-related misfolded ER protein, and we hypothesize that ERAMS plays a role in pathological features such as mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s42003-021-02873-w

Exp Gerontol. 2021 Nov 30. pii: S0531-5565(21)00430-7. [Epub ahead of print] 111648

Effects of high-intensity interval training on mitochondrial supercomplex assembly and biogenesis, mitophagy, and the AMP-activated protein kinase pathway in the soleus muscle of aged female rats.

Chong Han, Peng Lu, Shi-Zhan Yan.

PURPOSE: Exercise helps improve mitochondrial function to combat sarcopenia. Certain parts of the mitochondrial respiratory chain complex can form a higher-order structure called "supercomplex" to reduce the production of reactive oxygen species and improve muscle mass. The effect of exercise on the assembly of the mitochondrial supercomplex is still unclear. The aim of this study was to investigate the effects of long-term high-intensity interval training (HIIT) on mitochondrial biogenesis, mitophagy, and mitochondrial supercomplexes (mitoSCs) assembly in aging soleus muscle.METHODS: Female Sprague-Dawley rats (n = 36) were randomly divided into four groups: young sedentary (Y-SED, 8 months old, n = 12), old sedentary (O-SED, 26 months old, n = 12), moderate-intensity continuous training (MICT, from 18 to 26 months old, n = 12), and HIIT (from 18 to 26 months old, n = 12). Rats in the MICT and HIIT groups were subjected to an 8-month training program. Real-time fluorescent quantitative polymerase chain reaction was used to measure the expression of the antioxidative factors, inflammatory factors, and mitochondrial fusion- and division-related genes. Western blotting was used to detect the expression of mitochondrial biogenesis and mitophagy markers and AMP-activated protein kinase (AMPK) pathway proteins. Enzyme-linked immunosorbent assays were used to determine serum irisin contents. Blue native polyacrylamide gel electrophoresis was used to assess the formation of mitochondrial supercomplexes.
RESULTS: Compared with the Y-SED group, the soleus muscle and mitochondria in the O-SED group showed reduced expression of mitophagy- and mitochondrial biogenesis-related proteins. In the HIIT group, the expression of autophagy-related proteins in the soleus muscle and mitochondria was significantly increased compared with that in the MICT group. Serum irisin and mitochondrial fusion protein levels significantly decreased with age. Superoxide dismutase 2 protein levels and AMPK pathway protein expression were significantly increased in the HIIT group compared with those in the other groups. Additionally, the expression levels of mitoSCs and the mRNA levels of interleukin-15 and optical atrophy 1 increased in the HIIT group compared with that in the MICT group.
CONCLUSION: Compared with MICT, HIIT activated the AMPK pathway to upregulate mitochondrial biogenesis- and mitophagy-related proteins, and promote the assembly and formation of mitoSCs to improve the mitochondrial function of aging soleus muscles.

Keywords: AMPK pathway; High-intensity interval training, aging; Mitochondrial supercomplex; Mitophagy

DOI: https://doi.org/10.1016/j.exger.2021.111648

Nat Commun. 2021 Dec 03. 12(1): 7056

High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content.

Cesare Granata, Nikeisha J Caruana, Javier Botella, Nicholas A Jamnick, Kevin Huynh, Jujiao Kuang, Hans A Janssen, Boris Reljic, Natalie A Mellett, Adrienne Laskowski, Tegan L Stait, Ann E Frazier, Melinda T Coughlan, Peter J Meikle, David R Thorburn, David A Stroud, David J Bishop.

Mitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible, inexpensive therapeutic intervention that can improve mitochondrial bioenergetics and quality of life. By combining multiple omics techniques with biochemical and in silico normalisation, we removed the bias arising from the training-induced increase in mitochondrial content to unearth an intricate and previously undemonstrated network of differentially prioritised mitochondrial adaptations. We show that changes in hundreds of transcripts, proteins, and lipids are not stoichiometrically linked to the overall increase in mitochondrial content. Our findings suggest enhancing electron flow to oxidative phosphorylation (OXPHOS) is more important to improve ATP generation than increasing the abundance of the OXPHOS machinery, and do not support the hypothesis that training-induced supercomplex formation enhances mitochondrial bioenergetics. Our study provides an analytical approach allowing unbiased and in-depth investigations of training-induced mitochondrial adaptations, challenging our current understanding, and calling for careful reinterpretation of previous findings.

DOI: https://doi.org/10.1038/s41467-021-27153-3

Am J Physiol Cell Physiol. 2021 Dec 01.

Aerobic exercise and resistance exercise alleviate skeletal muscle atrophy through IGF-1/IGF-1R-PI3K/Akt pathway in mice with myocardial infarction.

Feng Li-Li, Li Bo-Wen, Xi Yue, Tian Zhen-Jun, Cai Meng-Xin.

OBJECTIVES: Myocardial infarction (MI)-induced heart failure (HF) is commonly accompanied with profound effects on skeletal muscle. With the process of MI-induced HF, perturbations in skeletal muscle contribute to muscle atrophy. Exercise is viewed as a feasible strategy to prevent muscle atrophy. The aims of this study were to investigate whether exercise could alleviate MI-induced skeletal muscle atrophy via insulin-like growth factor 1 (IGF-1) pathway in mice.MATERIALS AND METHODS: Male C57/BL6 mice were used to establish the MI model and divided into three groups: sedentary MI group, MI with aerobic exercise group and MI with resistance exercise group, sham-operated group was used as control. Exercise-trained animals were subjected to four-weeks of aerobic exercise (AE) or resistance exercise (RE). Cardiac function, muscle weight, myofiber size, levels of IGF-1 signaling and proteins related to myogenesis, protein synthesis and degradation and cell apoptosis in gastrocnemius muscle were detected. And H2O2-treated C2C12 cells were intervened with recombinant human IGF-1, IGF-1R inhibitor NVP-AEW541 and PI3K inhibitor LY294002 to explore the mechanism. Results：Exercises up-regulated the IGF-1/IGF-1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling, increased the expressions of Pax7, myogenic regulatory factors (MRFs) and protein synthesis, reduced protein degradation and cell apoptosis in MI-mice. In vitro, IGF-1 up-regulated the levels of Pax7 and MRFs, mTOR and P70S6K, reduced MuRF1, MAFbx and inhibited cell apoptosis via IGF-1R-PI3K/Akt pathway.
CONCLUSION: AE and RE, safely and effectively, alleviate skeletal muscle atrophy by regulating the levels of myogenesis, protein degradation and cells apoptosis in mice with MI via activating IGF-1/IGF-1R-PI3K/Akt pathway.

Keywords: aerobic exercise; insulin-like growth factor-1; myocardial infarction; resistance exercise; skeletal muscle atrophy

DOI: https://doi.org/10.1152/ajpcell.00344.2021