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Loss of high‐temperature requirement protein A2 protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia
Author(s) -
Zhou Haohan,
Yuan Danni,
Gao Weinan,
Tian Jiayi,
Sun Hongyu,
Yu Shuang,
Wang Jincheng,
Sun Liankun
Publication year - 2020
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.2289
Subject(s) - proteostasis , biology , mitochondrial biogenesis , microbiology and biotechnology , mitochondrion , unfolded protein response , sarcopenia , proteases , endocrinology , biochemistry , endoplasmic reticulum , enzyme
Cellular homeostasis requires tight coordination between nucleus and mitochondria, organelles that each possesses their own genomes. Disrupted mitonuclear communication has been found to be implicated in many aging processes. However, little is known about mitonuclear signaling regulator in sarcopenia which is a major contributor to the risk of poor health‐related quality of life, disability, and premature death in older people. High‐temperature requirement protein A2 (HtrA2/Omi) is a mitochondrial protease and plays an important role in mitochondrial proteostasis. HtrA2 mnd2(−/−) mice harboring protease‐deficient HtrA2/Omi Ser276Cys missense mutants exhibit premature aging phenotype. Additionally, HtrA2/Omi has been established as a signaling regulator in nervous system and tumors. We therefore asked whether HtrA2/Omi participates in mitonuclear signaling regulation in muscle degeneration. Using motor functional, histological, and molecular biological methods, we characterized the phenotype of HtrA2 mnd2(−/−) muscle. Furthermore, we isolated the gastrocnemius muscle of HtrA2 mnd2(−/−) mice and determined expression of genes in mitochondrial unfolded protein response (UPR mt ), mitohormesis, electron transport chain (ETC), and mitochondrial biogenesis. Here, we showed that HtrA2/Omi protease deficiency induced denervation‐independent skeletal muscle degeneration with sarcopenia phenotypes. Despite mitochondrial hypofunction, upregulation of UPR mt and mitohormesis‐related genes and elevated total reactive oxygen species (ROS) production were not observed in HtrA2 mnd2(−/−) mice, contrary to previous assumptions that loss of protease activity of HtrA2/Omi would lead to mitochondrial dysfunction as a result of proteostasis disturbance and ROS burst. Instead, we showed that HtrA2/Omi protease deficiency results in different changes between the expression of nuclear DNA‐ and mitochondrial DNA‐encoded ETC subunits, which is in consistent with their transcription factors, nuclear respiratory factors 1 and 2, and coactivator peroxisome proliferator‐activated receptor γ coactivator 1α. These results reveal that loss of HtrA2/Omi protease activity induces mitonuclear imbalance via differential regulation of mitochondrial biogenesis in sarcopenia. The novel mechanistic insights may be of importance in developing new therapeutic strategies for sarcopenia.