Journal
SCIENCE ADVANCES
Volume 8, Issue 30, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abo0340
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Funding
- National Natural Science Foundation of China [91857105, 31771291, 31922033, 32071136, 32100922, 32125021]
- Ministry of Science and Technology of China (National Key R&D Program of China) [2018YFA0800700]
- Natural Science Foundation of Jiangsu Province [BK20170014, SWYY-002]
- Fundamental Research Funds for the Central Universities [090314380036, 021414380517, 021414380524, 021414380511]
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Mitochondrial quality in skeletal muscle is crucial for energy homeostasis; LONP1 plays a critical role in maintaining mitochondrial protein and systemic metabolic homeostasis; Imbalance in mitochondrial protein turnover leads to unfolded protein response and modulates adipose tissue and liver metabolism.
Mitochondrial quality in skeletal muscle is crucial for maintaining energy homeostasis during metabolic stresses. However, how muscle mitochondrial quality is controlled and its physiological impacts remain unclear. Here, we demonstrate that mitoprotease LONP1 is essential for preserving muscle mitochondrial proteostasis and systemic metabolic homeostasis. Skeletal muscle-specific deletion of Lon protease homolog, mitochondrial (LONP1) impaired mitochondrial protein turnover, leading to muscle mitochondrial proteostasis stress. A benefit of this adaptive response was the complete resistance to diet-induced obesity. These favorable metabolic phenotypes were recapitulated in mice overexpressing LONP1 substrate Delta OTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPRmt) in muscle that acts distally to modulate adipose tissue and liver metabolism. Unexpectedly, contrary to its previously proposed role, ATF4 is dispensable for the long-range protective response of skeletal muscle. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial proteostasis in directing muscle UPRmt to regulate systemic metabolism.
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