Guo 2022 Sci Adv

Guo Q, Xu Z, Zhou D, Fu T, Wang W, Sun W, Xiao L, Liu L, Ding C, Yin Y, Zhou Z, Sun Z, Zhu Y, Zhou W, Jia Y, Xue J, Chen Y, Chen XW, Piao HL, Lu B, Gan Z (2022) Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4. https://doi.org/10.1126/sciadv.abo0340

» Sci Adv 8:eabo0340. PMID: 35895846 Open Access

Guo Qiqi, Xu Zhisheng, Zhou Danxia, Fu Tingting, Wang Wen, Sun Wanping, Xiao Liwei, Liu Lin, Ding Chenyun, Yin Yujing, Zhou Zheng, Sun Zongchao, Zhu Yuangang, Zhou Wenjing, Jia Yuhuan, Xue Jiachen, Chen Yuncong, Chen Xiao-Wei, Piao Hai-Long, Lu Bin, Gan Zhenji (2022) Sci Adv

Abstract: 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 ΔOTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPR^mt) 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 UPR^mt to regulate systemic metabolism.

• Bioblast editor: Plangger M

Labels: MiParea: Respiration  Pathology: Obesity 

HRR: Oxygraph-2k 

2022-08