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GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity

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posted on 22.11.2021, 21:00 by Qiongya Zhao, Ting Luo, Feng Gao, Yinxu Fu, Bin Li, Xiaoli Shao, Haifeng Chen, Zhuohua Zhou, Sihan Guo, Lijun Shen, Liqin Jin, Dong Cen, Huaibin Zhou, Jianxin Lyu, Hezhi Fang
GRP75, defined as a major component of both mitochondrial quality control system and mitochondria-associated membrane, plays a key role in mitochondrial homeostasis. In this study, we assessed the roles of GRP75, other than as a component, in insulin action in both in vitro and in vivo models with insulin resistance. We found that GRP75 was downregulated in HFD-fed mice, and induction of Grp75 in mice could prevent HFD induced obesity and insulin resistance. Mechanistically, GRP75 influenced insulin sensitivity by regulating mitochondrial function through its modulation of mitochondrial-supercomplex turnover rather than MAM communication: GRP75 was negatively associated with respiratory-chain complex activity and was essential for mitochondrial-supercomplex assembly and stabilization. Moreover, mitochondrial dysfunction in Grp75-knockdown cells might further increase mitochondrial fragmentation, thus trigger cytosolic mitochondrial DNA release and activate the cGAS/STING-dependent pro-inflammatory response. Therefore, GRP75 can serve as a potential therapeutic target of insulin resistant-related diabetes or other metabolic diseases.

Funding

This work was supported by the General Program of the National Natural Science Foundation of China (82072338 to H.Z, 82072366 to J.L.), Key Program of the National Natural Science Foundation of China (81830071 to J.L.) , the Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A) and Wenzhou Municipal Science and Technology Bureau (Y20210107 to H.Z).

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