Zhao 2021 Diabetes

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Zhao Q, Luo T, Gao F, Fu Y, Li B, Shao X, Chen H, Zhou Z, Guo S, Shen L, Jin L, Cen D, Zhou H, Lyu J, Fang H (2021) GRP75 regulates mitochondrial-supercomplex turnover to modulate insulin sensitivity. Diabetes [Epub ahead of print].

» PMID: 34810178 Open Access

Zhao Qiongya, Luo Ting, Gao Feng, Fu Yinxu, Li Bin, Shao Xiaoli, Chen Haifeng, Zhou Zhuohua, Guo Sihan, Shen Lijun, Jin Liqin, Cen Dong, Zhou Huaibin, Lyu Jianxin, Fang Hezhi (2021) Diabetes

Abstract: 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.

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