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).