GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity

GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity
james freeman diabetes freedom

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.

Diabetes Journal publish ahead of print articles
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.
james freeman diabetes freedom

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