GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity.
Diabetes
; 71(2): 233-248, 2022 02 01.
Article
de En
| MEDLINE
| ID: mdl-34810178
ABSTRACT
GRP75 (75-kDA glucose-regulated protein), defined as a major component of both the 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 mice fed a high-fat diet (HFD) and that 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 mitochondria-associated membrane 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 triggering cytosolic mtDNA release and activating the cGAS/STING-dependent proinflammatory response. Therefore, GRP75 can serve as a potential therapeutic target of insulin resistant-related diabetes or other metabolic diseases.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Insulinorésistance
/
Protéines du choc thermique HSP70
/
Protéines membranaires
/
Mitochondries
Type d'étude:
Diagnostic_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Diabetes
Année:
2022
Type de document:
Article
Pays d'affiliation:
Chine