2. Academic Validation
  3. Acetylation of the Mitochondrial Chaperone GRP75 Governs ER-Mitochondrial Calcium Homeostasis and Hepatocyte Insulin Resistance

Acetylation of the Mitochondrial Chaperone GRP75 Governs ER-Mitochondrial Calcium Homeostasis and Hepatocyte Insulin Resistance

  • Adv Sci (Weinh). 2025 Sep 26:e08991. doi: 10.1002/advs.202508991.
Danni Wang 1,  Jiaqi Zhang 2,  Xinyu Yang 1,  Qiqi Zhang 1,  Xiuya Hu 1,  Xin Lu 1,  Hanni Li 1,  Xue Bai 3,  Kai Zhang 3,  Michael N Sack 4,  Yongsheng Chang 2,  Yingmei Wang 5,  Lingdi Wang 2,  Lu Zhu 1
Affiliations

Affiliations

  • 1 Department of Pharmacology, State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital, and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  • 2 Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Cell Homeostasis and Major Diseases, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  • 4 Laboratory of Mitochondrial Biology and Metabolism, NHLBI, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 5 Department of Gynecology and Obstetrics, Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, 300052, China.
PMID: 41001747 DOI: 10.1002/advs.202508991
Abstract

Overnutrition exacerbates Insulin resistance (IR) and is linked to excessive mitochondrial protein acetylation. However, the molecular mechanism by which mitochondrial protein acetylation influences hepatic IR remains incompletely elucidated. To investigate this biology, GCN5L1 liver knockout mice (LKO), which exhibit blunted mitochondrial protein acetylation are utilized. Interestingly, the hepatocytes of LKO mice exhibit impaired Insulin signaling and exaggerated endoplasmic reticulum (ER) stress. To explore putative mechanisms, protein-interaction and acetyl-proteome analyses are conducted following hepatic induction of GCN5L1. The mitochondrial chaperone GRP75 interacts with GCN5L1 and is acetylated on lysine residues K567 and K612 by GCN5L1 overexpression. Furthermore, GRP75-K567/612 acetylation reduces the assemble of IP3R1-GRP75-VDAC complex, which in turn leads to the maintenance of ER calcium homeostasis and Insulin sensitivity. Interestingly, during high-fat diet feeding, mitochondria-localized GCN5L1 is significantly translocated to the cytosol. This translocation attenuates the acetylation of GRP75 at K567/612 and consequently enhances ER-mitochondrial calcium flux and induces ER stress. In parallel, deacetylation-mimicking mutated GRP75-K567/612 promotes IR in vivo. Consequently, these findings demonstrate that the acetylation-dependent modification of GRP75 plays a functional role in regulating overnutrition-induced IR.

Keywords

acetylation; insulin resistance; liver; metabolism; mitochondria.

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