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IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling

Yuan, Ming, Gong, Mengqi, He, Jinli, Xie, Bingxin, Zhang, Zhiwei, Meng, Lei, Tse, Gary, Zhao, Yungang, Bao, Qiankun, Zhang, Yue, and others. (2022) IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling. Redox Biology, 52 . Article Number 102289. E-ISSN 2213-2317. (doi:10.1016/j.redox.2022.102289) (KAR id:98717)



Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are important mechanisms of atrial remodeling, predisposing to the development of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). However, the molecular mechanisms underlying these processes especially their interactions have not been fully elucidated.


To explore the potential role of ER stress–mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes.

Methods and results

Mouse atrial cardiomyocytes (HL-1 cells) and rats with T2DM were used as study models. Significant ER stress was observed in the diabetic rat atria. After treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) identified several known ER stress and calmodulin proteins, including heat shock protein family A (HSP70) member [HSPA] 5 [GRP78]) and HSPA9 (GRP75, glucose-regulated protein 75). In situ proximity ligation assay indicated that TM led to increased protein expression of the IP3R1–GRP75–VDAC1 (inositol 1,4,5-trisphosphate receptor 1–glucose-regulated protein 75–voltage-dependent anion channel 1) complex in HL-1 cells. Small interfering RNA silencing of GRP75 in HL-1 cells and GRP75 conditional knockout in a mouse model led to impaired calcium transport from the ER to the mitochondria and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuated atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice.


The IP3R1–GRP75–VDAC1 complex mediates ER stress–mitochondrial oxidative stress and plays an important role in diabetic atrial remodeling.

Item Type: Article
DOI/Identification number: 10.1016/j.redox.2022.102289
Uncontrolled keywords: Endoplasmic reticulum stress; IP3R1–GRP75–VDAC1 complexMitochondria; Diabetes; Atrial fibrillation
Subjects: R Medicine > R Medicine (General)
Divisions: Divisions > Division of Natural Sciences > Kent and Medway Medical School
Funders: National Natural Science Foundation of China (
Depositing User: Manfred Gschwandtner
Date Deposited: 05 Dec 2022 17:57 UTC
Last Modified: 13 Dec 2022 11:50 UTC
Resource URI: (The current URI for this page, for reference purposes)

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