Academic Journal
Hyperacetylation escalates myocardial susceptibility to ischemia reperfusion injury by mediating mitochondrial supercomplexes assembly in T2DM.
| Title: | Hyperacetylation escalates myocardial susceptibility to ischemia reperfusion injury by mediating mitochondrial supercomplexes assembly in T2DM. |
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| Authors: | Deng Y; Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China., Yang W; Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China., Yang J; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China., Ji L; Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China., Xie M; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China., Tang K; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China., He Q; Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China., Hu G; Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL, USA., Shangguan W; Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China. Electronic address: sgwning@163.com., Jiang C; Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: jiangchunling@scu.edu.cn., Li T; Department of Anesthesiology, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital of Sichuan University, Chengdu, 610041, China; Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: scutaoli1981@scu.edu.cn. |
| Source: | Redox biology [Redox Biol] 2026 Jun; Vol. 93, pp. 104163. Date of Electronic Publication: 2026 Apr 08. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Amsterdam]: Elsevier, B.V., [2013]- |
| MeSH Terms: | Sirtuin 3*/genetics , Sirtuin 3*/metabolism , Sirtuin 3*/deficiency , Myocardial Reperfusion Injury*/metabolism , Myocardial Reperfusion Injury*/pathology , Myocardial Reperfusion Injury*/etiology , Myocardial Reperfusion Injury*/genetics , Diabetes Mellitus, Type 2*/metabolism , Diabetes Mellitus, Type 2*/complications , Diabetes Mellitus, Type 2*/pathology , Diabetes Mellitus, Type 2*/genetics , Mitochondria, Heart*/metabolism , Mitochondria*/metabolism, Reactive Oxygen Species/metabolism ; Mitochondrial Proteins/metabolism ; Myocardium/metabolism ; Myocardium/pathology ; Diabetes Mellitus, Experimental/metabolism ; Animals ; Acetylation ; Mice ; Mice, Knockout ; Male ; Disease Susceptibility ; Disease Models, Animal |
| Abstract: | Background: Type 2 diabetes mellitus (T2DM) markedly increases susceptibility to myocardial ischemia/reperfusion (I/R) injury, contributing to elevated mortality. Sirtuin 3 (Sirt3), a mitochondrial NAD+-dependent deacetylase, is downregulated in T2DM and is closely associated with mitochondrial protein hyperacetylation, possibly as a mediator of this effect. This study aimed to elucidate the molecular mechanisms underlying increased susceptibility to myocardial I/R injury in T2DM, with a particular focus on Sirt3 deficiency-mediated mitochondrial protein hyperacetylation. Methods: Wild-type (WT) and Sirt3-knockout (KO) mice were fed a high-fat diet (HFD) for 8 weeks and received intraperitoneal injections of streptozotocin (STZ, 50 mg/kg for three consecutive days) beginning at week 5 to establish a T2DM model. Both in vitro and in vivo models were used to examine the effects of Sirt3 deficiency-induced hyperacetylation on mitochondrial function, reactive oxygen species (ROS) production, and myocardial I/R injury. Mitochondrial supercomplex (SC) assembly and the activities of respiratory chain complexes I, II, III and IV were assessed by blue-native PAGE or a microplate assay kit. Protein-protein interactions were analyzed using proximity ligation assay, and Western blot and functional experiments were performed to explore the underlying molecular mechanisms. Results: In T2DM, the Sirt3 deficiency-induced mitochondrial protein hyperacetylation significantly increased myocardial susceptibility to I/R injury. Mitochondrial hyperacetylation impaired mitochondrial respiratory function and increased mitochondrial ROS production. Mechanistically, Sirt3 deficiency-induced hyperacetylation of SC-associated mitochondrial proteins disrupted mitochondrial SC assembly, thereby compromising mitochondrial integrity and function. Conclusions: These findings demonstrate that the increased myocardial susceptibility to I/R injury in T2DM is driven, at least in part, by Sirt3 deficiency-mediated hyperacetylation of mitochondrial SC-associated proteins. Disruption of SC assembly leads to mitochondrial dysfunction and ROS accumulation, providing a mechanistic link between metabolic dysregulation and heightened cardiac I/R injury in T2DM. (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Diabetes; Heart; Ischemia-reperfusion injury; Mitochondrial supercomplexes; Protein acetylation; Reactive oxidative species |
| Substance Nomenclature: | EC 3.5.1.- (Sirtuin 3) 0 (Reactive Oxygen Species) 0 (Sirt3 protein, mouse) 0 (Mitochondrial Proteins) |
| Entry Date(s): | Date Created: 20260412 Date Completed: 20260714 Latest Revision: 20260714 |
| Update Code: | 20260715 |
| PubMed Central ID: | PMC13091559 |
| DOI: | 10.1016/j.redox.2026.104163 |
| PMID: | 41967292 |
| Database: | MEDLINE |
| ISSN: | 2213-2317 |
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| DOI: | 10.1016/j.redox.2026.104163 |