2. Academic Validation
  3. Mitochondrial SIRT2-mediated CPT2 deacetylation prevents diabetic cardiomyopathy by impeding cardiac fatty acid oxidation

Mitochondrial SIRT2-mediated CPT2 deacetylation prevents diabetic cardiomyopathy by impeding cardiac fatty acid oxidation

  • Int J Biol Sci. 2025 Jan 1;21(2):725-744. doi: 10.7150/ijbs.102834.
Yaoyao Guo 1 2 3,  Ziyin Zhang 1 2 3,  Zheng Wen 4 5,  Xiaonan Kang 1 2 3,  Dan Wang 1 2 3,  Lu Zhang 1 2 3,  Mengke Cheng 1 2 3,  Gang Yuan 1 2 3,  Huihui Ren 1 2 3
Affiliations

Affiliations

  • 1 Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Hubei Clinical Medical Research Center for Endocrinology and Metabolic Diseases, Hubei, China.
  • 3 Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China.
  • 4 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Hubei, China.
PMID: 39781464 DOI: 10.7150/ijbs.102834
Abstract

Dysregulated energy metabolism, particularly lipid metabolism disorders, has been identified as a key factor in the development of diabetic cardiomyopathy (DCM). Sirtuin 2 (SIRT2) is a deacetylase involved in the regulation of metabolism and cellular energy homeostasis, yet its role in the progression of DCM remains unclear. We observed significantly reduced SIRT2 expression in DCM model mice. Cardiac-specific overexpression of SIRT2 protected mice from streptozotocin/high-fat diet (STZ/HFD)-induced Insulin resistance (IR), cell Apoptosis, and cardiac dysfunction, whereas its downregulation exacerbated these conditions. Moreover, we found that SIRT2 regulated cardiac lipid accumulation and fatty acid oxidation (FAO), and identified its localization in cardiac mitochondria. Mechanistically, we determined carnitine palmitoyltransferase 2 (CPT2) as a critical substrate of SIRT2, which is implicated in DCM. SIRT2-mediated deacetylation at K239 enhanced CPT2 ubiquitination, resulting in decreased protein stability and subsequent inhibition of FAO and Reactive Oxygen Species (ROS) production. Taken together, these findings suggest that the SIRT2/CPT2 signaling pathway plays a crucial role in DCM progression.

Keywords

CPT2; SIRT2; deacetylation; diabetic cardiomyopathy; fatty acid oxidation.

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