Sirt5 improves cardiomyocytes fatty acid metabolism and ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via CPT2 de-succinylation

• DOI: 10.1016/j.redox.2024.103184
• Publication Date: 2024-05-05T05:24:04Z
• Authors: Maoxiong Wu; Jing Tan; Zhengyu Cao; Yangwei Cai; Zhaoqi Huang; Zhiteng Chen; Wanbing He; Xiao Liu; Yuan Jiang; Qingyuan Gao; Bingqing Deng; Jingfeng Wang; Woliang Yuan; Haifeng Zhang; Yangxin Chen
• Keywords: Lipotoxicity; Succinylation; Diabetic Cardiomyopathy; Acyl-CoA

The disruption of the balance between fatty acid (FA) uptake and oxidation (FAO) leads to cardiac lipotoxicity, serving as driving force behind diabetic cardiomyopathy (DbCM). Sirtuin 5 (Sirt5), a lysine de-succinylase, could impact diverse metabolic pathways, including FA metabolism. Nevertheless, precise roles Sirt5 in lipotoxicity DbCM remain unknown. This study aims elucidate role underlying mechanism context DbCM. expression myocardial was found be modestly elevated heart failure patients mice. Cardiac dysfunction, hypertrophy were exacerbated by ablation but improved forced Notably, deficiency impaired FAO without affecting capacity heart, leading accumulation intermediate metabolites, which mainly included medium- long-chain acyl-carnitines. Mechanistically, succinylomics analyses identified carnitine palmitoyltransferase 2 (CPT2), crucial enzyme involved reconversion acyl-carnitines acyl-CoA facilitating FAO, functional succinylated substrate mediator Sirt5. Succinylation Lys424 CPT2 significantly increased deficiency, inactivation its enzymatic activity subsequent K424R mutation, mitigated succinylation modification, counteracted reduction mediated thereby attenuating knockout-induced impairment lipid deposition. impairs through CPT2. underscores potential therapeutic targets for addressing