Mitochondrial H 2 S Regulates BCAA Catabolism in Heart Failure

作者：Zhen Li, Huijing Xia, Thomas E. Sharp, Kyle B. LaPenna, John W. Elrod, Kevin M. Casin, Ken Liu, John W. Calvert, Vinh Q. Chau, Fadi N. Salloum, Shi Xu, Ming Xian, Noriyuki Nagahara, Traci Goodchild, David J. Lefer · 发表于：Circulation Research · 年份：2022 · DOI：10.1161/circresaha.121.319817 · 被引用次数：66 · 研究领域：Sulfur Compounds in Biology、Amino Acid Enzymes and Metabolism、Redox biology and oxidative stress

Background: Hydrogen sulfide (H 2 S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H 2 S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload–induced heart failure. Methods: Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency. Results: Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branch...