Chronic alcohol consumption induces myocardial damage and a type of non-ischemic cardiomyopathy termed alcoholic cardiomyopathy, where mitochondrial ultrastructural damages and suppressed fusion activity promote cardiomyocyte apoptosis. The aim of the present study is to determine the role of mitochondrial fission proteins and/or other proteins that localise on cardiac mitochondria for apoptosis upon ethanol consumption. In vivo and in vitro chronic alcohol exposure increased mitochondrial Drp1 levels but knockdown of the same did not confer cardioprotection in H9c2 cells. These cells displayed downregulated expression of MFN2 and OPA1 for Bak-mediated cytochrome c release and apoptosis. Dysregulated PTEN/AKT cell survival signal in both ethanol treated and Drp1 knockdown cells augmented oxidative stress by promoting mitochondrial PTEN-L and MFN1 interaction. Inhibiting this interaction with VO–OHpic, a reversible PTEN inhibitor, prevented Bak insertion into the mitochondria and release of cytochrome c to cytoplasm. Thus, our study provides evidence that Drp1-mediated mitochondrial fission is dispensable for ethanol-induced cardiotoxicity and that stress signals induce mitochondrial PTEN-L accumulation for structural and functional dyshomeostasis. Our in vivo results also demonstrates the therapeutic potential of VO–OHpic for habitual alcoholics developing myocardial dysfunction.

长期饮酒会引起心肌损伤，一种称为酒精性心肌病的非缺血性心肌病，其中线粒体的超微结构损伤和抑制的融合活性会促进心肌细胞凋亡。本研究的目的是确定线粒体裂变蛋白和/或定位在心脏线粒体上的其他蛋白在消耗乙醇时的凋亡作用。在体内和体外，慢性酒精暴露会增加线粒体Drp1的水平，但敲除相同的物质不会在H9c2细胞中赋予心脏保护作用。这些细胞显示Bak介导的细胞色素c释放和凋亡的MFN2和OPA1表达下调。在乙醇处理过的和Drp1中， PTEN / AKT细胞存活信号失调敲低的细胞通过促进线粒体PTEN-L和MFN1相互作用来增加氧化应激。抑制与可逆性PTEN抑制剂VO-OHpic的这种相互作用，可防止Bak插入线粒体并将细胞色素c释放到细胞质中。因此，我们的研究提供了证据，证明Drp1介导的线粒体裂变对于乙醇诱导的心脏毒性是必不可少的，并且应激信号诱导线粒体PTEN-L积累导致结构和功能异常。我们的体内结果还证明了VO-OHpic对习惯性酗酒者发展心肌功能障碍的治疗潜力。