Cardiac Mitochondrial PTEN-L determines cell fate between apoptosis and survival during chronic alcohol consumption
Cardiac Mitochondrial PTEN-L determines cell fate between apoptosis and survival during chronic alcohol consumption
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DOI：
10.1007/s10495-020-01616-2
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发表时间：
2020-06-26
期刊：
影响因子：
7.2
通讯作者：
Balakrishnan, Rekha
中科院分区：
文献类型：
--
作者：
Sivakumar, Anusha;Shanmugarajan, Suresh;Balakrishnan, Rekha
慢性酒精消耗诱导心肌损伤和一种称为酒精性心肌病的非缺血性心肌病，其中线粒体超微结构损伤和抑制的融合活性促进心肌细胞凋亡。本研究的目的是确定线粒体分裂蛋白和/或其他蛋白质的作用，定位于心脏线粒体细胞凋亡后，乙醇消耗。在体内和体外慢性酒精暴露增加线粒体Drp 1水平，但敲低相同的H9 c2细胞没有赋予心脏保护。这些细胞表现出MFN 2和OPA 1的表达下调，用于Bak-mediated细胞色素c释放和凋亡。在乙醇处理和Drp 1敲低细胞中，PTEN/AKT细胞存活信号失调通过促进线粒体PTEN-L和MFN 1相互作用增强氧化应激。抑制这种相互作用与VO-OHpic，一种可逆的PTEN抑制剂，防止巴克插入线粒体和细胞色素c释放到细胞质。因此，我们的研究提供的证据表明，Drp 1介导的线粒体分裂是乙醇诱导的心脏毒性和应激信号诱导线粒体PTEN-L积累的结构和功能失调。我们的体内研究结果也证明了VO-OHpic对发生心肌功能障碍的习惯性酗酒者的治疗潜力。
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 andDrp1knockdown 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.