Upregulation of mitochondrial E3 ubiquitin ligase 1 in rat heart contributes to ischemia/reperfusion injury
Upregulation of mitochondrial E3 ubiquitin ligase 1 in rat heart contributes to ischemia/reperfusion injury
复制标题
大鼠心脏线粒体E3泛素连接酶1的上调导致缺血/再灌注损伤
DOI：
10.1139/cjpp-2019-0285
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发表时间：
2020
影响因子：
2.1
通讯作者：
Peng Jun
中科院分区：
文献类型：
--
作者：
Wang Shi-Jing;Chen Heng;Tang Li-Jing;Tu Hua;Liu Bin;Li Nian-Sheng;Luo Xiu-Ju;Peng Jun
线粒体功能障碍是心肌缺血/再灌注损伤的重要原因，线粒体E3泛素连接酶1（Mul 1）在维持线粒体功能中起重要作用。本研究旨在探讨Mul 1在心肌I/R损伤中的作用及其机制。Sprague-Dawley大鼠心脏经历1小时缺血加3小时再灌注，这表明I/R损伤（梗死面积增加和肌酸激酶释放）以及Mul 1和p53的总蛋白和线粒体蛋白水平升高，同时Mul 1和p53之间的相互作用增强。p53以及p53和小的泛蛋白样修饰剂（SUMO 1）。缺氧/复氧（H/R）处理的心肌细胞（H9 c2）出现细胞损伤（凋亡和坏死），Mul 1和p53的总蛋白和线粒体蛋白水平上调，以及p53和SUMO 1之间的相互作用增强，伴随线粒体功能障碍（线粒体膜电位和活性氧产生增加，ATP产生减少）;这些现象通过Mul 1表达的敲低而减弱。基于这些观察结果，我们得出结论，Mul 1的一个新的作用已被确定在心肌线粒体，Mul 1稳定和激活p53通过其功能的SUMO化后I/R，导致p53介导的线粒体功能障碍和细胞死亡。
Mitochondrial dysfunctions are responsible for myocardial injury upon ischemia/reperfusion (I/R), and mitochondrial E3 ubiquitin ligase 1 (Mul1) plays an important role in maintaining mitochondrial functions. This study aims to explore the function of Mul1 in myocardial I/R injury and the underlying mechanisms. The Sprague–Dawley rat hearts were subjected to 1 h of ischemia plus 3 h of reperfusion, which showed the I/R injury (increase in infarct size and creatine kinase release) and the elevated total and mitochondrial protein levels of Mul1 and p53 accompanied by the enhanced interactions between Mul1 and p53 as well as p53 and small a ubiquitin-like modifier (SUMO1). Consistently, hypoxia/reoxygenation (H/R) treated cardiac (H9c2) cells displayed cellular injury (apoptosis and necrosis), upregulation of total and mitochondrial protein levels of Mul1 and p53, and enhanced interactions between p53 and SUMO1 concomitant with mitochondrial dysfunctions (an increase in mitochondrial membrane potential and reactive oxygen species production with a decrease in ATP production); these phenomena were attenuated by knockdown of Mul1 expression. Based on these observations, we conclude that a novel role of Mul1 has been identified in the myocardial mitochondria, where Mul1 stabilizes and activates p53 through its function of SUMOylation following I/R, leading to p53-mediated mitochondrial dysfunction and cell death.