Mitochondrial miR-762 regulates apoptosis and myocardial infarction by impairing ND2
Mitochondrial miR-762 regulates apoptosis and myocardial infarction by impairing ND2
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线粒体 miR-762 通过损害 ND2 调节细胞凋亡和心肌梗死
DOI：
10.1038/s41419-019-1734-7
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发表时间：
2019-06-24
影响因子：
9
通讯作者：
Wang, Kun
中科院分区：
文献类型：
--
作者：
Yan, Kaowen;An, Tao;Wang, Kun
线粒体功能障碍在心血管疾病的发病机制中起重要作用。MicroRNAs(MiRNAs)是一种小RNA，可以作为基因表达的负调控因子，但miRNAs如何影响心脏中的线粒体功能尚不清楚。利用miRNA微阵列分析，我们发现miR-762主要易位于线粒体，并且在缺氧/复氧(A/R)处理后显著上调。敲除内源性miR-762可明显减轻A/R引起的心肌细胞内ATP水平下降、ROS水平升高、线粒体复合体I酶活性下降和细胞凋亡性死亡的增加。此外，敲除miR-762可改善小鼠心肌缺血/再灌注(I/R)损伤。在机制上，我们发现miR-762的增强表达显著降低了内源NADH脱氢酶亚单位2(ND2)的蛋白水平，但对ND2的转录水平没有影响。荧光素酶报告实验表明miR-762与ND2的编码序列结合。此外，下调内源性ND2可显著降低A/R诱导的心肌细胞内ATP水平，增加ROS水平，降低线粒体复合体I酶活性，增加细胞凋亡率。此外，我们还发现，nd2基因敲除可减弱miR-762下调的抑制作用。因此，我们的研究结果提示miR-762参与了线粒体复合体I的核心组装亚单位ND2对线粒体功能和心肌细胞凋亡的调控。我们的结果表明，线粒体miR-762作为线粒体功能障碍的新参与者，可能为心肌梗死提供新的治疗靶点。
Mitochondrial dysfunction plays a major role in the pathogenesis of cardiovascular diseases. MicroRNAs (miRNAs) are small RNAs that act as negative regulators of gene expression, but how miRNAs affect mitochondrial function in the heart is unclear. Using a miRNA microarray assay, we found that miR-762 predominantly translocated in the mitochondria and was significantly upregulated upon anoxia/reoxygenation (A/R) treatment. Knockdown of endogenous miR-762 significantly attenuated the decrease in intracellular ATP levels, the increase in ROS levels, the decrease in mitochondrial complex I enzyme activity and the increase in apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. In addition, knockdown of miR-762 ameliorated myocardial ischemia/reperfusion (I/R) injury in mice. Mechanistically, we showed that enforced expression of miR-762 dramatically decreased the protein levels of endogenous NADH dehydrogenase subunit 2 (ND2) but had no effect on the transcript levels of ND2. The luciferase reporter assay showed that miR-762 bound to the coding sequence of ND2. In addition, knockdown of endogenous ND2 significantly decreased intracellular ATP levels, increased ROS levels, reduced mitochondrial complex I enzyme activity and increased apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. Furthermore, we found that the inhibitory effect of miR-762 downregulation was attenuated by ND2 knockdown. Thus, our findings suggest that miR-762 participates in the regulation of mitochondrial function and cardiomyocyte apoptosis by ND2, a core assembly subunit of mitochondrial complex I. Our results revealed that mitochondrial miR-762, as a new player in mitochondrial dysfunction, may provide a new therapeutic target for myocardial infarction.