miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1
miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1
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Mir-499 通过靶向钙调磷酸酶和动力相关蛋白 1 调节线粒体动力学
DOI：
10.1038/nm.2282
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发表时间：
2011-01-01
期刊：
影响因子：
82.9
通讯作者：
Li, Pei-Feng
中科院分区：
文献类型：
--
作者：
Wang, Jian-Xun;Jiao, Jian-Qin;Li, Pei-Feng
心肌梗死是世界范围内死亡的主要原因。在这里，我们报道了microRNA-499(miR-499)水平的调节影响细胞凋亡以及缺血-再灌流引起的心肌梗死和心功能障碍的严重程度。我们发现，钙调神经磷酸酶催化亚基的α和β亚基都是miR-499的直接靶点，miR-499通过抑制钙调神经磷酸酶介导的动力蛋白相关蛋白-1(Drp1)的去磷酸化而抑制心肌细胞凋亡，从而减少Drp1在线粒体中的积聚，并通过Drp1介导的线粒体分裂程序的激活。我们还发现，p53在转录水平上下调miR-499的表达。我们的数据揭示了miR-499在调节线粒体分裂机制中的作用，我们认为miR-499水平的调节可能为治疗心肌梗死提供一种治疗方法。
Myocardial infarction is a leading cause of mortality worldwide. Here we report that modulation of microRNA-499 (miR-499) levels affects apoptosis and the severity of myocardial infarction and cardiac dysfunction induced by ischemia-reperfusion. We found that both the alpha-and beta-isoforms of the calcineurin catalytic subunit are direct targets of miR-499 and that miR-499 inhibits cardiomyocyte apoptosis through its suppression of calcineurin-mediated dephosphorylation of dynamin-related protein-1 (Drp1), thereby decreasing Drp1 accumulation in mitochondria and Drp1-mediated activation of the mitochondrial fission program. We also found that p53 transcriptionally downregulates miR-499 expression. Our data reveal a role for miR-499 in regulating the mitochondrial fission machinery and we suggest that modulation of miR-499 levels may provide a therapeutic approach for treating myocardial infarction.