miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1

Jian-Xun Wang et al . show that mitochondrial fission, which occurs during cell death, is regulated in cardiomyocytes by the microRNA miR-499 through a mechanism involving the phosphatase calcineurin and its substrate Drp1. Overexpression of miR-499 was able to reduce mitochondrial fission and apoptosis in the hearts of mice or rats injured by ischemia-reperfusion and to improve heart function, suggesting new therapeutic approaches for myocardial injury. 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 α- and β-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.