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

Abstract

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.

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Figure 1: miR-499 prevents apoptosis and myocardial infarction.
Figure 2: miR-499 transgenic mice are resistant to left ventricular remodeling after ischemia-reperfusion.
Figure 3: CnAα and CnAβ are targets of miR-499.
Figure 4: Drp1 participates in the regulation of mitochondrial fission and apoptosis in cardiomyocytes.
Figure 5: miR-499 regulates mitochondrial fission through calcineurin and Drp1.
Figure 6: p53 transcriptionally downregulates miR-499.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (30730045, 31010103911) and the National Basic Research Program of China (973 Program, 2007CB512000, 2011CB965300). pαMHC-clone26 was kindly provided by Z. Yang (Nanjing University). CnAα and CnAβ cDNAs were kindly provided by T. Kuno (Kobe University). The antibody to phospho-Drp1 (Ser656) was kindly provided by S. Strack (University of Iowa).

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P.-F.L. and J.-X.W. designed research. J.-X.W. performed cellular experiments. J.-Q.J. conducted animal experiments. Y.-R.L. created 3′ UTR constructs. Q.L. and B.L. constructed adenoviruses and generated miR-499 transgenic mice. J.-P.L. measured calcium. K.W. analyzed hypertrophy. P.-F.L. and J.-X.W. wrote the manuscript.

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Correspondence to Pei-Feng Li.

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Wang, JX., Jiao, JQ., Li, Q. et al. miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med 17, 71–78 (2011). https://doi.org/10.1038/nm.2282

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