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

Nature Medicine volume 17, pages 71–78 (2011)Cite this article

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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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  1. Jian-Xun Wang and Jian-Qin Jiao: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cardiovascular Research, National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Jian-Xun Wang, Jian-Qin Jiao, Qian Li, Bo Long, Kun Wang, Jin-Ping Liu, Yan-Rui Li & Pei-Feng Li

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Contributions

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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