title: 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.
authors.affiliation: Division of Cardiovascular Research, National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jian-Xun
authors.initials: JX
authors.lastname: Wang
authors.forename: Jian-Qin
authors.initials: JQ
authors.lastname: Jiao
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Long
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Liu
authors.forename: Yan-Rui
authors.initials: YR
authors.lastname: Li
authors.forename: Pei-Feng
authors.initials: PF
authors.lastname: Li
mesh_terms: D000818:Animals; D001483:Base Sequence; D019703:Calcineurin / Q000502:physiology*; D004285:Dogs; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology* / Q000627:therapeutic use; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D008929:Mitochondria, Heart / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009203:Myocardial Infarction / Q000188:drug therapy; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy; D016415:Sequence Alignment; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: C548683:MIRN499 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D016159:Tumor Suppressor Protein p53; D019703:Calcineurin; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins