Wang K, Liu C-Y, Zhang X-J, Feng C, Zhou L-Y, Zhao Y, Li P-F
1] Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China [2] Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.
Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Cell Death Differ. 2015 Jun;22(6):1058-68. doi: 10.1038/cdd.2014.200. Epub 2014 Dec 12.
Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Emerging evidences suggest that the abnormal mitochondrial fission participates in pathogenesis of cardiac diseases, including myocardial infarction (MI) and heart failure. However, the molecular components regulating mitochondrial network in the heart remain largely unidentified. Here we report that miR-361 and prohibitin 1 (PHB1) constitute an axis that regulates mitochondrial fission and apoptosis. The results show that PHB1 attenuates mitochondrial fission and apoptosis in response to hydrogen peroxide treatment in cardiomyocytes. Cardiac-specific PHB1 transgenic mice show reduced mitochondrial fission and myocardial infarction sizes after myocardial infarction surgery. MiR-361 is responsible for the dysfunction of PHB1 and suppresses the translation of PHB1. Knockdown of miR-361 reduces mitochondrial fission and apoptosis in vivo and in vitro. MiR-361 cardiac-specific transgenic mice represent elevated mitochondrial fission and myocardial infarction sizes upon myocardial ischemia injury. This study identifies a novel signaling pathway composed of miR-361 and PHB1 that regulates mitochondrial fission program and apoptosis. This discovery will shed new light on the therapy of myocardial infarction and heart failure.
心血管疾病仍然是全球发病和死亡的主要原因。新出现的证据表明，异常的线粒体分裂参与了包括心肌梗死（MI）和心力衰竭在内的心脏疾病的发病机制。然而，调节心脏线粒体网络的分子成分在很大程度上仍未明确。在此，我们报告miR-361和抑制素1（PHB1）构成了一个调节线粒体分裂和凋亡的轴。结果表明，PHB1可减轻过氧化氢处理后心肌细胞中的线粒体分裂和凋亡。心脏特异性PHB1转基因小鼠在心肌梗死手术后线粒体分裂减少，心肌梗死面积减小。miR-361导致PHB1功能障碍并抑制PHB1的翻译。敲低miR-361可在体内和体外减少线粒体分裂和凋亡。miR-361心脏特异性转基因小鼠在心肌缺血损伤后线粒体分裂增加，心肌梗死面积增大。本研究确定了一条由miR-361和PHB1组成的新信号通路，该通路调节线粒体分裂程序和凋亡。这一发现将为心肌梗死和心力衰竭的治疗提供新的思路。
