Wang K, Zhang D-L, Long B, An T, Zhang J, Zhou L-Y, Liu C-Y, Li P-F
Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.
Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
Cell Death Dis. 2015 Dec 3;6(12):e2007. doi: 10.1038/cddis.2015.348.
Emerging evidence suggest that the abnormal mitochondrial fission participates in pathogenesis of cardiac diseases, including myocardial infarction and heart failure. However, the molecular components regulating mitochondrial network in heart remain largely unidentified. Here we report that NFAT4, miR-324-5p and mitochondrial fission regulator 1 (Mtfr1) function in one signaling axis that regulates mitochondrial morphology and cardiomyocyte cell death. Knocking down Mtfr1 suppresses mitochondrial fission, apoptosis and myocardial infarction. Mtfr1 is a direct target of miR-324-5p, and miR-324-5p attenuates mitochondrial fission, cardiomyocyte apoptosis and myocardial infarction by suppressing Mtfr1 translation. Finally, we show that transcription factor NFAT4 inhibits miR-324-5p expression. Knockdown of NFAT4 suppresses mitochondrial fission and protects cardiomyocyte from apoptosis and myocardial infarction. Our study defines the NFAT4/ miR-324-5p/Mtfr1 axis, which participates in the regulation of mitochondrial fission and cardiomyocyte apoptosis, and suggests potential new treatment avenues for cardiac diseases.
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不明确。在此，我们报告核因子活化T细胞4（NFAT4）、微小RNA-324-5p（miR-324-5p）和线粒体分裂调节因子1（Mtfr1）在一个调节线粒体形态和心肌细胞死亡的信号轴中发挥作用。敲低Mtfr1可抑制线粒体分裂、细胞凋亡和心肌梗死。Mtfr1是miR-324-5p的直接靶点，miR-324-5p通过抑制Mtfr1的翻译来减轻线粒体分裂、心肌细胞凋亡和心肌梗死。最后，我们表明转录因子NFAT4抑制miR-324-5p的表达。敲低NFAT4可抑制线粒体分裂，并保护心肌细胞免受凋亡和心肌梗死。我们的研究确定了NFAT4/miR-324-5p/Mtfr1轴，其参与线粒体分裂和心肌细胞凋亡的调节，并为心脏疾病提示了潜在的新治疗途径。
