Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Nat Commun. 2012 Apr 17;3:781. doi: 10.1038/ncomms1770.
Mitochondria constantly undergo fusion and fission, two necessary processes for the maintenance of organelle fidelity. The abnormal mitochondrial fission participates in the pathogenesis of many diseases, but its regulation remains poorly understood. Here we show that miR-484 can suppress translation of mitochondrial fission protein Fis1, and inhibit Fis1-mediated fission and apoptosis in cardiomyocytes and in the adrenocortical cancer cells. We demonstrate that Fis1 is necessary for mitochondrial fission and apoptosis, and is upregulated during anoxia, whereas miR-484 is downregulated. miR-484 is able to attenuate Fis1 upregulation and mitochondrial fission, by binding to the amino acid coding sequence of Fis1 and inhibiting its translation. In exploring the underlying mechanism of miR-484 downregulation upon apoptosis, we observe that Foxo3a transactivates miR-484 expression. Foxo3a transgenic or knockout mice exhibit, respectively, a high or low level of miR-484 and a reduced or enhanced mitochondrial fission, apoptosis and myocardial infarction. Our data reveal a model of mitochondrial fission regulation by a microRNA.
线粒体不断经历融合和裂变，这是细胞器保真度维持的两个必要过程。异常的线粒体裂变参与了许多疾病的发病机制，但对其调节仍知之甚少。在这里，我们表明 miR-484 可以抑制线粒体裂变蛋白 Fis1 的翻译，并抑制心肌细胞和肾上腺皮质癌细胞中 Fis1 介导的裂变和细胞凋亡。我们证明 Fis1 对于线粒体裂变和凋亡是必需的，并且在缺氧时上调，而 miR-484 下调。miR-484 通过结合 Fis1 的氨基酸编码序列并抑制其翻译，能够减弱 Fis1 的上调和线粒体裂变。在探索凋亡时 miR-484 下调的潜在机制时，我们观察到 Foxo3a 反式激活 miR-484 的表达。Foxo3a 转基因或敲除小鼠分别表现出高或低水平的 miR-484 和减少或增强的线粒体裂变、细胞凋亡和心肌梗死。我们的数据揭示了一种由 microRNA 调节线粒体裂变的模型。
