Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization
Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization
复制标题
DOI：
10.1016/j.devcel.2007.11.019
复制
发表时间：
2008-02-01
影响因子：
11.8
通讯作者：
Nunnari, Jodi
中科院分区：
文献类型：
--
作者：
Cassidy-Stone, Ann;Chipuk, Jerry E.;Nunnari, Jodi
线粒体的融合和分裂在细胞凋亡的调控中起重要作用。线粒体融合蛋白通过抑制细胞色素c从线粒体的释放来减弱细胞凋亡，部分是通过控制嵴结构。线粒体分裂通过一种未知的机制促进细胞凋亡。我们解决了如何使用线粒体分裂抑制剂的化学筛选中确定的分裂蛋白调节细胞凋亡。最有效的抑制剂mdivi-1（线粒体分裂抑制剂）通过选择性抑制线粒体分裂发动蛋白来减弱酵母和哺乳动物细胞中的线粒体分裂。在细胞中，mdivi-1通过抑制线粒体外膜透化来延缓细胞凋亡。在体外，mdivi-1有效地阻断Bid激活的Bax/Bak依赖的细胞色素c从线粒体释放。这些数据表明，线粒体分裂动力蛋白直接调节线粒体外膜透化独立的Drp 1介导的分裂。我们的研究结果提出了一个有趣的可能性，即mdivi-1代表了中风、心肌梗死和神经退行性疾病的一类疗法。
Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.