Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis
Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis
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DOI：
10.1073/pnas.1417253111
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发表时间：
2014-10-14
影响因子：
11.1
通讯作者：
Wang, Xiaodong
中科院分区：
文献类型：
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作者：
Jiang, Xian;Jiang, Hui;Wang, Xiaodong
固有的凋亡刺激通过首先激活只含有BH3(BH3)的蛋白来启动哺乳动物细胞的凋亡程序，例如细胞死亡的Bcl-2相互作用介质(Bim)和截短的BH3相互作用死亡结构域激动剂(TbID)，进而触发BCL2相关的X(Bax)和BCL2拮抗剂/杀手(Bak)蛋白的构象变化，使线粒体上形成寡聚体，导致细胞色素c和其他膜间隙中的凋亡蛋白泄漏。然后，泄漏的细胞色素c通过明确定义的生化途径启动凋亡的caspase激活。然而，寡聚化的Bax和Bak如何导致细胞色素c从线粒体释放仍不清楚。我们在此报告了可诱导表达Bim或TBID的细胞系的建立，从而以受控、定量的方式启动细胞凋亡。我们使用这些细胞系来检测Bax和Bak齐聚之后，但在细胞色素c释放之前的凋亡事件。线粒体金属蛋白酶OMA1在该系统中以Bax和Bak依赖的方式被激活。激活的OMA1裂解了动力蛋白样GTPase，视神经萎缩1，这是一个对线粒体嵴重塑至关重要的事件。在这些细胞中，OMA1基因的敲除或敲除会减弱细胞色素c的释放。因此，很明显，寡聚化的Bax和Bak通过引起线粒体外膜的通透性和激活OMA1来触发细胞凋亡。
Intrinsic apoptotic stimuli initiate mammalian cells' apoptotic program by first activating the proteins that have only Bcl-2 homology domain 3 (BH3), such as Bcl-2 interacting mediator of cell death (Bim) and truncated BH3 interacting death domain agonist (tBid), which in turn trigger conformational changes in BCL2-associated X (Bax) and BCL2-antagonist/killer (Bak) proteins that enable oligomer formation on the mitochondria, causing cytochrome c and other apoptogenic proteins in the intermembrane space to leak out. Leaked cytochrome c then initiates apoptotic caspase activation through a well-defined biochemical pathway. However, how oligomerized Bax and Bak cause cytochrome c release from mitochondria remains unknown. We report here the establishment of cell lines in which Bim or tBid can be inducibly expressed to initiate apoptosis in a controlled, quantitative manner. We used these cell lines to examine apoptotic events after Bax and Bak oligomerization but before cytochrome c release. The mitochondrial metalloprotease OMA1 was activated in this system in a Bax- and Bak-dependent fashion. Activated OMA1 cleaved the dynamin-like GTPase, optical nerve atrophy 1, an event that is critical for remodeling of mitochondrial cristae. Knockdown or knockout of OMA1 in these cells attenuated cytochrome c release. Thus it is clear that oligomerized Bax and Bak trigger apoptosis by causing both the permeabilization of the mitochondrial outer membrane and activation OMA1.