Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli.
Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli.
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DOI：
10.1083/jcb.200207071
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发表时间：
2002-12-23
影响因子：
7.8
通讯作者：
Ameisen, Jean Claude
中科院分区：
文献类型：
--
作者：
Arnoult, Damien;Parone, Philippe;Martinou, Jean-Claude;Antonsson, Bruno;Estaquier, Jerome;Ameisen, Jean Claude
线粒体外膜透化的促凋亡Bcl-2家族蛋白，如Bax，在细胞凋亡诱导中起着至关重要的作用。然而，这是否仅导致胞浆内释放半胱天冬酶依赖性死亡的诱导物，如细胞色素c，或半胱天冬酶非依赖性死亡的诱导物，如凋亡诱导因子（AIF）仍不清楚。在这里，我们表明，在分离的线粒体，Bax导致细胞色素c的释放，但不是AIF，AIF与线粒体内膜的协会提供了一个简单的解释，其缺乏释放后，Bax介导的外膜透化。在过度表达Bax或Bax或Bak依赖性促凋亡药物星形孢菌素或放线菌素D，或过氧化氢处理的细胞中，半胱天冬酶抑制剂不影响细胞色素c的胞内易位，但防止AIF。这些结果提供了一个范例，其中AIF不能取代caspase的执行者，因为它的胞内释放发生下游的细胞色素c的依赖性死亡途径。
Mitochondrial outer membrane permeabilization by proapoptotic Bcl-2 family proteins, such as Bax, plays a crucial role in apoptosis induction. However, whether this only causes the intracytosolic release of inducers of caspase-dependent death, such as cytochrome c, or also of caspase-independent death, such as apoptosis-inducing factor (AIF) remains unknown. Here, we show that on isolated mitochondria, Bax causes the release of cytochrome c, but not of AIF, and the association of AIF with the mitochondrial inner membrane provides a simple explanation for its lack of release upon Bax-mediated outer membrane permeabilization. In cells overexpressing Bax or treated either with the Bax- or Bak-dependent proapoptotic drugs staurosporine or actinomycin D, or with hydrogen peroxide, caspase inhibitors did not affect the intracytosolic translocation of cytochrome c, but prevented that of AIF. These results provide a paradigm for mitochondria-dependent death pathways in which AIF cannot substitute for caspase executioners because its intracytosolic release occurs downstream of that of cytochrome c.