Arnoult Damien, Parone Philippe, Martinou Jean-Claude, Antonsson Bruno, Estaquier Jerome, Ameisen Jean Claude
EMI-U 9922 Institut National de la Santé et de la Recherche Medicale (INSERM)/Université Paris 7, IFR02, AP-HP, CHU Bichat, 75018 Paris, France.
J Cell Biol. 2002 Dec 23;159(6):923-9. doi: 10.1083/jcb.200207071. Epub 2002 Dec 16.
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.
促凋亡Bcl-2家族蛋白（如Bax）引起的线粒体外膜通透性改变在诱导细胞凋亡中起关键作用。然而，这仅仅是导致依赖半胱天冬酶的死亡诱导剂（如细胞色素c）的胞质内释放，还是也导致不依赖半胱天冬酶的死亡诱导剂（如凋亡诱导因子，AIF）的胞质内释放，目前尚不清楚。在此，我们表明，在分离的线粒体上，Bax可导致细胞色素c的释放，但不会导致AIF的释放，并且AIF与线粒体内膜的结合为其在Bax介导的外膜通透性改变时不释放提供了一个简单的解释。在过表达Bax的细胞中，或者用依赖Bax或Bak的促凋亡药物星形孢菌素或放线菌素D处理，或者用过氧化氢处理后，半胱天冬酶抑制剂不影响细胞色素c的胞质内转运，但可阻止AIF的胞质内转运。这些结果为线粒体依赖性死亡途径提供了一个范例，其中AIF不能替代半胱天冬酶执行器，因为其胞质内释放发生在细胞色素c之后。
