The pro-apoptotic Bcl-2 protein Bax can permeabilize the outer mitochondrial membrane and therefore commit human cells to apoptosis. Bax is regulated by constant translocation to the mitochondria and retrotranslocation back into the cytosol. Bax retrotranslocation depends on pro-survival Bcl-2 proteins and stabilizes inactive Bax. Here we show that Bax retrotranslocation shuttles membrane-associated and membrane-integral Bax from isolated mitochondria. We further discover the mitochondrial porin voltage-dependent anion channel 2 (VDAC2) as essential component and platform for Bax retrotranslocation. VDAC2 ensures mitochondria-specific membrane association of Bax and in the absence of VDAC2 Bax localizes towards other cell compartments. Bax retrotranslocation is also regulated by nucleotides and calcium ions, suggesting a potential role of the transport of these ions through VDAC2 in Bax retrotranslocation. Together, our results reveal the unanticipated bifunctional role of VDAC2 to target Bax specifically to the mitochondria and ensure Bax inhibition by retrotranslocation into the cytosol.

中文翻译：

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孔蛋白VDAC2是Bax逆转的线粒体平台。

凋亡前Bcl-2蛋白Bax可以透化线粒体外膜，从而使人类细胞凋亡。Bax通过恒定易位至线粒体和逆转易位回到细胞质中来调节。Bax逆转位依赖于生存前Bcl-2蛋白并稳定无活性的Bax。在这里，我们显示Bax逆向转运从分离的线粒体穿梭膜相关和膜整合Bax。我们进一步发现线粒体孔蛋白电压依赖性阴离子通道2（VDAC2）是Bax逆转必不可少的组成部分和平台。VDAC2确保Bax的线粒体特异性膜结合，并且在不存在VDAC2的情况下，Bax定位于其他细胞区室。Bax逆向转运也受核苷酸和钙离子的调节，提示这些离子通过VDAC2的转运在Bax逆转转运中的潜在作用。在一起，我们的结果揭示了VDAC2出乎意料的双重功能，即将Bax特异性靶向线粒体，并通过逆向转运到细胞质中来确保Bax抑制。