Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Sci Rep. 2016 Sep 13;6:32994. doi: 10.1038/srep32994.
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.
促凋亡 Bcl-2 蛋白 Bax 可以通透外线粒体膜，从而使人类细胞发生细胞凋亡。Bax 通过持续向线粒体易位和反向易位回细胞质来调节。Bax 反向易位依赖于生存促进的 Bcl-2 蛋白，并稳定无活性的 Bax。在这里，我们表明 Bax 反向易位将膜相关和膜整合的 Bax 从分离的线粒体中穿梭出来。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 反向易位的必需组成部分和平台。VDAC2 确保 Bax 与线粒体的特异性膜结合，并且在没有 VDAC2 的情况下，Bax 定位于其他细胞区室。Bax 反向易位还受到核苷酸和钙离子的调节，提示这些离子通过 VDAC2 转运在 Bax 反向易位中的潜在作用。总之，我们的结果揭示了 VDAC2 意想不到的双重作用，即特异性将 Bax 靶向线粒体，并确保 Bax 通过反向易位回细胞质而被抑制。
