Shoshan-Barmatz V, Israelson A, Brdiczka D, Sheu S S
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
Curr Pharm Des. 2006;12(18):2249-70. doi: 10.2174/138161206777585111.
Research over the last decade has extended the prevailing view of mitochondria to include functions well beyond the critical bioenergetics role in supplying ATP. It is now recognized that mitochondria play a crucial role in cell signaling events, inter-organelle communication, aging, many diseases, cell proliferation and cell death. Apoptotic signal transmission to the mitochondria results in the efflux of a number of potential apoptotic regulators to the cytosol that trigger caspase activation and lead to cell destruction. Accumulating evidence indicates that the voltage-dependent anion channel (VDAC) is involved in this release of proteins via the outer mitochondrial membrane. VDAC in the outer mitochondrial membrane is in a crucial position in the cell, forming the main interface between the mitochondrial and the cellular metabolisms. VDAC has been recognized as a key protein in mitochondria-mediated apoptosis since it is the proposed target for the pro- and anti-apoptotic Bcl2-family of proteins and due to its function in the release of apoptotic proteins located in the inter-membranal space. The diameter of the VDAC pore is only about 2.6-3 nm, which is insufficient for passage of a folded protein like cytochrome c. New work suggests pore formation by homo-oligomers of VDAC or hetero-oligomers composed of VDAC and pro-apoptotic proteins such as Bax or Bak. This review provides insights into the central role of VDAC in cell life and death and emphasizes its function in the regulation of mitochondria-mediated apoptosis and, thereby, its potential as a rational target for new therapeutics.
过去十年的研究拓展了人们对线粒体的普遍认知，其功能远不止于在提供ATP方面的关键生物能量作用。现在人们认识到，线粒体在细胞信号转导事件、细胞器间通讯、衰老、多种疾病、细胞增殖和细胞死亡中都起着至关重要的作用。凋亡信号传递至线粒体导致多种潜在凋亡调节因子外流至细胞质，从而触发半胱天冬酶激活并导致细胞破坏。越来越多的证据表明，电压依赖性阴离子通道（VDAC）参与了蛋白质通过线粒体外膜的释放过程。线粒体外膜中的VDAC在细胞中处于关键位置，形成了线粒体与细胞代谢之间的主要界面。VDAC被认为是线粒体介导的凋亡中的关键蛋白，因为它是促凋亡和抗凋亡Bcl2蛋白家族的假定靶点，并且因其在释放位于膜间空间的凋亡蛋白方面的功能。VDAC孔的直径仅约2.6 - 3纳米，不足以让像细胞色素c这样的折叠蛋白通过。新的研究表明，VDAC的同型寡聚体或由VDAC与促凋亡蛋白如Bax或Bak组成的异型寡聚体可形成孔道。本综述深入探讨了VDAC在细胞生死中的核心作用，并强调了其在调节线粒体介导的凋亡中的功能，进而突出了其作为新型治疗药物合理靶点的潜力。
