Veenman Leo, Shandalov Yulia, Gavish Moshe
Department of Molecular Pharmacology, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Ephron Street, Bat-Galim, Haifa, Israel.
J Bioenerg Biomembr. 2008 Jun;40(3):199-205. doi: 10.1007/s10863-008-9142-1.
The voltage dependent anion channel (VDAC), located in the outer mitochondrial membrane, functions as a major channel allowing passage of small molecules and ions between the mitochondrial inter-membrane space and cytoplasm. Together with the adenine nucleotide translocator (ANT), which is located in the inner mitochondrial membrane, the VDAC is considered to form the core of a mitochondrial multiprotein complex, named the mitochondrial permeability transition pore (MPTP). Both VDAC and ANT appear to take part in activation of the mitochondrial apoptosis pathway. Other proteins also appear to be associated with the MPTP, for example, the 18 kDa mitochondrial Translocator Protein (TSPO), Bcl-2, hexokinase, cyclophylin D, and others. Interactions between VDAC and TSPO are considered to play a role in apoptotic cell death. As a consequence, due to its apoptotic functions, the TSPO has become a target for drug development directed to find treatments for neurodegenerative diseases and cancer. In this context, TSPO appears to be involved in the generation of reactive oxygen species (ROS). This generation of ROS may provide a link between activation of TSPO and of VDAC, to induce activation of the mitochondrial apoptosis pathway. ROS are known to be able to release cytochrome c from cardiolipins located at the inner mitochondrial membrane. In addition, ROS appear to be able to activate VDAC and allow VDAC mediated release of cytochrome c into the cytosol. Release of cytochrome c from the mitochondria forms the initiating step for activation of the mitochondrial apoptosis pathway. These data provide an understanding regarding the mechanisms whereby VDAC and TSPO may serve as targets to modulate apoptotic rates. This has implications for drug design to treat diseases such as neurodegeneration and cancer.
电压依赖性阴离子通道（VDAC）位于线粒体外膜，作为主要通道，允许小分子和离子在线粒体膜间隙与细胞质之间通过。与位于线粒体内膜的腺嘌呤核苷酸转位酶（ANT）一起，VDAC被认为形成了线粒体多蛋白复合物的核心，即线粒体通透性转换孔（MPTP）。VDAC和ANT似乎都参与了线粒体凋亡途径的激活。其他蛋白质似乎也与MPTP相关，例如18 kDa线粒体转位蛋白（TSPO）、Bcl-2、己糖激酶、亲环蛋白D等。VDAC与TSPO之间的相互作用被认为在凋亡性细胞死亡中起作用。因此，由于其凋亡功能，TSPO已成为药物开发的靶点，旨在寻找神经退行性疾病和癌症的治疗方法。在这种情况下，TSPO似乎参与了活性氧（ROS）的产生。ROS的产生可能提供了TSPO和VDAC激活之间的联系，以诱导线粒体凋亡途径的激活。已知ROS能够从位于线粒体内膜的心磷脂中释放细胞色素c。此外，ROS似乎能够激活VDAC，并允许VDAC介导的细胞色素c释放到细胞质中。线粒体中细胞色素c的释放形成了线粒体凋亡途径激活的起始步骤。这些数据提供了关于VDAC和TSPO可能作为调节凋亡率靶点的机制的理解。这对治疗神经退行性疾病和癌症等疾病的药物设计具有启示意义。
