INSERM U916, Université Bordeaux 2, Institut Bergonié, 33076 Bordeaux, France.
Cell Res. 2009 Dec;19(12):1363-76. doi: 10.1038/cr.2009.98. Epub 2009 Aug 11.
Voltage-dependent anion channel (VDAC)1 is the main channel of the mitochondrial outer membrane (MOM) and it has been proposed to be part of the permeability transition pore (PTP), a putative multiprotein complex candidate agent of the mitochondrial permeability transition (MPT). Working at the single live cell level, we found that overexpression of VDAC1 triggers MPT at the mitochondrial inner membrane (MIM). Conversely, silencing VDAC1 expression results in the inhibition of MPT caused by selenite-induced oxidative stress. This MOM-MIM crosstalk was modulated by Cyclosporin A and mitochondrial Cyclophilin D, but not by Bcl-2 and Bcl-X(L), indicative of PTP operation. VDAC1-dependent MPT engages a positive feedback loop involving reactive oxygen species and p38-MAPK, and secondarily triggers a canonical apoptotic response including Bax activation, cytochrome c release and caspase 3 activation. Our data thus support a model of the PTP complex involving VDAC1 at the MOM, and indicate that VDAC1-dependent MPT is an upstream mechanism playing a causal role in oxidative stress-induced apoptosis.
电压依赖性阴离子通道 1（VDAC1）是线粒体外膜（MOM）的主要通道，它被提议成为通透性转换孔（PTP）的一部分，PTP 是线粒体通透性转换（MPT）的假定多蛋白复合物候选介质。在单个活细胞水平上的工作表明，VDAC1 的过表达会引发线粒体内膜（MIM）的 MPT。相反，沉默 VDAC1 的表达会抑制亚硒酸盐诱导的氧化应激引起的 MPT。这种 MOM-MIM 串扰受环孢菌素 A 和线粒体亲环素 D 调节，但不受 Bcl-2 和 Bcl-X(L)调节，表明 PTP 的作用。VDAC1 依赖性 MPT 涉及活性氧和 p38-MAPK 的正反馈环，并且随后引发包括 Bax 激活、细胞色素 c 释放和 caspase 3 激活在内的经典凋亡反应。因此，我们的数据支持涉及 MOM 中 VDAC1 的 PTP 复合物模型，并表明 VDAC1 依赖性 MPT 是一种上游机制，在氧化应激诱导的细胞凋亡中起因果作用。
