Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death
Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death
复制标题
DOI：
10.1038/ncb1575
复制
发表时间：
2007-05-01
影响因子：
21.3
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
Baines, Christopher P.;Kaiser, Robert A.;Molkentin, Jeffery D.
线粒体在钙超载、缺氧和氧化损伤所致的坏死性细胞死亡中起重要作用。线粒体通透性转换(MPT)孔是一种跨越线粒体内外膜的蛋白质复合体，被认为是这一事件的中介，并被假设为最小限度地由外膜的电压依赖性阴离子通道(VDAC)、内膜的腺嘌呤核苷酸转位酶(Ant)和基质中的亲环素-D组成(1-3)。在这里，我们报告了三个哺乳动物VDAC基因的缺失对线粒体依赖性细胞死亡的影响。来自Vdac1、Vdac3和Vdac1-Vdac3缺失小鼠的线粒体表现出钙离子和氧化应激诱导的MPT，这与野生型线粒体没有区别。同样，在缺乏Vdac1、Vdac2、Vdac3、Vdac1-Vdac3和Vdac1-Vdac2-Vdac3的成纤维细胞中，钙离子和氧化应激诱导的MPT和细胞死亡没有改变，甚至加剧。野生型和VDAC缺陷的线粒体和细胞也表现出相同的细胞色素c释放、caspase裂解和细胞死亡，以响应亲死亡的Bcl-2家族成员Bax和Bid。这些结果表明，Vdacs在MPT和Bcl2家族成员诱导的细胞死亡中都是必不可少的。
Mitochondria are critically involved in necrotic cell death induced by Ca2+ overload, hypoxia and oxidative damage. The mitochondrial permeability transition (MPT) pore-a protein complex that spans both the outer and inner mitochondrial membranes - is considered the mediator of this event and has been hypothesized to minimally consist of the voltage-dependent anion channel (Vdac) in the outer membrane, the adenine-nucleotide translocase (Ant) in the inner membrane and cyclophilin-D in the matrix(1-3). Here, we report the effects of deletion of the three mammalian Vdac genes on mitochondrial-dependent cell death. Mitochondria from Vdac1-, Vdac3-, and Vdac1-Vdac3-null mice exhibited a Ca2+- and oxidative stress- induced MPT that was indistinguishable from wild- type mitochondria. Similarly, Ca2+- and oxidative- stress- induced MPT and cell death was unaltered, or even exacerbated, in fibroblasts lacking Vdac1, Vdac2, Vdac3, Vdac1-Vdac3 and Vdac1-Vdac2-Vdac3. Wildtype and Vdac-deficient mitochondria and cells also exhibited equivalent cytochrome c release, caspase cleavage and cell death in response to the pro- death Bcl-2 family members Bax and Bid. These results indicate that Vdacs are dispensable for both MPT and Bcl-2 family member-driven cell death.