Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis
Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis
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DOI：
10.1074/jbc.m109950200
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发表时间：
2002-03-01
影响因子：
4.8
通讯作者：
Hoek, JB
中科院分区：
文献类型：
--
作者：
Pastorino, JG;Shulga, N;Hoek, JB
促凋亡蛋白（例如 Bax）在细胞凋亡过程中易位至线粒体，在线粒体中介导包括细胞色素 c 在内的膜间隙蛋白的释放。 Bax 与电压依赖性阴离子通道 (VDAC) 结合。 VDAC 是一种位于线粒体外膜的 β 桶蛋白。在平面脂质双层中，Bax 和 VDAC 形成细胞色素 c 可以通过的通道。己糖激酶 II (HXK II) 也与 VDAC 结合。 HXK II 催化糖酵解的第一步，并在转化细胞中高度表达，其中超过 70% 与线粒体结合。本研究表明 HXK II 干扰 Bax 与线粒体结合并释放细胞色素 c 的能力。 HXK II 从 HeLa 细胞中分离出的富含线粒体的组分中分离，促进了重组 Bax-Delta19 的结合以及随后细胞色素 c 的释放。同样，将重组 HXK II 添加到从肝细胞（不内源表达 HXK II 的细胞）中分离的富含线粒体的级分中，可阻止重组 Bax-Delta19 与线粒体结合并促进细胞色素 c 释放的能力。在完整细胞中也发现了类似的结果，其中线粒体结合 HXK II 的脱离或其过度表达分别增强和抑制了 Bax 诱导的线粒体功能障碍和细胞死亡。
Proapoptotic proteins such as Bax, undergo translocation to the mitochondria during apoptosis, where they mediate the release of intermembrane space proteins including cytochrome c. Bax binds to the voltage-dependent anion channel (VDAC). VDAC is a beta-barrel protein located in the outer mitochondrial membrane. In planar lipid bilayers, Bax and VDAC form a channel through which cytochrome c can pass. Hexokinase II (HXK II) also binds to VDAC. HXK II catalyzes the first step of glycolysis and is highly expressed in transformed cells, where over 70% of it is bound to the mitochondria. The present study demonstrates that HXK II interferes with the ability of Bax to bind to mitochondria an release cytochrome c. Detachment of HXK II from the mitochondria-enriched fraction isolated from HeLa cells promoted the binding of recombinant Bax-Delta19 and subsequent cytochrome c release. Similarly, the addition of recombinant HXK II to the mitochondria-enriched fraction isolated from hepatocytes, cells that do not express HXK II endogenously, prevented the ability of recombinant Bax-Delta19 to bind to the mitochondria and promote cytochrome c release. Similar results were found in intact cells, in which the detachment of mitochondrial bound HXK II or its overexpression potentiated and inhibited, respectively, Bax-induced mitochondrial dysfunction and cell death.