Early mitochondrial activation and cytochrome c up-regulation during apoptosis
Early mitochondrial activation and cytochrome c up-regulation during apoptosis
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DOI：
10.1074/jbc.m207622200
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发表时间：
2002-12-27
影响因子：
4.8
通讯作者：
Tang, DG
中科院分区：
文献类型：
--
作者：
Chandra, D;Liu, JW;Tang, DG
多种刺激诱导的细胞凋亡需要线粒体呼吸链(MRC)的功能。在研究这种AIRC依赖的细胞凋亡途径的分子机制时，我们发现，在多种刺激诱导多种细胞类型的凋亡之前，早期诱导了MRC蛋白，如细胞色素c(由核基因编码)和细胞色素c氧化酶亚基II(由线粒体基因组编码)。定位于线粒体的几种非MRC蛋白，如Smac、Bim、Bak和Bcl2也迅速上调。其中许多蛋白质(如细胞色素c、环氧合酶II和Bim)的上调是各自基因转录激活的结果。上调的胞浆细胞色素c迅速转移到线粒体，导致全细胞色素c在线粒体中积聚，同时增加全细胞色素c释放到细胞质中。细胞色素c从细胞质到线粒体的转运增加并不依赖于线粒体蛋白质合成或MRC本身。相反，线粒体细胞色素c的释放涉及Bcl2家族蛋白的动态变化(如Bak、Bcl2和Bclx(L)上调)、通透性转换孔的开放和线粒体膜电位的丧失。细胞色素c的过度表达增强了caspase的激活并促进了细胞的死亡，但使用蜕皮激素诱导系统简单地上调细胞色素c本身并不足以诱导细胞凋亡。综上所述，这些结果表明，许多刺激诱导的细胞凋亡涉及线粒体的早期激活，这可能是随后MRC功能中断、DelTapsi(M)丢失、细胞色素c释放，最终导致细胞死亡的原因。
Apoptosis induced by many stimuli requires the mitochondrial respiratory chain (MRC) function. While studying the molecular mechanisms underlying this AIRC-dependent apoptotic pathway, we find that apoptosis in multiple cell types induced by a variety of stimuli is preceded by an early induction of MRC proteins such as cytochrome c (which is encoded by a nuclear gene) and cytochrome c oxidase subunit II (COX II) (which is encoded by the mitochondrial genome). Several non-MRC proteins localized in the mitochondria, e.g. Smac, Bim, Bak, and Bcl-2, are also rapidly up-regulated. The up-regulation of many of these proteins (e.g. cytochrome c, COX II, and Bim) results from transcriptional activation of the respective genes. The up-regulated cytosolic cytochrome c rapidly translocates to the mitochondria, resulting in an accumulation of holocytochrome c in the mitochondria accompanied by increasing holocytochrome c release into the cytosol. The increased cytochrome c transport from cytosol to the mitochondria does not depend on the mitochondrial protein synthesis or MRC per se. In contrast, cytochrome c release from the mitochondria involves dynamic changes in Bcl-2 family proteins (e.g. up-regulation of Bak, Bcl-2, and Bcl-x(L)), opening of permeability transition pore, and loss of mitochondrial membrane potential. Overexpression of cytochrome c enhances caspase activation and promotes cell death in response to apoptotic stimulation, but simple up-regulation of cytochrome c using an ecdysone-inducible system is, by itself, insufficient to induce apoptosis. Taken together, these results suggest that apoptosis induced by many stimuli involves an early mitochondrial activation, which may be responsible for the subsequent disruption of MRC functions, loss of Deltapsi(m), cytochrome c release, and ultimately cell death.