Molecular characterization of mitochondrial apoptosis-inducing factor
Molecular characterization of mitochondrial apoptosis-inducing factor
复制标题
DOI：
10.1038/17135
复制
发表时间：
1999-02-04
期刊：
影响因子：
64.8
通讯作者：
Kroemer, G
中科院分区：
文献类型：
--
作者：
Susin, SA;Lorenzo, HK;Kroemer, G
线粒体在细胞凋亡（细胞死亡）的调节中起关键作用（1，2）。它们的膜间隙含有几种通过外膜释放的蛋白质，以参与细胞凋亡的降解阶段（3-9）。在这里，我们报告的鉴定和克隆的凋亡诱导因子，AIF（5），这是足以诱导细胞核的细胞凋亡。AIF是一种相对分子质量为57，000的黄素蛋白，与细菌氧化还原酶具有同源性;它通常局限于线粒体，但在诱导细胞凋亡时移位到细胞核。重组AIF引起分离的细胞核中的染色质凝聚和DNA的大规模片段化。它诱导纯化的线粒体释放促凋亡蛋白细胞色素c和半胱天冬酶-9。将AIF显微注射到完整细胞的细胞质中诱导染色质的浓缩、线粒体跨膜电位的消散和质膜中磷脂酰丝氨酸的暴露。这些作用都不能被广泛的半胱天冬酶抑制剂Z-VAD. fmk阻止。Bcl-2的过表达控制线粒体通透性转换孔的开放，阻止AIF从线粒体释放，但不影响其促凋亡活性。这些结果表明，AIF是凋亡性细胞死亡的线粒体效应子。
Mitochondria play a key part in the regulation of apoptosis (cell death)(1,2). Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis(3-9). Here we report the identification and cloning of an apoptosis-inducing factor, AIF(5), which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death.