Apoptosis-inducing factor (AIF):: key to the conserved caspase-independent pathways of cell death?
Apoptosis-inducing factor (AIF):: key to the conserved caspase-independent pathways of cell death?
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DOI：
10.1242/jcs.00210
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发表时间：
2002-12-15
影响因子：
4
通讯作者：
Kroemer, G
中科院分区：
文献类型：
--
作者：
Candé, C;Cecconi, F;Kroemer, G
许多促凋亡信号转导分子作用于线粒体并引起线粒体外膜的透化，从而触发潜在毒性线粒体蛋白的释放。这些蛋白质之一，骨化诱导因子（AIF），是一种遗传上古老的黄素蛋白，在健康细胞中，局限于线粒体膜间隙。在致死信号传导后，AIF通过胞质溶胶易位到细胞核，在细胞核中它与DNA结合并引起不依赖于半胱天冬酶的染色质凝聚。已经确定了人和小鼠AIF的晶体结构，并阐明了其氧化还原酶活性及其与双链DNA的静电相互作用的精细机制。重要的是，AIF的致突变和氧化还原酶功能可以分离。因此，消除AIF-DNA相互作用的突变抑制AIF诱导的染色质凝聚，但对NADH氧化酶活性没有影响。最近的研究表明，AIF是一个主要因素，决定半胱天冬酶非依赖性神经元死亡，强调线粒体在控制生理和病理细胞死亡的中心作用。
Numerous pro-apoptotic signal transducing molecules act on mitochondria and provoke the permeabilization of the outer mitochondrial membrane, thereby triggering the release of potentially toxic mitochondrial proteins. One of these proteins, apoptosis-inducing factor (AIF), is a phylogenetically old flavoprotein which, in healthy cells, is confined to the mitochondrial intermembrane space. Upon lethal signaling, AIF translocates, via the cytosol, to the nucleus where it binds to DNA and provokes caspase-independent chromatin condensation. The crystal structures of both human and mouse AIF have been determined, and the fine mechanisms accounting for its oxidoreductase activity and its electrostatic interaction with double-stranded DNA have been elucidated. Importantly, the apoptogenic and oxidoreductase functions of AIF can be dissociated. Thus, mutations that abolish the AIF-DNA interaction suppress AIF-induced chromatin condensation, yet have no effect on the NADH oxidase activity. Recent studies suggest AIF to be a major factor determining caspase-independent neuronal death, emphasizing the central role of mitochondria in the control of physiological and pathological cell demise.