Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death
Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death
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DOI：
10.1038/35069004
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发表时间：
2001-03-29
期刊：
影响因子：
64.8
通讯作者：
Penninger, JM
中科院分区：
文献类型：
--
作者：
Joza, N;Susin, SA;Penninger, JM
程序性细胞死亡是胚胎发生、器官变态和组织稳态的基本要求。在哺乳动物中，线粒体细胞色素 c 的释放导致细胞凋亡体的胞质组装，凋亡体是一种涉及 Apaf1 和 caspase-9 的 caspase 激活复合物，可诱导细胞凋亡的标志。然而，线粒体调节的细胞死亡途径是 独立于Apaf1/caspase-9，我们之前克隆了一种与程序性细胞死亡相关的分子，称为凋亡诱导因子（AIF），与细胞色素c一样，AIF定位于线粒体并响应死亡刺激而释放。在这里，我们发现AIF的基因失活使胚胎干细胞在血清剥夺后对细胞死亡具有抵抗力。此外，AIF对于胚体空化过程中的程序性细胞死亡至关重要，这是小鼠形态发生中不可缺少的第一波细胞死亡，AIF依赖性细胞死亡表现出细胞凋亡的结构特征，并且可以在基因上与Apaf1和caspase-9表达脱钩。我们的数据为控制早期形态发生的不依赖半胱天冬酶的程序性细胞死亡途径提供了遗传证据。
Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis and tissue homeostasis, In mammals, release of mitochondrial cytochrome c leads to the cytosolic assembly of the apoptosome - a caspase activation complex involving Apaf1 and caspase-9 that induces hallmarks of apoptosis, There are, however, mitochondrially regulated cell death pathways that are independent of Apaf1/caspase-9, We have previously cloned a molecule associated with programmed cell death called apoptosis-inducing factor (AIF), Like cytochrome c,AIF is localized to mitochondria and released in response to death stimuli. Here we show that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation, Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies-the very first wave of cell death indispensable for mouse morphogenesis, AIF-dependent cell death displays structural features of apoptosis, and can be genetically uncoupled from Apaf1 and caspase-9 expression. Our data provide genetic evidence for a caspase-independent pathway of programmed cell death that controls early morphogenesis.