Bid-induced release of AIF from mitochondria causes immediate neuronal cell death
Bid-induced release of AIF from mitochondria causes immediate neuronal cell death
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DOI：
10.1038/cdd.2008.78
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发表时间：
2008-10-01
影响因子：
12.4
通讯作者：
Culmsee, C.
中科院分区：
文献类型：
--
作者：
Landshamer, S.;Hoehn, M.;Culmsee, C.
线粒体功能障碍和促凋亡因子如细胞色素c或凋亡诱导因子（AIF）从线粒体释放是神经元细胞死亡的关键特征。然而，这些蛋白质如何从线粒体释放的精确机制以及它们在神经元细胞死亡信号传导中的特定作用在很大程度上是未知的。在这里，我们通过荧光视频显微镜证明，诱导谷氨酸毒性后8-10小时，AIF迅速从线粒体易位到细胞核，并在短短几分钟内诱导核碎裂和细胞死亡。AIF向细胞核的这种显著快速的易位之前，促凋亡bcl-2家族成员Bid（BH 3-相互作用结构域死亡激动剂）向线粒体的易位增加，负载Bid的线粒体的核周积累，以及线粒体膜完整性的丧失。一个小分子Bid抑制剂保存线粒体膜电位，防止核转位的AIF，并废除谷氨酸诱导的神经元细胞死亡，如实验所示，使用Bid小干扰RNA（siRNA）。AIF siRNA抑制截短Bid诱导的细胞死亡，表明不依赖于caspase的AIF信号转导是Bid介导细胞死亡的主要途径。这进一步得到了实验的支持，实验表明，尽管caspase-3被激活，但特异性caspase-3抑制并不能保护神经元细胞免受谷氨酸毒性。总之，BID介导的线粒体释放AIF，然后快速核转位是谷氨酸诱导的神经元死亡的主要机制。
Mitochondrial dysfunction and release of pro-apoptotic factors such as cytochrome c or apoptosis-inducing factor (AIF) from mitochondria are key features of neuronal cell death. The precise mechanisms of how these proteins are released from mitochondria and their particular role in neuronal cell death signaling are however largely unknown. Here, we demonstrate by fluorescence video microscopy that 8-10 h after induction of glutamate toxicity, AIF rapidly translocates from mitochondria to the nucleus and induces nuclear fragmentation and cell death within only a few minutes. This markedly fast translocation of AIF to the nucleus is preceded by increasing translocation of the pro-apoptotic bcl-2 family member Bid (BH3-interacting domain death agonist) to mitochondria, perinuclear accumulation of Bid-loaded mitochondria, and loss of mitochondrial membrane integrity. A small molecule Bid inhibitor preserved mitochondrial membrane potential, prevented nuclear translocation of AIF, and abrogated glutamate-induced neuronal cell death, as shown by experiments using Bid small interfering RNA (siRNA). Cell death induced by truncated Bid was inhibited by AIF siRNA, indicating that caspase-independent AIF signaling is the main pathway through which Bid mediates cell death. This was further supported by experiments showing that although caspase-3 was activated, specific caspase-3 inhibition did not protect neuronal cells against glutamate toxicity. In conclusion, Bid-mediated mitochondrial release of AIF followed by rapid nuclear translocation is a major mechanism of glutamate-induced neuronal death.