Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms
Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms
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DOI：
10.1523/jneurosci.4261-04.2005
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发表时间：
2005-02-09
影响因子：
5.3
通讯作者：
Slack, RS
中科院分区：
文献类型：
--
作者：
Cheung, ECC;Melanson-Drapeau, L;Slack, RS
线粒体释放蛋白同时传播caspase依赖和caspase非依赖的细胞死亡途径。凋亡诱导因子(AIF)是多条神经损伤通路中重要的caspase非依赖性死亡调节因子。目前，AIF在氧化应激或兴奋性毒性等神经元损伤中是否具有神经保护作用或促凋亡作用仍存在较大争议。为了评估AIF在Bax依赖性(DNA损伤诱导)和Bax非依赖性(兴奋性毒性)神经元死亡中的作用，我们使用了AIF亚型的小丑(HQ)小鼠。携带HQ/Apaf1(-/-)双突变的神经元在caspase依赖和AIF介导的线粒体细胞死亡途径中都受到损害。这些突变细胞对DNA损伤和谷氨酸诱导的兴奋性毒性表现出延长的神经保护作用。具体地说，AIF参与了NMDA和海人藻酸的兴奋毒性，但不参与AMPA诱导的兴奋性毒性。使用海人酸致癫痫的体内兴奋毒性研究表明，HQ小鼠的海马区损伤明显低于野生型小鼠。我们的结果表明，AIF在Bax依赖和Bax非依赖的神经元损伤机制中都扮演着重要的角色。
Mitochondria release proteins that propagate both caspase-dependent and caspase-independent cell death pathways. AIF (apoptosis-inducing factor) is an important caspase-independent death regulator in multiple neuronal injury pathways. Presently, there is considerable controversy as to whether AIF is neuroprotective or proapoptotic in neuronal injury, such as oxidative stress or excitotoxicity. To evaluate the role of AIF in BAX-dependent (DNA damage induced) and BAX-independent (excitotoxic) neuronal death, we used Harlequin ( Hq) mice, which are hypomorphic for AIF. Neurons carrying double mutations for Hq/ Apaf1 (-/ -) ( apoptosis proteases-activating factor) are impaired in both caspase- dependent and AIF- mediated mitochondrial cell death pathways. These mutant cells exhibit extended neuroprotection against DNA damage, as well as glutamate- induced excitotoxicity. Specifically, AIF is involved in NMDA- and kainic acid- but not AMPA- induced excitotoxicity. In vivo excitotoxic studies using kainic acid- induced seizure showed that Hq mice had significantly less hippocampal damage than wild- type littermates. Our results demonstrate an important role for AIF in both BAX-dependent and BAX- independent mechanisms of neuronal injury.