Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis
Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis
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DOI：
10.1038/sj.emboj.7601276
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发表时间：
2006-09-06
期刊：
影响因子：
11.4
通讯作者：
Slack, Ruth S.
中科院分区：
文献类型：
--
作者：
Cheung, Eric C. C.;Joza, Nicholas;Slack, Ruth S.
线粒体蛋白凋亡诱导因子（AIF）易位到细胞核并诱导细胞凋亡。然而，最近的研究表明AIF对于线粒体中的存活的重要性。由于没有办法将这两种职能分开，因此，临时政府的确切作用仍然不清楚。在这里，我们解离这些双重作用，使用神经锚定的AIF，不能在细胞凋亡过程中释放。前脑特异性AIF null（tel. Aif（Delta））小鼠由于线粒体呼吸缺陷而具有缺陷的皮质发育和减少的神经元存活。AIF缺陷神经元的线粒体被异常嵴碎片化，表明AIF在控制线粒体结构中的新作用。虽然tel。Aif Delta Apaf 1-/-神经元对DNA损伤保持敏感，这些细胞中的神经锚定AIF表达显著提高了存活率。不能转位入核的AIF突变体不能诱导细胞死亡。这些结果表明，AIF的促凋亡作用可以从其生理功能中解耦。AIF诱导的细胞死亡是通过其一旦易位到细胞核的促凋亡活性，而不是由于线粒体中AIF的丢失。
The mitochondrial protein apoptosis-inducing factor (AIF) translocates to the nucleus and induces apoptosis. Recent studies, however, have indicated the importance of AIF for survival in mitochondria. In the absence of a means to dissociate these two functions, the precise roles of AIF remain unclear. Here, we dissociate these dual roles using mitochondrially anchored AIF that cannot be released during apoptosis. Forebrain-specific AIF null (tel. Aif(Delta)) mice have defective cortical development and reduced neuronal survival due to defects in mitochondrial respiration. Mitochondria in AIF deficient neurons are fragmented with aberrant cristae, indicating a novel role of AIF in controlling mitochondrial structure. While tel. Aif Delta Apaf1-/- neurons remain sensitive to DNA damage, mitochondrially anchored AIF expression in these cells significantly enhanced survival. AIF mutants that cannot translocate into nucleus failed to induce cell death. These results indicate that the proapoptotic role of AIF can be uncoupled from its physiological function. Cell death induced by AIF is through its proapoptotic activity once it is translocated to the nucleus, not due to the loss of AIF from the mitochondria.