Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis
Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis
复制标题
AIF 和 CHCHD4 之间的相互作用调节呼吸链生物发生。
DOI：
10.1016/j.molcel.2015.04.020
复制
发表时间：
2015-06-18
期刊：
影响因子：
16
通讯作者：
Modjtahedi, Nazanine
中科院分区：
文献类型：
--
作者：
Hangen, Emilie;Feraud, Olivier;Modjtahedi, Nazanine
凋亡诱导因子（AIF）是一种线粒体黄素蛋白，除了其凋亡功能外，还需要主要呼吸链复合体的正常表达。在这里，我们确定了一个AIF相互作用蛋白，CHCHD4，这是一个氧化还原敏感的线粒体膜间空间输入机器的核心组成部分。AIF的缺失或亚型突变通过减少其线粒体输入而引起CHCHD4蛋白的下调。CHCHD4耗尽足以诱导呼吸缺陷，其模拟在AIF缺陷细胞中观察到的呼吸缺陷。CHCHD4水平可以通过加强其AIF非依赖性线粒体定位在AIF缺陷细胞中恢复。这种修饰的CHCHD4蛋白在AIF缺陷细胞中重建了呼吸功能，并使AIF缺陷胚状体能够经历空化，这是胚胎形态发生所需的程序性细胞死亡过程。这些发现解释了AIF如何有助于呼吸链复合物的生物发生，并且它们在AIF的重要功能与细胞发生凋亡的倾向之间建立了意想不到的联系。
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein that, beyond its apoptotic function, is required for the normal expression of major respiratory chain complexes. Here we identified an AIF-interacting protein, CHCHD4, which is the central component of a redox-sensitive mitochondrial intermembrane space import machinery. Depletion or hypomorphic mutation of AIF caused a downregulation of CHCHD4 protein by diminishing its mitochondrial import. CHCHD4 depletion sufficed to induce a respiratory defect that mimicked that observed in AIF-deficient cells. CHCHD4 levels could be restored in AIF-deficient cells by enforcing its AIF-independent mitochondrial localization. This modified CHCHD4 protein reestablished respiratory function in AIF-deficient cells and enabled AIF-deficient embryoid bodies to undergo cavitation, a process of programmed cell death required for embryonic morphogenesis. These findings explain how AIF contributes to the biogenesis of respiratory chain complexes, and they establish an unexpected link between the vital function of AIF and the propensity of cells to undergo apoptosis.