In the mitochondria of healthy cells, Apoptosis-Inducing factor (AIF) is required for the optimal functioning of the respiratory chain machinery, mitochondrial integrity, cell survival, and proliferation. In all analysed species, it was revealed that the downregulation or depletion of AIF provokes mainly the post-transcriptional loss of respiratory chain Complex I protein subunits. Recent progress in the field has revealed that AIF fulfils its mitochondrial pro-survival function by interacting physically and functionally with CHCHD4, the evolutionarily-conserved human homolog of yeast Mia40. The redox-regulated CHCHD4/Mia40-dependent import machinery operates in the intermembrane space of the mitochondrion and controls the import of a set of nuclear-encoded cysteine-motif carrying protein substrates. In addition to their participation in the biogenesis of specific respiratory chain protein subunits, CHCHD4/Mia40 substrates are also implicated in the control of redox regulation, antioxidant response, translation, lipid homeostasis and mitochondrial ultrastructure and dynamics. Here, we discuss recent insights on the AIF/CHCHD4-dependent protein import pathway and review current data concerning the CHCHD4/Mia40 protein substrates in metazoan. Recent findings and the identification of disease-associated mutations in AIF or in specific CHCHD4/Mia40 substrates have highlighted these proteins as potential therapeutic targets in a variety of human disorders.

中文翻译：

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AIF符合CHCHD4 / Mia40依赖性线粒体导入途径。

在健康细胞的线粒体中，凋亡诱导因子（AIF）是呼吸链机器，线粒体完整性，细胞存活和增殖的最佳功能所必需的。在所有分析的物种中，揭示了AIF的下调或耗竭主要是引起呼吸链复合物I蛋白亚基的转录后丢失。该领域的最新进展表明，AIF通过与CHCHD4（酵母Mia40的进化保守人类同源物）在物理上和功能上相互作用来实现其线粒体的生存前功能。氧化还原调节的CHCHD4 / Mia40依赖的进口机器在线粒体的膜内空间中运行，并控制一组携带蛋白质底物的核编码半胱氨酸基序的进口。除了参与特定呼吸链蛋白亚基的生物发生之外，CHCHD4 / Mia40底物还参与氧化还原调节，抗氧化反应，翻译，脂质稳态和线粒体超微结构和动力学的控制。在这里，我们讨论有关AIF / CHCHD4依赖的蛋白质进口途径的最新见解，并审查有关后生动物中CHCHD4 / Mia40蛋白质底物的最新数据。最近的发现和对AIF或特定CHCHD4 / Mia40底物中疾病相关突变的鉴定，突显了这些蛋白作为多种人类疾病的潜在治疗靶标。脂质稳态和线粒体超微结构和动力学。在这里，我们讨论有关AIF / CHCHD4依赖的蛋白质进口途径的最新见解，并审查有关后生动物中CHCHD4 / Mia40蛋白质底物的最新数据。最近的发现和对AIF或特定CHCHD4 / Mia40底物中疾病相关突变的鉴定，突显了这些蛋白作为多种人类疾病的潜在治疗靶标。脂质稳态和线粒体超微结构和动力学。在这里，我们讨论有关AIF / CHCHD4依赖的蛋白质进口途径的最新见解，并审查有关后生动物中CHCHD4 / Mia40蛋白质底物的最新数据。最近的发现和对AIF或特定CHCHD4 / Mia40底物中疾病相关突变的鉴定，突显了这些蛋白作为多种人类疾病的潜在治疗靶标。