[en] Apoptosis Inducing Factor/genetics/metabolism ; Cysteine/genetics/metabolism ; Disulfides/metabolism ; Electron Transport Complex I/genetics/metabolism ; Gene Expression Regulation ; Humans ; Mitochondria/genetics/metabolism ; Mitochondrial Membrane Transport Proteins/genetics ; Mitochondrial Precursor Protein Import Complex Proteins ; Mitochondrial Proteins/genetics ; Mutation/genetics ; Protein Transport/genetics ; Saccharomyces cerevisiae/genetics/metabolism ; Disulfide relay system ; Metabolism ; Mitochondria ; Mitochondrial protein import ; Respiratory chain machinery
[en] 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.
[Université Paris-Saclay, Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire, 94805 Villejuif, France.]
