Proteins destined for the intermembrane space of mitochondria follow which pathway?
Intermembrane space houses many small proteins twin cysteine motifs serving redox sensing copper delivery assembly such as small Tim family Tim9 Tim10 Tim13 Cox17 copper chaperone cytochrome oxidase Erv1 sulfhydryl oxidase Mia40 receptor. Most contain CX3C or CX9C helical hairpin stabilized two disulfide bonds. Import after TOM entry IMS relies dedicated MIA pathway mitochondrial IMS import and assembly comprising oxidoreductase Mia40 CHCHD4 mammals hydrophobic binding cleft redox-active CPC disulfide sulfhydryl oxidase Erv1 ALR FAD cofactor. Mechanism oxidative folding trap: Mia40 recognizes reduced unfolded substrate hydrophobic cleft forming transient intermolecular mixed disulfide via substrate cysteine attack Mia40 CPC; subsequent attack second substrate cysteine introduces intramolecular disulfide substrate concomitant release oxidized folded substrate reduced Mia40. Erv1 reoxidizes Mia40 disulfide transferring electrons FAD cytochrome c respiratory chain completing catalytic cycle generating disulfide. Trapping mechanism does not require membrane potential or ATP unlike TIM23 motor resembles ER PDI-Ero1 but mitochondria specific. TOM-MIA pathway defines IMS proteome via disulfide relay ensuring retention and functional folding quality control and biogenesis.
Ref: Herrmann & Riemer, Curr Opin Cell Biol 2012: MIA40 pathway for IMS protein oxidative folding.