Coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4)

CHCHD4 (Coiled-coil-helix-coiled-coil-helix domain-containing protein 4), also known as MIA40, is a highly conserved, redox-active oxidoreductase enzyme located in the mitochondrial intermembrane space[2][5]. It acts as a central component of the mitochondrial disulfide relay system, where it serves as a chaperone that catalyzes the import, oxidative folding, and assembly of numerous essential small cysteine-rich proteins—critical for the biogenesis of the mitochondrial respiratory chain complexes and other mitochondrial functions[5][2][3]. CHCHD4 recognizes mitochondrial targeting signals in substrate proteins, forms transient intermolecular disulfide bonds through its CPC motif, and is subsequently reoxidized by the sulfhydryl oxidase GFER/Erv1 in a relay that supports continual catalytic activity[2][5]. Disruption of CHCHD4 in animal models results in defects in mitochondrial respiration, iron homeostasis, and multiple human disease phenotypes, highlighting its essential and non-redundant role in cell metabolism and survival[2][4][5]. Currently, there are no clinically approved drugs targeting CHCHD4, but its central role in mitochondrial protein import and redox biology makes it an attractive putative therapeutic target for mitochondrial diseases, neurodegeneration, and cancer[5][2].

Other names

Mitochondrial intermembrane space import and assembly protein 40CHCHD4MIA40TIMM40FLJ31709Coiled-coil-helix-coiled-coil-helix domain-containing protein 4Translocase of inner mitochondrial membrane 40 homolog (S. cerevisiae)Mitochondrial intermembrane space import and assembly 40 homolog (S. cerevisiae)

Induction of oxidative folding by disulfide relay system; Protein import facilitation via oxidation of substrate thiols