Abstract

In the bacterial periplasm and in the ER of eukaryotic cells, sulfhydryl oxidases catalyze the formation of disulfide bridges between cysteine residues in order to induce or stabilize protein folding. In contrast, other cellular compartments are assumed to be generally counteracting the formation of disulfide bridges to maintain proteins in a reduced state.

It therefore was completely unexpected when recently a machinery was identified in the intermembrane space of mitochondria that catalyzes the oxidative folding of proteins. This machinery is essential for protein translocation of certain cysteine-containing precursor proteins and consists of two components which are highly conserved and essential for viability: The oxidoreductase Mia40 and the sulfhydryl oxidase Erv1. Mia40 serves as import receptor that covalently binds to proteins after their passage through the TOM complex, thereby converting them to their oxidized state. Since only unfolded, reduced proteins can traverse the TOM channel, this irreversibly traps the imported proteins in the mitochondria. Finally, Mia40 is reoxidized by Erv1.

Thus, the principle to oxidize proteins was presumably conserved from the bacterial periplasm to the intermembrane space of mitochondria, but this system was adapted during evolution so that it now mediates the vectorial translocation of proteins from the cytosol into the organelle.