Mitochondrial disulfide relay and its substrates: mechanisms in health and disease

Eukaryotic cells harbor membrane-enclosed compartments to spatially separate different biochemical processes. As a result, proteins that become synthesized in the cytosol but fulfill their function in another compartment require translocation machineries. In the intermembrane space (IMS) of mitochondria, the mitochondrial disulfide relay is responsible for the import of many soluble proteins in an oxidation-dependent manner. These IMS proteins carry out important tasks and therefore their import, folding and maintenance are crucial for the remainder of the cell. In this review, we first describe the machinery for oxidative protein folding in the IMS and then focus on recent developments, which especially concern the mammalian machinery, its substrates and its physiological role.