Disulfide bond formation drives protein import of most proteins of the mitochondrial intermembrane space (IMS). The main components of this disulfide relay machinery are the oxidoreductase Mia40 and the sulfhydryl oxidase Erv1/ALR. Their precise functions have been elucidated in molecular detail for the yeast and human enzymes in vitro and in intact cells. However, we still lack knowledge on how Mia40 and Erv1/ALR impact cellular and organism physiology and whether they have functions beyond their role in disulfide bond formation. Here we summarize the principles of oxidation-dependent protein import mediated by the mitochondrial disulfide relay. We proceed by discussing recently described functions of Mia40 in the hypoxia response and of ALR in influencing mitochondrial morphology and its importance for tissue development and embryogenesis. We also include a discussion of the still mysterious function of Erv1/ALR in liver regeneration. 1. Introduction Because almost all proteins in eukaryotic cells are synthesized by cytosolic ribosomes, protein translocation across membranes is critical for organelle biogenesis. The invention of organelle-specific targeting systems in the cytosol was instrumental to facilitate correct translocation events and to avoid mistargeting. These pathways are usually complemented by machineries in the organelle lumen which provide driving force and ensure directionality. For example, in the endoplasmic reticulum (ER) and the mitochondrial matrix members of the Hsp70 family of chaperones bind incoming substrates and thereby prevent their backsliding (ratchet-like mechanism) [1]. A similar mechanism is employed for protein import into the mitochondrial intermembrane space (IMS). Here formation of inter- and intramolecular disulfide bonds by the essential mitochondrial disulfide relay is critical for translocation across the mitochondrial outer membrane [2–6]. In this review, we will discuss the disulfide relay and its components, compare and contrast the machineries in yeast and human cells, and discuss additional potentially nonoxidative functions of disulfide relay components in human cells. 2. Substrates of the Mitochondrial Disulfide Relay Most proteins that are imported into mitochondria contain either a mitochondrial targeting signal (MTS) or internal targeting sequences [4, 7, 8]. They are thereby targeted into the mitochondrial matrix or to the two mitochondrial membranes. In contrast, only few of the precursors of IMS proteins carry the so-called bipartite presequences consisting of an MTS and a hydrophobic sorting
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