Redox regulation of proteins of the mitochondrial intermembrane space

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Proteins of the mitochondrial intermembrane space play important roles in cellular energy metabolism, in the transport of metal ions, metabolites and proteins between both mitochondrial membranes and in the regulation of apoptosis. Many of these proteins contain disulfide bonds presumably reflecting the evolutionary origin of the intermembrane space from the periplasm of bacteria. We recently identified a machinery (called the mitochondrial disulfide relay) which uses protein oxidation to drive the translocation of newly synthesized proteins across the outer membrane. During the previous funding period we characterized the proteins Erv1 and Mia40, the central players of the disulfide relay, in the folding of simply structured helix-loop-helix proteins. In the next funding period we want to study intermembrane space proteins that contain conserved cysteine patterns. One group of proteins that is poorly characterized so far consists of Twin Cx9C proteins. Employing a proteomic screen we want to identify stable and transient interaction partners of these conserved components and explore their function in the biogenesis of mitochondria. Moreover, we want to investigate the oxidation of proteins that have more complex cysteine patterns and/or are not of simple helix-loop-helix structure. One of our model proteins is Atp23, a protease in the intermembrane space, which contains ten conserved cysteine residues. In vivo Atp23 is completely oxidized in a Mia40-dependent process. We want to understand how the correct connectivity of the five disulfide bonds in Atp23 is reached and how the isomerisation of disulfide bonds in this compartment is catalyzed. In a further approach, we want to address the oxidation of proteins that are imported into mitochondria in a Mia40-independent reaction. Our preliminary results suggest that oxidation of cysteine residues is used to regulate protein activity in the intermembrane space. From these projects we expect fundamental insight into the molecular mechanisms of the biogenesis and redox control of mitochondrial proteins.