NOVEL TARGETS OF THE SULFHYDRYL : CYTOCHROME C OXIDOREDUCTASE ALR

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Disulfide formation in the mitochondrial intermembrane space (IMS) is an essential process that serves in establishing and maintaining protein structures, in regulating protein functions and in driving enzyme reactions as parts of reaction cycles. The mitochondrial disulfide relay, consisting of the two core components ALR/Erv1 and CHCHD4/Mia40, catalyzes disulfide formation in the IMS. CHCHD4 thereby is crucial for IMS import and oxidative folding of many substrates. The major function of ALR was mainly thought to involve regeneration of CHCHD4 to maintain it in its active state. To this end, ALR receives electrons from CHCHD4 and passes them on to cytochrome c in an electron relay reaction. We hypothesize that the role of human ALR expands beyond its originally proposed role as regenerating enzyme for CHCHD4. Instead, we propose that ALR serves as a central electron relay station in the IMS. We recently obtained insights that ALR targets a broad variety of different proteins by identifying interaction partners in proteomic approaches. With this project, we will test whether ALR exerts alternative functions in different tissues, and will therefore identify tissue-specific substrate interactions. We will then characterize the mechanistic, functional and physiological consequences of ALR-dependent oxidation for two novel ALR targets. Moreover, we will investigate the mechanistic differences between substrate handling by CHCHD4 and ALR using a set of different ALR and CHCHD4 targets.Collectively, our work will provide new insights into essential mitochondrial disulfide relay machinery, the biology of the mitochondrial intermembrane space, and into oxidative protein folding in general.