Protein import into the intermembrane space of mitochondria

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Proteins of the intermembrane space (IMS) of mitochondria are crucial for many mitochondrial and cellular processes, such as energy metabolism, apoptosis and the transport of metabolites and proteins. Thus, it is essential for mitochondrial and cellular homeostasis that IMS proteins are imported and correctly folded in the IMS. Indeed, defects in their biogenesis play a role in many diseases. Many IMS proteins are imported by the mitochondrial disulfide relay system (DRS) consisting of two essential proteins: the redox receptor Mia40 and the sulfhydryl-electron transferase Erv1. The Mia40/Erv1-DRS introduces disulfide bonds in substrate proteins, triggering their folding and import into the IMS. However, many fundamental and disease-relevant questions regarding the Mia40/Erv1-DRS, its regulation and the import of IMS proteins remain.We will focus on three main objectives concerning the import of IMS proteins. The first objective will address the regulation of the import of substrate proteins of the Mia40/Erv1-DRS. As first part of the objective, we will elucidate cytosolic processes involved in the protein transport of the Mia40/Erv1-DRS pathway and its regulation. We will identify and characterize cytosolic proteins that interact with newly synthesized substrate proteins in the cytosol. As second part, we will test the function of mitochondrial redox proteins in the IMS, such as the thioredoxin system and the peroxidase Hyr1, and analyze their role in the Mia40/Erv1 import pathway.The second objective is to characterize the link between the physiological function of the Mia40/Erv1-disulfide relay system and the disease phenotype observed in patients with mutations in human ERV1. By studying the consequences of these mutations in the yeast model system and in patients fibroblasts, we will elucidate the molecular basis of the disease phenotype.We have shown that the Mia40/Erv1-DRS has a broader substrate specificity than previously thought. The third objective is to identify and characterize novel substrates of the yeast DRS and to characterize the import of IMS proteins that lack sequence features of substrates with known import pathways.By identifying cytosolic proteins interacting with DRS substrates and by elucidating the function of redox proteins in the DRS import pathway we will provide valuable insights into this pathway and its regulation. The studies, to identify novel DRS substrates, to characterize the import of IMS proteins with as yet unknown pathway and to elucidate the pathomechanisms of the huERV1 mutants, will contribute to obtain a comprehensive picture of the biogenesis of IMS proteins and their role for mitochondrial physiology and diseases.