The Mitochondrial Intermembrane Space: A Hub for Oxidative Folding Linked to Protein Biogenesis

Abstract

The introduction of disulfide bonds in proteins of the mitochondrial intermembrane space (IMS) is fundamental for their folding and assembly. This oxidative folding process depends on the disulfide donor/import receptor Mia40 and the flavin adenine dinucleotide oxidase Erv1 and concerns proteins involved in mitochondrial biogenesis, respiratory complex assembly, and metal transfer. The recently determined structural basis of the interaction between Mia40 and some substrates provides a framework for the electron transfer process. A possible proofreading role for the cellular reductant glutathione has been proposed, while other studies suggest the association of Mia40 and Erv1 in dynamic multiprotein complexes in the IMS. The association of Mia40 with Erv1 and substrates in large multiprotein complexes is critical. Completion of substrate folding by additional disulfide bonds after initial binding to Mia40 remains unclear. Furthermore, a more general role for Mia40 in recognizing substrates targeted to other compartments, or even without specific cysteine motifs, remains an intriguing possibility. Dissecting a regulatory role of intramitochondrial protein complex organization and small redox-active molecules will be crucial for understanding oxidative folding in the IMS. This should have an impact on the physiology of human cells, as disease-linked mutations of key components of this process have been manifested, and their expression in stem cells appears crucial for development.