The Mitochondrial Disulfide Relay System: Roles in Oxidative Protein Folding and Beyond
Figure 3
Functions of human Mia40. The protein exists in two different isoforms. Differences in function between the isoforms are not known. Oxidative Import. Mia40 is the main receptor for import and oxidation of twin-CX9C and twin-CX3C proteins in the IMS. Holdase Function. Mia40 shields hydrophobic patches on proteins imported into the IMS, thus allowing proper folding of these proteins. Mitochondrial Morphology. Reduced amounts of Mia40 lead to increased mitochondrial fission and the formation of a more fragmented mitochondrial network. Hypoxia Response. Under normoxic conditions the protein HIF1 is constantly degraded. This degradation is mediated by hydroxylation by prolyl hydroxylase domain enzymes (PHD) and ubiquitination by the Hippel-Lindau E3 ligase (VHL). Upon hypoxia oxygen as substrate of PHD is missing resulting in impaired HIF1 degradation and increased stability. If not degraded HIF1 can dimerize with constitutively expressed HIF1 and induce the hypoxia response. Silencing Mia40 using RNAi prevents stabilization of HIF1 under hypoxic conditions. In contrast increased amounts of Mia40 as can also be found in certain tumors result in increased stabilization of HIF1.
