The Mitochondrial Disulfide Relay System: Roles in Oxidative Protein Folding and Beyond
Figure 5
Open questions. Hypoxia. Why Mia40 is required for the stabilization of HIF1 under hypoxic conditions is unknown. It will be interesting to reveal the underlying mechanism and if the influence of Mia40 is direct or indirect. New Substrates. During the last years proteins were found to be dependent on Mia40 that do not share the same motifs as the classical twin-CX9C and twin-CX3C substrates. They are either dependent on the function of Mia40 as oxidoreductase or holdase. Initial Degradation and Cytosolic Chaperones/Targeting Factors. In yeast a portion of IMS proteins is directly degraded after translation. However, it is not known if this takes place in other organisms, how it is regulated, and how it works at the molecular level. Moreover, it remains unclear how proteins after translation are kept import competent and targeted to mitochondria. Redox Regulation. The mitochondrial disulfide relay is known to introduce structural disulfide bonds which are required for protein stability. However, it is not known if Mia40 or Erv1/ALR can regulate the activity of IMS proteins by reversible oxidation or reduction.
