The Mitochondrial Disulfide Relay System: Roles in Oxidative Protein Folding and Beyond

Abstract

Disulfide bond formation drives protein import of most proteins of the mitochondrial intermembrane space (IMS). The main components of this disulfide relay machinery are the oxidoreductase Mia40 and the sulfhydryl oxidase Erv1/ALR. Their precise functions have been elucidated in molecular detail for the yeast and human enzymes in vitro and in intact cells. However, we still lack knowledge on how Mia40 and Erv1/ALR impact cellular and organism physiology and whether they have functions beyond their role in disulfide bond formation. Here we summarize the principles of oxidation-dependent protein import mediated by the mitochondrial disulfide relay. We proceed by discussing recently described functions of Mia40 in the hypoxia response and of ALR in influencing mitochondrial morphology and its importance for tissue development and embryogenesis. We also include a discussion of the still mysterious function of Erv1/ALR in liver regeneration.

Cytosolic Fe-S Cluster Protein Maturation and Iron Regulation Are Independent of the Mitochondrial Erv1/Mia40 Import System

“…Erv1 has a clear, undisputed function in facilitating import of nuclear-encoded proteins into the mitochondrial intermembrane space. Substrates of the Erv1-Mia40 import system include assembly factors and components of the respiratory chain, chaperones that facilitate protein import into mitochondrial compartments and membranes, and chaperones for antioxidant enzymes (54). Thus, it is not surprising that Erv1 dysfunction has pleotropic effects on mitochondrial biogenesis, function, and morphology.…”

The Diabetes Drug Target MitoNEET Governs a Novel Trafficking Pathway to Rebuild an Fe-S Cluster into Cytosolic Aconitase/Iron Regulatory Protein 1

“…Mössbauer and NMR Spectroscopy-Mössbauer spectra of purified 57 Fe-labeled mNT 33-108 in 50 mM phosphate (pH 8.0), 50 mM NaCl were recorded at 4.2 K on a low-field Mössbauer spectrometer equipped with a Janis SVT-400 cryostat and weak field permanent magnets. The spectrometer was operated in a constant acceleration mode in transmission geometry (28).…”

“…ALR is a multifunctional protein also involved in import of cysteine-containing proteins (e.g. Tim and Cox proteins), which, in turn, may affect respiratory chain assembly (33). Therefore, we asked whether ALR-dependent mNT maturation could result from an impairment of ALR-dependent mNT import to mitochondria.…”

Activation of Mitochondrial Protein Phosphatase SLP2 by MIA40 Regulates Seed Germination

“…Collectively, these findings support AtMIA40 activation of AtSLP2 through the catalyzed formation of disulfide bridges. Like other MIA40 substrates, this may function to trap AtSLP2 in the IMS by providing correct tertiary structure (Fischer and Riemer, 2013).…”