Mitochondrial Thiols in Antioxidant Protection and Redox Signaling: Distinct Roles for Glutathionylation and Other Thiol Modifications

Significance: The mitochondrial matrix contains much of the machinery at the heart of metabolism. This compartment is also exposed to a high and continual flux of superoxide, hydrogen peroxide, and related reactive species. To protect mitochondria from these sources of oxidative damage, there is an integrated set of thiol systems within the matrix comprising the thioredoxin/peroxiredoxin/methionine sulfoxide reductase pathways and the glutathione/glutathione peroxidase/glutathione-S-transferase/glutaredoxin pathways that in conjunction with protein thiols prevent much of this oxidative damage. In addition, the changes in the redox state of many components of these mitochondrial thiol systems may transduce and relay redox signals within and through the mitochondrial matrix to modulate the activity of biochemical processes. Recent Advances: Here, mitochondrial thiol systems are reviewed, and areas of uncertainty are pointed out, focusing on recent developments in our understanding of their roles. Critical Issues: The areas of particular focus are on the multiple, overlapping roles of mitochondrial thiols and on understanding how these thiols contribute to both antioxidant defenses and redox signaling. Future Directions: Recent technical progress in the identification and quantification of thiol modifications by redox proteomics means that many of the questions raised about the multiple roles of mitochondrial thiols can now be addressed. Antioxid. Redox Signal. 16, 476-495.