Mitochondrial thiols in the regulation of cell death pathways

Significance: Regulation of mitochondrial H₂O₂ homeostasis and its involvement in the regulation of redox-sensitive signaling and transcriptional pathways is the consequence of the concerted activities of the mitochondrial energy- and redox systems. Recent Advances: The energy component of this mitochondrial energy-redox axis entails the formation of reducing equivalents and their flow through the respiratory chain with the consequent electron leak to generate and H₂O₂. The mitochondrial redox component entails the thiol-based antioxidant system, largely accounted for by glutathione- and thioredoxin-based systems that support the activities of glutathione peroxidases, peroxiredoxins, and methionine sulfoxide reductase. The ultimate reductant for these systems is NADPH: mitochondrial sources of NADPH are the nicotinamide nucleotide transhydrogenase, isocitrate dehydrogenase-2, and malic enzyme. NADPH also supports the glutaredoxin activity that regulates the extent of S-glutathionylation of mitochondrial proteins in response to altered redox status. Critical Issues: The integrated network of these mitochondrial thiols constitute a regulatory device involved in the maintenance of steady-state levels of H₂O ₂, mitochondrial and cellular redox and metabolic homeostasis, as well as the modulation of cytosolic redox-sensitive signaling; disturbances of this regulatory device affects transcription, growth, and ultimately influences cell survival/death. Future Directions: The modulation of key mitochondrial thiol proteins, which participate in redox signaling, maintenance of the bioenergetic machinery, oxidative stress responses, and cell death programming, provides a pivotal direction in developing new therapies towards the prevention and treatment of several diseases.