Hyperoxidation of mitochondrial peroxiredoxin limits H₂O₂-induced cell death in yeast

Hydrogen peroxide (H₂O₂) plays important roles in cellular signaling, yet nonetheless is toxic at higher concentrations. Surprisingly, the mechanism(s) of cellular H₂O₂ toxicity remain poorly understood. Here, we reveal an important role for mitochondrial 1-Cys peroxiredoxin from budding yeast, Prx1, in regulating H₂O₂-induced cell death. We show that Prx1 efficiently transfers oxidative equivalents from H₂O₂ to the mitochondrial glutathione pool. Deletion of PRX1 abrogates glutathione oxidation and leads to a cytosolic adaptive response involving upregulation of the catalase, Ctt1. Both of these effects contribute to improved cell viability following an acute H₂O₂ challenge. By replacing PRX1 with natural and engineered peroxiredoxin variants, we could predictably induce widely differing matrix glutathione responses to H₂O₂. Therefore, we demonstrated a key role for matrix glutathione oxidation in driving H₂O₂-induced cell death. Finally, we reveal that hyperoxidation of Prx1 serves as a switch-off mechanism to limit oxidation of matrix glutathione at high H₂O₂ concentrations. This enables yeast cells to strike a fine balance between H₂O₂ removal and limitation of matrix glutathione oxidation.