Hyperoxidation of mitochondrial peroxiredoxin limits H 2 O 2 -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.