Hyperoxidation of mitochondrial peroxiredoxin limits H(2)O(2)‐induced cell death in yeast

Hydrogen peroxide (H(2)O(2)) plays important roles in cellular signaling, yet nonetheless is toxic at higher concentrations. Surprisingly, the mechanism(s) of cellular H(2)O(2) toxicity remain poorly understood. Here, we reveal an important role for mitochondrial 1‐Cys peroxiredoxin from budding yeast, Prx1, in regulating H(2)O(2)‐induced cell death. We show that Prx1 efficiently transfers oxidative equivalents from H(2)O(2) 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 H(2)O(2) challenge. By replacing PRX1 with natural and engineered peroxiredoxin variants, we could predictably induce widely differing matrix glutathione responses to H(2)O(2). Therefore, we demonstrated a key role for matrix glutathione oxidation in driving H(2)O(2)‐induced cell death. Finally, we reveal that hyperoxidation of Prx1 serves as a switch‐off mechanism to limit oxidation of matrix glutathione at high H(2)O(2) concentrations. This enables yeast cells to strike a fine balance between H(2)O(2) removal and limitation of matrix glutathione oxidation.