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 PRX 1 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 PRX 1 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.