Hydrogen peroxide (H₂ O₂ ) plays important roles in cellular signaling, yet nonetheless is toxic at higher concentrations. Surprisingly, the mechanism(s) of cellular H₂ O₂ toxicity remain poorly understood. Here, we reveal an important role for mitochondrial 1-Cys peroxiredoxin from budding yeast, Prx1, in regulating H₂ O₂ -induced cell death. We show that Prx1 efficiently transfers oxidative equivalents from H₂ O₂ 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 H₂ O₂ challenge. By replacing PRX1 with natural and engineered peroxiredoxin variants, we could predictably induce widely differing matrix glutathione responses to H₂ O₂ . Therefore, we demonstrated a key role for matrix glutathione oxidation in driving H₂ O₂ -induced cell death. Finally, we reveal that hyperoxidation of Prx1 serves as a switch-off mechanism to limit oxidation of matrix glutathione at high H₂ O₂ concentrations. This enables yeast cells to strike a fine balance between H₂ O₂ removal and limitation of matrix glutathione oxidation.

• PMID: 31389622
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Journal Article | Research Support, Non-U.S. Gov't

Authors

Calabrese G, Peker E, Amponsah PS, Hoehne MN, Riemer T, Mai M, Bienert GP, Deponte M, Morgan B, Riemer J

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