Hyperoxidation of mitochondrial peroxiredoxin limits H2 O2 -induced cell death in yeast.

Gaetano Calabrese,Prince Saforo Amponsah,Esra Peker,Marcel Deponte,Gerd Patrick Bienert,Marie Mai,Jan Riemer,Bruce Morgan,Trine Riemer,Michaela Nicole Hoehne

doi:10.15252/embj.2019101552

Abstract

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.

Highlights

Reactive oxygen species (ROS) are an unavoidable consequence of life in an oxygen-rich environment
By replacing endogenous Prx1 with these peroxiredoxin variants, we revealed a striking correlation between matrix glutathione oxidation and cell death
In wild-type cells, we found that the degree of cell death is limited by hyperoxidation-based inactivation of Prx1 at high H2O2 levels, which restricts oxidation of the matrix glutathione pool

Summary

Introduction

Reactive oxygen species (ROS) are an unavoidable consequence of life in an oxygen-rich environment. Once considered solely as harmful molecules, which cells seek to remove as efficiently as possible, it is accepted that some ROS have important physiological functions. In this regard, one of the best understood ROS is H2O2, which acts as a second messenger in several key cellular signaling pathways (Sundaresan et al, 1995; Delaunay et al, 2002; Sobotta et al, 2015; Stocker et al, 2018). Other possible triggers of H2O2-induced cell death have been proposed, including induction of apoptosis (Greetham et al, 2013), depletion of reduced cytosolic thioredoxins (Day et al, 2012), and disruption of redox signaling pathways (Sies, 2017), but well-defined molecular mechanisms remain largely elusive.

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Results

Conclusion