Department for Chemistry, Institute for Biochemistry, University of Cologne, Cologne, Germany.
Department for Biology, Cellular Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany.
EMBO J. 2019 Sep 16;38(18):e101552. doi: 10.15252/embj.2019101552. Epub 2019 Aug 7.
Hydrogen peroxide (H O ) plays important roles in cellular signaling, yet nonetheless is toxic at higher concentrations. Surprisingly, the mechanism(s) of cellular H O toxicity remain poorly understood. Here, we reveal an important role for mitochondrial 1-Cys peroxiredoxin from budding yeast, Prx1, in regulating H O -induced cell death. We show that Prx1 efficiently transfers oxidative equivalents from H O 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 O challenge. By replacing PRX1 with natural and engineered peroxiredoxin variants, we could predictably induce widely differing matrix glutathione responses to H O . Therefore, we demonstrated a key role for matrix glutathione oxidation in driving H O -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 O concentrations. This enables yeast cells to strike a fine balance between H O removal and limitation of matrix glutathione oxidation.
过氧化氢（H2O2）在细胞信号转导中发挥着重要作用，但在较高浓度下仍具有毒性。令人惊讶的是，细胞内 H2O2 毒性的机制仍未被充分理解。在这里，我们揭示了出芽酵母线粒体 1-Cys 过氧化物酶 Prx1 在调节 H2O2 诱导的细胞死亡中的重要作用。我们发现 Prx1 能够有效地将氧化还原当量从 H2O2 转移到线粒体谷胱甘肽池中。PRX1 的缺失消除了谷胱甘肽的氧化，并导致细胞溶质适应性反应，涉及过氧化氢酶 Ctt1 的上调。这两种效应都有助于在急性 H2O2 挑战后提高细胞活力。通过用天然和工程化的过氧化物酶变体替换 PRX1，我们可以预测性地诱导 H2O2 引起的基质谷胱甘肽反应的广泛差异。因此，我们证明了基质谷胱甘肽氧化在驱动 H2O2 诱导的细胞死亡中的关键作用。最后，我们揭示了 Prx1 的过氧化作用是一种关闭机制，可限制高 H2O2 浓度下基质谷胱甘肽的氧化。这使酵母细胞能够在 H2O2 的去除和基质谷胱甘肽氧化的限制之间取得良好的平衡。
