Increasing extracellular H2O2 produces a bi-phasic response in intracellular H2O2, with peroxiredoxin hyperoxidation only triggered once the cellular H2O2-buffering capacity is overwhelmed.
Increasing extracellular H2O2 produces a bi-phasic response in intracellular H2O2, with peroxiredoxin hyperoxidation only triggered once the cellular H2O2-buffering capacity is overwhelmed.
复制标题
DOI：
10.1016/j.freeradbiomed.2016.02.035
复制
发表时间：
2016-06
影响因子：
7.4
通讯作者：
Veal EA
中科院分区：
文献类型：
--
作者：
Tomalin LE;Day AM;Underwood ZE;Smith GR;Dalle Pezze P;Rallis C;Patel W;Dickinson BC;Bähler J;Brewer TF;Chang CJ;Shanley DP;Veal EA
活性氧，如H2O2，可以损伤细胞，但也促进基本过程，包括生长、分化和迁移。允许细胞对有毒或信号H2O2水平做出差异反应的机制尚不清楚。在这里，我们揭示了增加外部H2O2在细胞内产生双相反应H2O2。过氧化物还毒素（Prx）是一种丰富的过氧化物酶，可以防止基因组不稳定、衰老和癌症。我们开发了一个动态模型来模拟体内Prx氧化的变化。值得注意的是，我们发现Prx的硫氧还蛋白过氧化物酶活性对H2O2的外部升高没有提供任何显著的保护。相反，我们的模型和实验数据与其他依赖硫氧还蛋白的活性（包括硫醇蛋白质组中的H2O2活性半胱氨酸）有效缓冲低水平的细胞外H2O2一致。我们发现，当细胞外H2O2水平超过这种缓冲能力时，细胞内H2O2水平的上升会引发Prx的过度氧化，形成抗硫氧还蛋白、过氧化物酶无活性的形式。因此，Prx高氧化信号表明H2O2防御被破坏，转移硫氧还蛋白来修复损伤。模拟体内动态h2o2诱导的Prx氧化变化的数学模型。增加细胞外H2O2在细胞内产生双相反应。硫氧还蛋白和硫-蛋白质组可以有效缓冲低水平的H2O2。只有当H2O2缓冲能力达到饱和时，Prx才会发生过氧化。
Reactive oxygen species, such as H2O2, can damage cells but also promote fundamental processes, including growth, differentiation and migration. The mechanisms allowing cells to differentially respond to toxic or signaling H2O2 levels are poorly defined. Here we reveal that increasing external H2O2 produces a bi-phasic response in intracellular H2O2. Peroxiredoxins (Prx) are abundant peroxidases which protect against genome instability, ageing and cancer. We have developed a dynamic model simulating in vivo changes in Prx oxidation. Remarkably, we show that the thioredoxin peroxidase activity of Prx does not provide any significant protection against external rises in H2O2. Instead, our model and experimental data are consistent with low levels of extracellular H2O2 being efficiently buffered by other thioredoxin-dependent activities, including H2O2-reactive cysteines in the thiol-proteome. We show that when extracellular H2O2 levels overwhelm this buffering capacity, the consequent rise in intracellular H2O2 triggers hyperoxidation of Prx to thioredoxin-resistant, peroxidase-inactive form/s. Accordingly, Prx hyperoxidation signals that H2O2 defenses are breached, diverting thioredoxin to repair damage. Mathematical model simulating in vivo dynamic, H2O2-induced, changes in Prx oxidation. Increasing extracellular H2O2 produces a bi-phasic response in intracellular H2O2. Thioredoxin and the thiol-proteome can efficiently buffer low levels of H2O2. Prx hyperoxidation only occurs once this H2O2 buffering capacity is saturated.