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Increasing extracellular H₂O₂ produces a bi-phasic response in intracellular H₂O₂, with peroxiredoxin hyperoxidation only triggered once the cellular H₂O₂-buffering capacity is overwhelmed

Tomalin, Lewis Elwood and Day, Alison Michelle and Underwood, Zoe Elizabeth and Smith, Graham Robert and Dalle Pezze, Piero and Rallis, Charalampos and Patel, Waseema and Dickinson, Bryan Craig and Bähler, Jürg and Brewer, Thomas Francis and Chang, Christopher Joh-Leung and Shanley, Daryl Pierson and Veal, Elizabeth Ann (2016) 'Increasing extracellular H₂O₂ produces a bi-phasic response in intracellular H₂O₂, with peroxiredoxin hyperoxidation only triggered once the cellular H₂O₂-buffering capacity is overwhelmed.' Free Radical Biology and Medicine, 95. pp. 333-348. ISSN 0891-5849

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: Peroxiredoxin; Hydrogen peroxide; Thiol; Computational model; Signaling; Oxidation; Thioredoxin
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 18 Jun 2021 14:11
Last Modified: 06 Jan 2022 14:10
URI: http://repository.essex.ac.uk/id/eprint/26729

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