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; Day, Alison M.; Underwood, Zoe; Smith, Graham R.; Pezze, Piero Dalle; Rallis, Charalampos; Patel, Waseema; Dickinson, Bryan C.; Bähler, Jürg; Brewer, Thomas F.; Chang, Christopher J.; Shanley, Daryl P.; Veal, Elizabeth A.

doi:10.1016/j.freeradbiomed.2016.02.035

Cited by 44 publications

(45 citation statements)

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“…ROS molecules can have a signaling function, capable of regulating diverse biological processes . Low levels of ROS can elicit a biphasic response promoting fundamental processes, such as growth, differentiation and migration . This was observed here for low levels of peroxide when compared to control (Figs.…”

Section: Discussionsupporting

confidence: 61%

Resistance to Hydrogen Peroxide Highlights Gymnodinium catenatum (Dinophyceae) Sensitivity to Geomagnetic Activity

Vale

2017

Photochem & Photobiology

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The chain-forming dinoflagellate Gymnodinium catenatum was exposed to hydrogen peroxide. Microscopical examination revealed striking dose-response alterations in chain formation above 245 lM: singlets replaced the dominance of long chain formations. These observations were valid for cells acclimated to halogen light. Under fluorescent light, cells were more resistant to modifications in chain length after H 2 O 2 exposure. Growth along 9 h in the presence of extracellular H 2 O 2 followed an hormesis response in both light regimes. Under halogen light conditions, alterations in chain formation and net growth were related to culture time, inocula concentration and geomagnetic activity (GMA) in the proceeding hours. Below a 16 nT threshold in GMA average growth was 0%, while above 16 nT it was circa +9%, independently if the local static magnetic field was altered by a permanent magnet or not. Mycosporine-like amino acids that can have an antioxidant role and are easily oxidized decreased from 7.1 to 6.5 pg cell À1 (P < 0.05) under halogen light and exposure to 245 lM H 2 O 2 . GMA, as well as UV-A, increased stress responsiveness that can momentarily protect cells from extracellular H 2 O 2 addition. However, stress response is dependent on bio-availability of several micronutrients and macronutrients, many found at limiting concentrations in oceanic waters.

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Section: Discussionsupporting

confidence: 61%

Resistance to Hydrogen Peroxide Highlights Gymnodinium catenatum (Dinophyceae) Sensitivity to Geomagnetic Activity

Vale

2017

Photochem & Photobiology

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“…Surprisingly, this simple model for HEK293 cells (with T Trx  1.5 M) shows very good agreement with the experimental observations [19] of a threshold H2O2 bolus beyond which Prx hyperoxidation starts increasing, and intracellular H2O2 increases more steeply (SF10B,C).…”

Section: Pttrs Dynamicssupporting

confidence: 77%

“…Instead, our results (SF11) indicate that the threshold behavior described in ref. [19] is intrinsic to the dynamics of the PTTRS. Concretely, the steeper increase in cytoplasmic H2O2 concentration and hyperoxidation starts once the bolus becomes sufficient to fully oxidize Prx to Prx-SS, thereby sharply decreasing the cytoplasmic H2O2 clearance rate.…”

Section: Pttrs Dynamicsmentioning

confidence: 99%

“…In the latter case that fraction peaked at 80% for a 25 M bolus and progressively decreased for increasing boluses, presumably due to increasing double hyperoxidation of the dimers preventing disulfide formation. Tomalin et al [19] reported that treatment of 2×10 6 HEK293 cells/mL with 10 -80 M H2O2 boluses for 10 min caused a progressive increase in total hyperoxidation only after a 20 M H2O2 bolus threshold.…”

Section: Introductionmentioning

confidence: 99%

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Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin – thioredoxin system. 1. Understanding commonalities and differences among cell types

Selvaggio

Coelho

Salvador

2017

Preprint

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The system (PTTRS) formed by typical 2-Cys peroxiredoxins (Prx), thioredoxin (Trx), Trx reductase (TrxR), and sulfiredoxin (Srx) is central in antioxidant protection and redox signaling in the cytoplasm of eukaryotic cells. Understanding how the PTTRS integrates these functions requires tracing phenotypes to molecular properties, which is non-trivial. Here we analyze this problem based on a model that captures the PTTRS’ conserved features. We have mapped the conditions that generate each distinct response to H2O2 supply rates (νsup), and estimated the parameters for thirteen human cell types and for Saccharomyces cerevisiae. The resulting composition-to-phenotype map yielded the following experimentally testable predictions. The PTTRS permits many distinct responses including ultra-sensitivity and hysteresis. However, nearly all tumor cell lines showed a similar response characterized by limited Trx-S- depletion and a substantial but self-limited gradual accumulation of hyperoxidized Prx at high νsup. This similarity ensues from strong correlations between the TrxR, Srx and Prx activities over cell lines, which contribute to maintain the Prx-SS reduction capacity in slight excess over the maximal steady state Prx-SS production. In turn, in erythrocytes, hepatocytes and HepG2 cells high νsup depletes Trx-S- and oxidizes Prx mainly to Prx-SS. In all nucleated human cells the Prx-SS reduction capacity defined a threshold separating two different regimes. At sub-threshold νsup cytoplasmic H2O2 is determined by Prx, nM-range and spatially localized, whereas at supra-threshold νsup it is determined by much less active alternative sinks and μM-range throughout the cytoplasm. The yeast shows a distinct response where the Prx Tsa1 accumulates in sulfenate form at high νsup. This is mainly due to an exceptional stability of Tsa1’s sulfenate.The implications of these findings for thiol redox regulation and cell physiology are discussed. All estimates were thoroughly documented and provided, together with analytical approximations for system properties, as a resource for quantitative redox biology.AbbreviationsASK1, apoptosis signal-regulating kinase 1; Cat, catalase; GSH, glutathione; GPx1, glutathione peroxidase 1; Grx, glutaredoxin; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2-related factor 2; Prx, typical 2-Cys peroxiredoxin; PTTRS, peroxiredoxin / thioredoxin / thioredoxin reductase system; Srx, sulfiredoxin; Trx, thioredoxin; TrxR, thioredoxin reductase.

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“…Mathematical modeling has proved useful in assessing previous hypotheses and suggest new ones about the operation of thiol redox systems [39,16,40,18,19,41]. Here we draw on the present knowledge of the reactivity and cellular concentrations of 2-Cys peroxiredoxins, sulfiredoxin (Srx) and thioredoxin 1 (Trx1) [5,6,12,13,42,9,1] and apply an integrative computational approach to address the four questions raised above.…”

Section: Introductionmentioning

confidence: 99%

Localized redox relays as a privileged mode of cytoplasmic hydrogen peroxide signaling

Travasso

Aidos

Abranches

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C THydrogen peroxide (H 2 O 2 ) is a key signaling agent. Its best characterized signaling actions in mammalian cells involve the early oxidation of thiols in cytoplasmic phosphatases, kinases and transcription factors. However, these redox targets are orders of magnitude less H 2 O 2 -reactive and abundant than cytoplasmic peroxiredoxins. How can they be oxidized in a signaling time frame? Here we investigate this question using computational reaction-diffusion models of H 2 O 2 signaling. The results show that at H 2 O 2 supply rates commensurate with mitogenic signaling a H 2 O 2 concentration gradient with a length scale of a few tenths of μm is established. Even near the supply sites H 2 O 2 concentrations are far too low to oxidize typical targets in an early mitogenic signaling time frame. Furthermore, any inhibition of the peroxiredoxin or increase in H 2 O 2 supply able to drastically increase the local H 2 O 2 concentration would collapse the concentration gradient and/or cause an extensive oxidation of the peroxiredoxins I and II, inconsistent with experimental observations. In turn, the local concentrations of peroxiredoxin sulfenate and disulfide forms exceed those of H 2 O 2 by several orders of magnitude. Redox targets reacting with these forms at rate constants much lower than that for, say, thioredoxin could be oxidized within seconds. Moreover, the spatial distribution of the concentrations of these peroxiredoxin forms allows them to reach targets within 1 μm from the H 2 O 2 sites while maintaining signaling localized. The recruitment of peroxiredoxins to specific sites such as caveolae can dramatically increase the local concentrations of the sulfenic and disulfide forms, thus further helping these species to outcompete H 2 O 2 for the oxidation of redox targets. Altogether, these results suggest that H 2 O 2 signaling is mediated by localized redox relays whereby peroxiredoxins are oxidized to sulfenate and disulfide forms at H 2 O 2 supply sites and these forms in turn oxidize the redox targets near these sites.

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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

Cited by 44 publications

References 56 publications

Resistance to Hydrogen Peroxide Highlights Gymnodinium catenatum (Dinophyceae) Sensitivity to Geomagnetic Activity

Resistance to Hydrogen Peroxide Highlights Gymnodinium catenatum (Dinophyceae) Sensitivity to Geomagnetic Activity

Mapping the phenotypic repertoire of the cytoplasmic 2-Cys peroxiredoxin – thioredoxin system. 1. Understanding commonalities and differences among cell types

Localized redox relays as a privileged mode of cytoplasmic hydrogen peroxide signaling

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