The architecture of redox microdomains: Cascading gradients and peroxiredoxins’ redox-oligomeric coupling integrate redox signaling and antioxidant protection
In the cytosol of human cells under low oxidative loads, hydrogen peroxide is confined to microdomains around its supply sites, due to its fast consumption by peroxiredoxins. So are the sulfenic and disulfide forms of the 2-Cys peroxiredoxins, according to a previous theoretical analysis [Travasso e...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723004019 |
| _version_ | 1827397786365067264 |
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| author | Matthew Griffith Adérito Araújo Rui Travasso Armindo Salvador |
| author_facet | Matthew Griffith Adérito Araújo Rui Travasso Armindo Salvador |
| author_sort | Matthew Griffith |
| collection | DOAJ |
| description | In the cytosol of human cells under low oxidative loads, hydrogen peroxide is confined to microdomains around its supply sites, due to its fast consumption by peroxiredoxins. So are the sulfenic and disulfide forms of the 2-Cys peroxiredoxins, according to a previous theoretical analysis [Travasso et al., Redox Biology 15 (2017) 297]. Here, an extended reaction-diffusion model that for the first time considers the differential properties of human peroxiredoxins 1 and 2 and the thioredoxin redox cycle predicts important new aspects of the dynamics of redox microdomains. The peroxiredoxin 1 sulfenates and disulfides are more localized than the corresponding peroxiredoxin 2 forms, due to the former peroxiredoxin's faster resolution step. The thioredoxin disulfides are also localized. As the H2O2 supply rate (vsup) approaches and then surpasses the maximal rate of the thioredoxin/thioredoxin reductase system (V), these concentration gradients become shallower, and then vanish. At low vsup the peroxiredoxin concentration determines the H2O2 concentrations and gradient length scale, but as vsup approaches V, the thioredoxin reductase activity gains influence. A differential mobility of peroxiredoxin disulfide dimers vs. reduced decamers enhances the redox polarity of the cytosol: as vsup approaches V, reduced decamers are preferentially retained far from H2O2 sources, attenuating the local H2O2 buildup. Substantial total protein concentration gradients of both peroxiredoxins emerge under these conditions, and the concentration of reduced peroxiredoxin 1 far from the H2O2 sources even increases with vsup. Altogether, the properties of 2-Cys peroxiredoxins and thioredoxin are such that localized H2O2 supply induces a redox and functional polarization between source-proximal regions (redox microdomains) that facilitate peroxiredoxin-mediated signaling and distal regions that maximize antioxidant protection. |
| first_indexed | 2024-03-08T19:17:40Z |
| format | Article |
| id | doaj.art-8baca81b17594305b878708b9bfb1c71 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-08T19:17:40Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-8baca81b17594305b878708b9bfb1c712023-12-27T05:25:45ZengElsevierRedox Biology2213-23172024-02-0169103000The architecture of redox microdomains: Cascading gradients and peroxiredoxins’ redox-oligomeric coupling integrate redox signaling and antioxidant protectionMatthew Griffith0Adérito Araújo1Rui Travasso2Armindo Salvador3CNC - Centre for Neuroscience Cell Biology, University of Coimbra, UC-Biotech, Parque Tecnológico de Cantanhede, Núcleo 4, Lote 8, 3060-197, Cantanhede, Portugal; Department of Mathematical Sciences, University of Bath, Claverton Down, Bath, BA2 7AY, UKCMUC, Department of Mathematics, University of Coimbra, Largo D. Dinis, 3004-143, Coimbra, Portugal; Corresponding author. CMUC, Department of Mathematics, University of Coimbra, Portugal, .CFisUC, Department of Physics, University of Coimbra, Coimbra, Rua Larga, 3004-516, Coimbra, Portugal; Corresponding author. CFisUC, Departamento de Física, Rua Larga, 3004-516 Coimbra, Portugal, .CNC - Centre for Neuroscience Cell Biology, University of Coimbra, UC-Biotech, Parque Tecnológico de Cantanhede, Núcleo 4, Lote 8, 3060-197, Cantanhede, Portugal; Coimbra Chemistry Center ‐ Institute of Molecular Sciences (CQC‐IMS), University of Coimbra, Rua Larga, 3004-535, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão, Rua Dom Francisco de Lemos, 3030-789, Coimbra, Portugal; Corresponding author. Center for Neuroscience and Cell Biology, University of Coimbra, Portugal, .In the cytosol of human cells under low oxidative loads, hydrogen peroxide is confined to microdomains around its supply sites, due to its fast consumption by peroxiredoxins. So are the sulfenic and disulfide forms of the 2-Cys peroxiredoxins, according to a previous theoretical analysis [Travasso et al., Redox Biology 15 (2017) 297]. Here, an extended reaction-diffusion model that for the first time considers the differential properties of human peroxiredoxins 1 and 2 and the thioredoxin redox cycle predicts important new aspects of the dynamics of redox microdomains. The peroxiredoxin 1 sulfenates and disulfides are more localized than the corresponding peroxiredoxin 2 forms, due to the former peroxiredoxin's faster resolution step. The thioredoxin disulfides are also localized. As the H2O2 supply rate (vsup) approaches and then surpasses the maximal rate of the thioredoxin/thioredoxin reductase system (V), these concentration gradients become shallower, and then vanish. At low vsup the peroxiredoxin concentration determines the H2O2 concentrations and gradient length scale, but as vsup approaches V, the thioredoxin reductase activity gains influence. A differential mobility of peroxiredoxin disulfide dimers vs. reduced decamers enhances the redox polarity of the cytosol: as vsup approaches V, reduced decamers are preferentially retained far from H2O2 sources, attenuating the local H2O2 buildup. Substantial total protein concentration gradients of both peroxiredoxins emerge under these conditions, and the concentration of reduced peroxiredoxin 1 far from the H2O2 sources even increases with vsup. Altogether, the properties of 2-Cys peroxiredoxins and thioredoxin are such that localized H2O2 supply induces a redox and functional polarization between source-proximal regions (redox microdomains) that facilitate peroxiredoxin-mediated signaling and distal regions that maximize antioxidant protection.http://www.sciencedirect.com/science/article/pii/S2213231723004019Redox microdomainsHydrogen peroxidePeroxiredoxinsRedox signalingReaction-diffusion modelTotal protein concentration gradients |
| spellingShingle | Matthew Griffith Adérito Araújo Rui Travasso Armindo Salvador The architecture of redox microdomains: Cascading gradients and peroxiredoxins’ redox-oligomeric coupling integrate redox signaling and antioxidant protection Redox Biology Redox microdomains Hydrogen peroxide Peroxiredoxins Redox signaling Reaction-diffusion model Total protein concentration gradients |
| title | The architecture of redox microdomains: Cascading gradients and peroxiredoxins’ redox-oligomeric coupling integrate redox signaling and antioxidant protection |
| title_full | The architecture of redox microdomains: Cascading gradients and peroxiredoxins’ redox-oligomeric coupling integrate redox signaling and antioxidant protection |
| title_fullStr | The architecture of redox microdomains: Cascading gradients and peroxiredoxins’ redox-oligomeric coupling integrate redox signaling and antioxidant protection |
| title_full_unstemmed | The architecture of redox microdomains: Cascading gradients and peroxiredoxins’ redox-oligomeric coupling integrate redox signaling and antioxidant protection |
| title_short | The architecture of redox microdomains: Cascading gradients and peroxiredoxins’ redox-oligomeric coupling integrate redox signaling and antioxidant protection |
| title_sort | architecture of redox microdomains cascading gradients and peroxiredoxins redox oligomeric coupling integrate redox signaling and antioxidant protection |
| topic | Redox microdomains Hydrogen peroxide Peroxiredoxins Redox signaling Reaction-diffusion model Total protein concentration gradients |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723004019 |
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