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 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 HO supply rate (v) approaches and then surpasses the maximal rate of the thioredoxin/thioredoxin reductase system (V), these concentration gradients become shallower, and then vanish. At low v the peroxiredoxin concentration determines the HO concentrations and gradient length scale, but as v 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 v approaches V, reduced decamers are preferentially retained far from HO sources, attenuating the local HO buildup. Substantial total protein concentration gradients of both peroxiredoxins emerge under these conditions, and the concentration of reduced peroxiredoxin 1 far from the HO sources even increases with v. Altogether, the properties of 2-Cys peroxiredoxins and thioredoxin are such that localized HO 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.