How Gradients and Microdomains Determine H2O2 Redox Signaling

Hydrogen peroxide (H₂O₂) plays a central role in cellular signaling, but its signaling mechanisms are just beginning to be understood. Here we analyze and review the evidence about the spatial distribution of H₂O₂ in cells and its implications for redox relays, H₂O₂ channeling, and other redox signaling mechanisms. Altogether, theoretical and experimental approaches consistently support the conclusions that (1) basal mean cytosolic H₂O₂ concentrations in eukaryotic cells do not exceed the low-nanomolar range; (2) at low oxidative loads cytosolic H₂O₂ is confined to microdomains; (3) transmembrane gradients in cells exposed to sub-micromolar H₂O₂ are at least in the mid-hundredfold scale; (4) the low cytosolic H₂O₂ concentrations, their uneven spatial distribution, and the strong transmembrane gradients are mainly a consequence of the action of the peroxiredoxin/thioredoxin/thioredoxin reductase system; (5) the efficacy of the signal transmission by redox switches is modulated by their oxidation and reduction; (6) in the cytosol, signaling at low oxidative loads proceeds mainly by the formation of local microdomains, where oxidized forms of peroxiredoxins are also concentrated; and (7) in cellular compartments with higher levels of H₂O₂, like the endoplasmic reticulum, channeling H₂O₂ directly to the target is expected to constitute an important mechanism underlying signal transmission.