Interplay of carbon dioxide and peroxide metabolism in mammalian cells

The carbon dioxide/bicarbonate (CO₂/HCO₃^-) molecular pair is ubiquitous in mammalian cells and tissues, mainly as a result of oxidative decarboxylation reactions that occur during intermediary metabolism. CO₂ is in rapid equilibrium with HCO₃^-via the hydration reaction catalyzed by carbonic anhydrases. Far from being an inert compound in redox biology, CO₂ enhances or redirects the reactivity of peroxides, modulating the velocity, extent, and type of one- and two-electron oxidation reactions mediated by hydrogen peroxide (H₂O₂) and peroxynitrite (ONOO^-/ONOOH). Herein, we review the biochemical mechanisms by which CO₂ engages in peroxide-dependent reactions, free radical production, redox signaling, and oxidative damage. First, we cover the metabolic formation of CO₂ and its connection to peroxide formation and decomposition. Next, the reaction mechanisms, kinetics, and processes by which the CO₂/peroxide interplay modulates mammalian cell redox biology are scrutinized in-depth. Importantly, CO₂ also regulates gene expression related to redox and nitric oxide metabolism and as such influences oxidative and inflammatory processes. Accumulated biochemical evidence in vitro, in cellula, and in vivo unambiguously show that the CO₂ and peroxide metabolic pathways are intertwined and together participate in key redox events in mammalian cells.