Role of metabolic H2O2 generation: redox signaling and oxidative stress

Abstract

Hydrogen peroxide, the nonradical 2-electron reduction product of oxygen, is a normal aerobic metabolite occurring at about 10 nm intracellular concentration. In liver, it is produced at 50 nmol/min/g of tissue, which is about 2% of total oxygen uptake at steady state. Metabolically generated H2O2 emerged from recent research as a central hub in redox signaling and oxidative stress. Upon generation by major sources, the NADPH oxidases or Complex III of the mitochondrial respiratory chain, H2O2 is under sophisticated fine control of peroxiredoxins and glutathione peroxidases with their backup systems as well as by catalase. Of note, H2O2 is a second messenger in insulin signaling and in several growth factor-induced signaling cascades. H2O2 transport across membranes is facilitated by aquaporins, denoted as peroxiporins. Specialized protein cysteines operate as redox switches using H2O2 as thiol oxidant, making this reactive oxygen species essential for poising the set point of the redox proteome. Major processes including proliferation, differentiation, tissue repair, inflammation, circadian rhythm, and aging use this low molecular weight oxygen metabolite as signaling compound.

Keywords: Aquaporin; Catalase; Glutathione Peroxidase; Hydrogen Peroxide; Insulin; Mitochondria; NADPH Oxidase; Peroxiredoxin; Redox; Second Messenger.

FIGURE 1.

Demonstration of steady-state H₂O₂ generation in intact liver by organ spectrophotometry. A, the absorbance difference between 640 and 660 nm is used for monitoring catalase Compound I (top) and oxygen concentration in effluent perfusate (bottom). Anoxia and reoxygenation (argon and oxygen, arrows) and methanol (arrow) as hydrogen donor modulate, and thereby prove the existence of, H₂O₂ steady states; from Sies and Chance (6) with permission. B, catalase minus catalase Compound I difference spectra. Left, isolated enzyme. Right, organ difference spectrum (trace A) and cyanide difference spectrum (trace B); from Sies et al. (8) with permission.

FIGURE 2.

Production of H₂O₂ during tadpole tail regeneration. Images on the bottom show the false color representation of [H₂O₂] at 2 min post amputation (mpa) of the tadpole tail and in hours (hpa) or days (dpa) post amputation. From Love et al. (13), with permission.

FIGURE 3.

Role of sulfiredoxin (Srx) as a regulator of peroxiredoxin (Prx) function and regulation of its expression. Relationship to external stimuli is also shown. From Jeong et al. (43), with permission.