Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress

Abstract

Hydrogen peroxide emerged as major redox metabolite operative in redox sensing, signaling and redox regulation. Generation, transport and capture of H₂O₂ in biological settings as well as their biological consequences can now be addressed. The present overview focuses on recent progress on metabolic sources and sinks of H₂O₂ and on the role of H₂O₂ in redox signaling under physiological conditions (1-10nM), denoted as oxidative eustress. Higher concentrations lead to adaptive stress responses via master switches such as Nrf2/Keap1 or NF-κB. Supraphysiological concentrations of H₂O₂ (>100nM) lead to damage of biomolecules, denoted as oxidative distress. Three questions are addressed: How can H₂O₂ be assayed in the biological setting? What are the metabolic sources and sinks of H₂O₂? What is the role of H₂O₂ in redox signaling and oxidative stress?

Keywords: H(2)O(2); Mitochondria; NADPH oxidases; Oxidative stress; Peroxiporins; Redox regulation.

Graphical abstract

Fig. 1

Timeline of hydrogen peroxide in chemistry and biology.

Fig. 2

Quantification of H₂O₂ production in intact perfused rat liver during decanoate oxidation. Catalase Compound I is monitored at 660–640 nm continuously against time by organ spectrophotometry. Calibration of the decanoate response is performed against the urate response. With the 1:1 stoichiometry of urate:H₂O₂ and measurement of the rate of urate removal in the effluent perfusate, the decanoate response is quantified to indicate an extra H₂O₂ production of 80 nmol H₂O₂/min per gram liver wet weight in this experiment. For details, see , .

Fig. 3

Role of hydrogen peroxide in oxidative stress. Top: Endogenous H₂O₂ sources include NADPH oxidases and other oxidases (membrane-bound or free) as well as the mitochondria. The superoxide anion radical is converted to hydrogen peroxide by the three superoxide dismutases (SODs 1,2,3). Hydrogen peroxide diffusion across membranes occurs by some aquaporins (AQP), known as peroxiporins. Bottom: In green, redox signaling comprises oxidative eustress (physiological oxidative stress). In red, excessive oxidative stress leads to oxidative damage of biomolecules and disrupted redox signaling, oxidative distress. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Estimated ranges of hydrogen peroxide concentration in oxidative stress with regard to cellular responses. The intracellular physiological range likely spans between 1 and 10 up to approx. 100 nM H₂O₂; the arrow indicates data from normally metabolizing liver. Stress and adaptive stress responses occur at higher concentrations. Even higher exposure leads to inflammatory response, growth arrest and cell death by various mechanisms. Green and red coloring denotes predominantly beneficial or deleterious responses, respectively. An estimated 100-fold concentration gradient from extracellular to intracellular is given for rough orientation; this gradient will vary with cell type, location inside cells and the activity of enzymatic sinks (see text). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)