Abstract
Redox status is a central determinant of cellular activities and redox imbalance is correlated with numerous diseases. NADPH oxidase activity results in formation of H2O2, that, in turn, sets cellular redox status, a key regulator of cellular homeostasis and responses to external stimuli. Hydrogen peroxide metabolism regulates cell redox status by driving changes in protein cysteine oxidation often via cycling of thioredoxin/peroxiredoxin and glutathione; however, regulation of enzymes controlling synthesis and utilization of H2O2 is not understood beyond broad outlines. The data presented here show that calcium-stimulated epithelial Duox H2O2 synthesis is transient, independent of intracellular calcium renormalization, H2O2 scavenging by antioxidant enzymes, or substrate depletion. The data support existence of a separate mechanism that restricts epithelial H2O2 synthesis to a burst and prevents harmful changes in redox tone following continuous stimulation. Elucidation of this H2O2 synthesis tempering mechanism is key to understanding cellular redox regulation and control of downstream effectors, and this observation provides a starting point for investigation of the mechanism that controls H2O2-mediated increases in redox tone.