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Regulation of dual oxidase hydrogen peroxide synthesis results in an epithelial respiratory burst.

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.

SUBMITTER: Conner GE

PROVIDER: S-EPMC8010520 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In humans, sulfite is generated endogenously by the metabolism of sulfur containing amino acids such as methionine and cysteine. Sulfite is also formed from exposure to sulfur dioxide, one of the major environmental pollutants. Sulfite is used as an antioxidant and preservative in dried fruits, vegetables, and beverages such as wine. Sulfite is also used as a stabilizer in many drugs. Sulfite toxicity has been associated with allergic reactions characterized by sulfite sensitivity, asthma, and anaphylactic shock. Sulfite is also toxic to neurons and cardiovascular cells. Recent studies suggest that the cytotoxicity of sulfite is mediated by free radicals; however, molecular mechanisms involved in sulfite toxicity are not fully understood. Cytochrome c (cyt c) is known to participate in mitochondrial respiration and has antioxidant and peroxidase activities. Studies were performed to understand the related mechanism of oxidation of sulfite and radical generation by ferric cytochrome c (Fe3+ cyt c) in the absence and presence of H2O2. Electron paramagnetic resonance (EPR) spin trapping studies using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) were performed with sulfite, Fe3+ cyt c, and H2O2. An EPR spectrum corresponding to the sulfite radical adducts of DMPO (DMPO-SO3-) was obtained. The amount of DMPO-SO3- formed from the oxidation of sulfite by the Fe3+ cyt c increased with sulfite concentration. In addition, the amount of DMPO-SO3- formed by the peroxidase activity of Fe3+ cyt c also increased with sulfite and H2O2 concentration. From these results, we propose a mechanism in which the Fe3+ cyt c and its peroxidase activity oxidizes sulfite to sulfite radical. Our results suggest that Fe3+ cyt c could have a novel role in the deleterious effects of sulfite in biological systems due to increased production of sulfite radical. It also shows that the increased production of sulfite radical may be responsible for neurotoxicity and some of the injuries which occur to humans born with molybdenum cofactor and sulfite oxidase deficiencies.

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Regulation of dual oxidase hydrogen peroxide synthesis results in an epithelial respiratory burst.

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