GAPDH inhibition mediated by thiol oxidation in human airway epithelial cells exposed to an environmental peroxide

• Published in: Redox biology Vol. 73; p. 103199
• Main Authors: Masood, Syed, Kim, Hye-Young H., Pennington, Edward R., Tallman, Keri A., Porter, Ned A., Bromberg, Philip A., Rice, Rebecca L., Gold, Avram, Zhang, Zhenfa, Samet, James M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-07-2024; Elsevier
• Subjects: Air pollution; Cellular bioenergetics; Epithelial Cells - drug effects; Epithelial Cells - metabolism; GAPDH (glyceraldehyde-3-phosphate dehydrogenase); Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism; Hemiterpenes - metabolism; Humans; Oxidation-Reduction; Oxidative stress; Oxidative Stress - drug effects; Peroxides - metabolism; Protein thiol oxidation; Research Paper; Secondary organic aerosols; Sulfhydryl Compounds - metabolism; GAPDH (glyceraldehyde-3-phosphate dehydrogenase); Oxidative stress; Air pollution; Secondary organic aerosols; Cellular bioenergetics; Protein thiol oxidation
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2024.103199

Intracellular redox homeostasis in the airway epithelium is closely regulated through adaptive signaling and metabolic pathways. However, inhalational exposure to xenobiotic stressors such as secondary organic aerosols (SOA) can alter intracellular redox homeostasis. Isoprene hydroxy hydroperoxide (ISOPOOH), a ubiquitous volatile organic compound derived from the atmospheric photooxidation of biogenic isoprene, is a major contributor to SOA. We have previously demonstrated that exposure of human airway epithelial cells (HAEC) to ISOPOOH induces oxidative stress through multiple mechanisms including lipid peroxidation, glutathione oxidation, and alterations of glycolytic metabolism. Using dimedone-based reagents and copper catalyzed azo-alkynyl cycloaddition to tag intracellular protein thiol oxidation, we demonstrate that exposure of HAEC to micromolar levels of ISOPOOH induces reversible oxidation of cysteinyl thiols in multiple intracellular proteins, including GAPDH, that was accompanied by a dose-dependent loss of GAPDH enzymatic activity. These results demonstrate that ISOPOOH induces an oxidative modification of intracellular proteins that results in loss of GAPDH activity, which ultimately impacts the dynamic regulation of the intracellular redox homeostatic landscape in HAEC.
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•Exposure to ISOPOOH induces oxidative protein modifications in HAEC.•ISOPOOH induces reversible inhibition of GAPDH activity in HAEC.•ISOPOOH induces GAPDH oxidation including sulfonylation in HAEC.•GAPDH inhibition underlies metabolic adaptation to ISOPOOH redox stress.