Hydrogen sulfide increases intracellular oxygen and regulates the HIF response
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Le résumé fourni par la source
ABSTRACT O 2 sensing by hypoxia-inducible factor (HIF) is a principal mechanism by which aerobic organisms adjust cellular energy metabolism and adapt to O 2 limitation. In this study, we show that H 2 S, a product of host and microbial metabolism, profoundly influences the threshold for HIF-dependent hypoxia-sensing by increasing intracellular O 2 . The dose-dependent destabilization of HIF by H 2 S is inversely correlated with sulfide quinone oxidoreductase, which oxidizes sulfide in the mitochondrion. Hypoxia sensors provide a quantitative estimate of the magnitude of H 2 S-induced perturbation. The O 2 concentration in cells grown in a 2% O 2 atmosphere is sensed as 5 or 15 % O 2 in the presence of 25 or 100 ppm H 2 S, respectively. Sustained exposure to H 2 S elicits the hallmarks of hyperoxia-associated cytotoxicity, including loss of Fe-S proteins in cellular and murine models. H 2 S thus emerges as a powerful regulator of O 2 sensing and signaling with possible implications for dysregulation in O 2 toxicity diseases. Significance Statement The mitochondrial electron transport chain (ETC) accounts for ∼90% of whole body O 2 consumption. However, our understanding of how metabolites modify ETC flux and therefore, intracellular O 2 availability, are poor. In this study, we demonstrate that hydrogen sulfide (H 2 S), which is produced by host and gut microbes alike, increases intracellular O 2 by decreasing ETC flux, and destabilizes the principal hypoxia sensor, HIF-1α. The upshift in intracellular O 2 levels is quantitatively significant, such that 2% O 2 is sensed as 5-15% O 2 at varying H 2 S concentrations, with concomitant destabilization of Fe-S proteins, a signature of cellular hyperoxia. Our study identifies H 2 S as a HIF-1α regulator with important implications for the large class of mitochondrial diseases characterized by dysregulated O 2 metabolism.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Hydrogen sulfide increases intracellular oxygen and regulates the HIF response
- Date Crossref
- 24/07/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Michigan Departments of Biological Chemistry pays non établi dans la noticeUniversité ou école supérieure
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Boston College Departments of Chemistry Department pays non établi dans la noticeUniversité ou école supérieure
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Michigan Medicine pays non établi dans la noticeÉtablissement de santé
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Michigan Center for Translational Pathology pays non établi dans la noticeStructure de recherche
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Michigan Cancer Research Consortium pays non établi dans la noticeInstitution
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Departments of Molecular and Integrative Physiology pays non établi dans la noticeInstitution
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Departments of Internal Medicine pays non établi dans la noticeInstitution
Departments of Biological Chemistry — University of Michigan, Departments of Chemistry Department — Boston College et Michigan Medicine, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.