Hydrogen sulfide increases intracellular oxygen and inhibits the HIF response

Oxygen (O₂) sensing by hypoxia-inducible factor (HIF) is a principal mechanism by which aerobic organisms adjust cellular energy metabolism and adapt to O₂ limitation. In this study, we show that hydrogen sulfide (H₂S), a product of host and microbial metabolism, profoundly influences the threshold for HIF-dependent hypoxia sensing by increasing intracellular O₂. The dose-dependent destabilization of HIF by H₂S is inversely correlated with sulfide quinone oxidoreductase, which oxidizes sulfide in the mitochondrion. Hypoxia sensors provide a semiquantitative estimate of the magnitude of H₂S-induced perturbation. Thus, the O₂ concentration in cells grown in a 2% O₂ atmosphere is sensed as 5% or 15% O₂ in the presence of 25 or 100 ppm H₂S, respectively. Sustained exposure to H₂S elicits the hallmarks of hyperoxia-associated cytotoxicity, including loss of iron-sulfur proteins in cellular and murine models. H₂S thus emerges as a powerful regulator of O₂ sensing and signaling with possible implications for dysregulation in O₂ toxicity diseases.