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.