Hydrogen sulfide increases intracellular oxygen and inhibits the HIF response

Oxygen (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 hydrogen sulfide (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 semiquantitative estimate of the magnitude of H 2 S-induced perturbation. Thus, 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 iron–sulfur 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.