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.