Hydrogen sulfide increases intracellular oxygen and regulates the HIF response

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. 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.