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.