Hydrogen sulfide increases intracellular oxygen and regulates the HIF response

Abstract

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 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 quantitative estimate of the magnitude of H2S-induced perturbation. 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 Fe-S 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. Significance StatementThe mitochondrial electron transport chain (ETC) accounts for [~]90% of whole body O2 consumption. However, our understanding of how metabolites modify ETC flux and therefore, intracellular O2 availability, are poor. In this study, we demonstrate that hydrogen sulfide (H2S), which is produced by host and gut microbes alike, increases intracellular O2 by decreasing ETC flux, and destabilizes the principal hypoxia sensor, HIF-1. The upshift in intracellular O2 levels is quantitatively significant, such that 2% O2 is sensed as 5-15% O2 at varying H2S concentrations, with concomitant destabilization of Fe-S proteins, a signature of cellular hyperoxia. Our study identifies H2S as a HIF-1 regulator with important implications for the large class of mitochondrial diseases characterized by dysregulated O2 metabolism.