Hydrogen sulfide increases intracellular oxygen and inhibits the HIF response

TL;DR

Hydrogen sulfide increases cell oxygen levels and disrupts hypoxia sensing, potentially affecting oxygen-related diseases.

Contribution

The study reveals that H2S modulates intracellular oxygen sensing and HIF response, offering new insights into oxygen regulation.

Findings

Hydrogen sulfide increases intracellular oxygen and destabilizes HIF in a dose-dependent manner.

Sustained H2S exposure causes hyperoxia-like toxicity, including loss of iron–sulfur proteins in models.

H2S alters perceived oxygen levels, shifting hypoxia sensing in low-oxygen environments.

Abstract

Oxygen (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 hydrogen sulfide (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 semiquantitative estimate of the magnitude of H2S-induced perturbation. Thus, 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 iron–sulfur 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.

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