Power and poison: The intersections of H2S and O2 metabolism

The metabolic interaction between hydrogen sulfide (H2S) and oxygen (O2) exemplifies the interplay between chemical power and poison at the electron transport chain as these gases influence the conversion of nutrient energy to cellular currency. H2S is a product of mammalian and microbial metabolism and is both an inorganic nutrient and a respiratory poison. In its former role, H2S transfers its reducing power to coenzyme Q as it is oxidized by sulfide quinone oxidoreductase in the inner mitochondrial membrane. As a respiratory poison, H2S inhibits complex IV and profoundly influences intracellular O2 levels with pleiotropic effects on hypoxia sensing and signaling, and on cellular metabolism, glimpses of which are only just beginning to emerge. The high concentration of luminal sulfide in the lower gut, combined with the steep radial O2 gradient, ranging from a virtually anoxic lumen to a highly vascular lamina propria, raises many questions about how the interaction between these gases plays out with local and long-range impacts on biology. Their interaction is equally germane in other hypoxic tissues where endogenous H2S production and/or constitutively low-sulfide oxidation capacity could potentially dial up O2 availability. Importantly, H2S oxidation can prevail even when its concentration rises to levels that poison complex IV and is enabled by rerouting electrons through complex II, using fumarate as a terminal electron acceptor. Methodological advancements that support the quantitative analysis of in vivo models will be critical for broadening our understanding of the metabolic and physiological import of the O2–H2S interplay.