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Sulfide (H 2 S in the gas form) is the third gaseous transmitter found in mammals. However, in contrast to nitric oxide (NO) or carbon monoxide (CO), sulfide is oxidized by a sulfide quinone reductase and generates electrons that enter the mitochondrial respiratory chain arriving ultimately at cytochrome oxidase, where they combine with oxygen to generate water. In addition, sulfide is also a strong inhibitor of cytochrome oxidase, similar to NO, CO and cyanide. The balance between the electron donor and the inhibitory role of sulfide is likely controlled by sulfide and oxygen availability. The present study aimed to evaluate if and how sulfide release and oxidation impacts on the cellular affinity for oxygen. Results : i ) when sulfide delivery approaches the maximal sulfide oxidation rate cells become exquisitely dependent on oxygen; ii ) a positive feedback makes the balance between sulfide-releasing and -oxidizing rates the relevant parameter rather than the absolute values of these rates, and; iii ) this altered dependence on oxygen is detected with sulfide concentrations that remain in the low micromolar range. Conclusions : i ) within the context of continuous release of sulfide stemming from cellular metabolism, alterations in the activity of the sulfide oxidation pathway fine-tunes the cell's affinity for oxygen, and; ii ) a decrease in the expression of the sulfide oxidation pathway greatly enhances the cell's dependence on oxygen concentration.

Sulfide shows the same toxicity as cyanide. This toxic effect results from the inhibition of the complex IV of the mitochondrial respiratory chain (cytochrome oxidase) that reduces oxygen into water. With the isolated enzyme the toxic effect is exerted in the high nanomolar range. However, significant inhibition of cellular/mitochondrial respiration needs μM concentrations (5–20 μM). In contrast at lower concentrations (nM) sulfide is an hydrogen donor used as a substrate by mitochondria in a majority of tissues/cells. The enzyme involved is a sulfide quinone reductase (SQR) associated with a dioxygenase and a sulfur transferase. Therefore according to the concentration sulfide has two opposite effects on respiration: it increases oxygen consumption and drives ATP production at low (nM) concentration whereas at high (μM) concentration sulfide inhibits respiration and has adverse effects on cellular bioenergetics. The present estimation of the endogenous sulfide release rates, the occurence of SQR in a large majority of the tissues/cells explored so far and its high affinity for sulfide make the SQR and mitochondrial respiration the major pathway maintaining intracellular sulfide in an acceptable non toxic low range of concentrations. Therefore mitochondrial respiration is both the sulfide sink and the target of sulfide toxicity. This paves the way for positive feedback effects making the orientation towards one or another of the opposite consequences of a given sulfide exposure highly sensitive to various factors. SQR is thus likely to interfere with any endogenous sulfide signaling and definitely needs to be taken into account when pharmacological intervention involves sulfide donors. The lumen of the colon hosts a bacterial communauty releasing sulfide and a value of 60 μM is proposed for the concentration of free sulfide in the human colon. Accordingly, the epithelial cells (colonocytes) are exposed to toxic sulfide concentrations. These colonocytes show a high SQR activity and cellular bioenergetics adaptations to increase their tolerance to sulfide. The mechanisms involved in mitochondrial sulfide bioenergetics as well as their consequences with regard to the signaling role of sulfide and to the use of sulfide donors will be explained.