Until recently, hydrogen sulfide (H2S) was exclusively viewed a toxic gas and an environmental hazard, with its toxicity primarily attributed to the inhibition of mitochondrial Complex IV, resulting in a shutdown of mitochondrial electron transport and cellular ATP generation. Work over the last decade established multiple biological regulatory roles of H2S, as an endogenous gaseous transmitter. H2S is produced by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). In striking contrast to its inhibitory effect on Complex IV, recent studies showed that at lower concentrations, H2S serves as a stimulator of electron transport in mammalian cells, by acting as a mitochondrial electron donor. Endogenous H2S, produced by mitochondrially localized 3-MST, supports basal, physiological cellular bioenergetic functions; the activity of this metabolic support declines with physiological aging. In specialized conditions (calcium overload in vascular smooth muscle, colon cancer cells), CSE and CBS can also associate with the mitochondria; H2S produced by these enzymes, serves as an endogenous stimulator of cellular bioenergetics. The current article overviews the biochemical mechanisms underlying the stimulatory and inhibitory effects of H2S on mitochondrial function and cellular bioenergetics and discusses the implication of these processes for normal cellular physiology. The relevance of H2S biology is also discussed in the context of colonic epithelial cell physiology: colonocytes are exposed to high levels of sulfide produced by enteric bacteria, and serve as a metabolic barrier to limit their entry into the mammalian host, while, at the same time, utilizing it as a metabolic 'fuel'.

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Hydrogen sulfide (H2S) is produced inside the intestine and is known as a poison that inhibits cellular respiration at the level of cytochrome oxidase. However, sulfide is used as an energetic substrate by many photo- and chemoautotrophic bacteria and by animals such as the lugworm Arenicola marina. The concentrations of sulfide present in their habitats are comparable with those present in the human colon. Using permeabilized colonic cells to which sulfide was added by an infusion pump we show that the maximal respiratory rate of colonocyte mitochondria in presence of sulfide compares with that obtained with succinate or L-alpha-glycerophosphate. This oxidation is accompanied by mitochondrial energization. In contrast, other cell types not naturally exposed to high concentration of sulfide showed much lower oxidation rates. Mitochondria showed a very high affinity for sulfide that permits its use as an energetic substrate at low micromolar concentrations, hence, below the toxic level. However, if the supply of sulfide exceeds the oxidation rate, poisoning renders mitochondria inefficient and our data suggest that an anaerobic mechanism involving partial reversion of Krebs cycle already known in invertebrates takes place. In conclusion, this work provides additional and compelling evidence that sulfide is not only a toxic compound. According to our study, sulfide appears to be the first inorganic substrate for mammalian cells characterized thus far.

Sulfide (H2S) is an inhibitor of mitochondrial cytochrome oxidase comparable to cyanide. In this study, poisoning of cells was observed with sulfide concentrations above 20 microM. Sulfide oxidation has been shown to take place in organisms/cells naturally exposed to sulfide. Sulfide is released as a result of metabolism of sulfur containing amino acids. Although in mammals sulfide exposure is not thought to be quantitatively important outside the colonic mucosa, our study shows that a majority of mammalian cells, by means of the mitochondrial sulfide quinone reductase (SQR), avidly consume sulfide as a fuel. The SQR activity was found in mitochondria isolated from mouse kidneys, liver, and heart. We demonstrate the precedence of the SQR over the mitochondrial complex I. This explains why the oxidation of the mineral substrate sulfide takes precedence over the oxidation of other (carbon-based) mitochondrial substrates. Consequently, if sulfide delivery rate remains lower than the SQR activity, cells maintain a non-toxic sulfide concentration (<1 microM) in their external environment. In the colonocyte cell line HT-29, sulfide oxidation provided the first example of reverse electron transfer in living cells, such a transfer increasing sulfide tolerance. However, SQR activity was not detected in brain mitochondria and neuroblastoma cells. Consequently, the neural tissue would be more sensitive to sulfide poisoning. Our data disclose new constraints concerning the emerging signaling role of sulfide.