Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms

Abstract

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'.

A Fast Hydrogen Sulfide–Releasing Donor Increases the Tumor Response to Radiotherapy

“…At lower sulfide concentration, the affinity of H 2 S for the heme center of cytochrome C oxidase is too low to produce detectable inhibition of the enzyme (2), justifying the absence of OCR inhibition at lower NaHS concentrations. Hence, the trend toward an increased OCR in cells exposed to 1.5 mmol/L NaHS corroborates that H 2 S may also act as a mitochondrial electron donor when present in low concentration (26). At 100 mmol/L NaHS, the same OCR inhibition as with rotenone, an inhibitor of mitochondrial respiration, was observed.…”

Hydrogen sulfide as an oxygen sensor

“…As described earlier, cells can use H 2 S as a substrate for ATP production and this can serve as an endogenous stimulator of cellular bioenergetics (49,157). These possibilities are currently being explored, albeit with limited success thus far, in protecting tissue from ischemia/reperfusion injury, organ preservation before transplantation, protective metabolic depression during bypass surgery or after severe trauma associated with shock, sepsis, and acute lung injury.…”

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid

“…We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may exert adverse effects on cellular homeostasis (20,21). Given the importance of H 2 S as a vasorelaxant (22)(23)(24)(25)(26)(27)(28)(29), proangiogenic agent (27,(30)(31)(32)(33)(34)(35)(36) and mitochondrial/bioenergetic modulator (20,21,35,(37)(38)(39)(40)(41)(42), here we examined whether the 3-MST/H 2 S system plays physiological regulatory roles in endothelial cells. Next, we examined whether a dysfunction of the 3-MST/H 2 S system develops in hyperglycemia/diabetes and tested whether this dysfunction can be corrected by DL-α-lipoic acid (LA), a known antioxidant and 3-MST cofactor (43)(44)(45).…”