Sulphide quinone reductase contributes to hydrogen sulphide metabolism in murine peripheral tissues but not in the CNS

Abstract

BACKGROUND AND PURPOSEHydrogen sulphide (H2S) is gaining acceptance as a gaseous signal molecule. However, mechanisms regarding signal termination are not understood. We used stigmatellin and antimycin A, inhibitors of sulphide quinone reductase (SQR), to test the hypothesis that the catabolism of H2S involves SQR. EXPERIMENTAL APPROACHH2S production and consumption were determined in living and intact mouse brain, liver and colonic muscularis externa using gas chromatography and HPLC. Expressions of SQR, ethylmalonic encephalopathy 1 (Ethe1) and thiosulphate transferase (TST; rhodanese) were determined by RT-PCR and immunohistochemistry. KEY RESULTSIn the colonic muscularis externa, H2 S that was probably bound to proteins. Levels of mRNA encoding SQR were higher in the colonic muscularis externa and the liver than in the brain. CONCLUSIONS AND IMPLICATIONSThese data support the concept that termination of endogenous H2S signalling in the colonic muscularis externa occurs via catabolism to thiosulphate and sulphate partially via a mechanism involving SQR. In the brain, it appears that H2S signal termination occurs partially through protein sequestration and partially through catabolism not involving SQR. As H2S has beneficial effects in animal models of human disease, we suggest that selective inhibition of SQR is an attractive target for pharmaceutical development. AbbreviationsDiSR, disulphide oxidoreductase flavoprotein; DTT, dithiothreitol; Ethe1, ethylmalonic encephalopathy 1; FCCP, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; GOI, gene of interest; HKG, housekeeping genes; SQR, sulphide quinone reductase; Sqrdl, sulphide quinone reductase domain-like; TRP, transient receptor potential; TST, thiosulphate sulphur transferase BJP British Journal of Pharmacology

Hydrogen sulfide as an oxygen sensor

“…In rat tissues, O 2 either inhibits H 2 S production or it may be associated with H 2 S consumption and both are reversed by hypoxia (30,44). Similar observations have been made in a variety of tissues from numerous vertebrates (32,89,94,126,128,186). A compelling argument for H 2 S-mediated O 2 sensing can be made by comparing bovine and sea lion lungs.…”

“…SQR is bound to the inner mitochondrial membrane, and it is believed that sulfur is shuttled from SQR by an as-yet unidentified mobile carrier, possibly glutathione (GSH), dihydrolipoate, Trx, or sulfite (59,63,165). SQR is found in all tissues except the brain (58,82,89) (but see ''2. ETHE1'' section), which may account for the pronounced sensitivity of the nervous system to H 2 S toxicity.…”

A Refined Analysis of Superoxide Production by Mitochondrial sn-Glycerol 3-Phosphate Dehydrogenase

“…Sulfide ubiquinone oxidoreductase is not highly expressed outside the colonic epithelium, but, of the tissues studied here, its activity has been investigated in brain and heart mitochondria (49,50). Although there was low activity observed in heart mitochondria, two studies demonstrated that there was no activity in brain tissue or mitochondria (49,50). We observe the opposite relative pattern for superoxide production assigned to mGPDH in these two tissues, indicating that sulfide ubiquinone oxidoreductase is not an important contributor to the attributed superoxide production.…”

A distal ligand mutes the interaction of hydrogen sulfide with human neuroglobin

“…Thus, whereas ␥-cystathionase is the major contributor to H 2 S generation via the transsulfuration pathway in liver (31), cystathionase ␤-synthase appears to assume this role in brain (32). The rate of H 2 S consumption in brain is ϳ6-fold slower than in liver and is insensitive to stigmatellin, an inhibitor of complex III (33). Similarly, when [ 35 S]H 2 S was used to track sulfide oxidation in brain homogenate, an insensitivity of sulfate and thiosulfate formation to stigmatellin was observed (33).…”

“…The rate of H 2 S consumption in brain is ϳ6-fold slower than in liver and is insensitive to stigmatellin, an inhibitor of complex III (33). Similarly, when [ 35 S]H 2 S was used to track sulfide oxidation in brain homogenate, an insensitivity of sulfate and thiosulfate formation to stigmatellin was observed (33). Very low levels of mRNA (and protein) encoding sulfide quinone oxidoreductase are found in brain (33).…”