Essential role of sulfide oxidation in brain health and neurological disorders

Abstract

Hydrogen sulfide (H₂S) is an environmental hazard well known for its neurotoxicity. In mammalian cells, H₂S is predominantly generated by transsulfuration pathway enzymes. In addition, H₂S produced by gut microbiome significantly contributes to the total sulfide burden in the body. Although low levels of H₂S is believed to exert various physiological functions such as neurotransmission and vasomotor control, elevated levels of H₂S inhibit the activity of cytochrome c oxidase (i.e., mitochondrial complex IV), thereby impairing oxidative phosphorylation. To protect the electron transport chain from respiratory poisoning by H₂S, the compound is actively oxidized to form persulfides and polysulfides by a mitochondrial resident sulfide oxidation pathway. The reaction, catalyzed by sulfide:quinone oxidoreductase (SQOR), is the initial and critical step in sulfide oxidation. The persulfide species are subsequently oxidized to sulfite, thiosulfate, and sulfate by persulfide dioxygenase (ETHE1 or SDO), thiosulfate sulfurtransferase (TST), and sulfite oxidase (SUOX). While SQOR is abundantly expressed in the colon, liver, lung, and skeletal muscle, its expression is notably low in the brains of most mammals. Consequently, the brain's limited capacity to oxidize H₂S renders it particularly sensitive to the deleterious effects of H₂S accumulation. Impaired sulfide oxidation can lead to fatal encephalopathy, and the overproduction of H₂S has been implicated in the developmental delays observed in Down syndrome. Our recent findings indicate that the brain's limited capacity to oxidize sulfide exacerbates its sensitivity to oxygen deprivation. The beneficial effects of sulfide oxidation are likely to be mediated not only by the detoxification of H₂S but also by the formation of persulfide, which exerts cytoprotective effects through multiple mechanisms. Therefore, pharmacological agents designed to scavenge H₂S and/or enhance persulfide levels may offer therapeutic potential against neurological disorders characterized by impaired or insufficient sulfide oxidation or excessive H₂S production.