Hydrogen Sulfide, an Endogenous Stimulator of Mitochondrial Function in Cancer Cells

Hydrogen sulfide (H₂S) has a long history as toxic gas and environmental hazard; inhibition of cytochrome c oxidase (mitochondrial Complex IV) is viewed as a primary mode of its cytotoxic action. However, studies conducted over the last two decades unveiled multiple biological regulatory roles of H₂S as an endogenously produced mammalian gaseous transmitter. Cystathionine -lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST) are currently viewed as the principal mammalian H₂S-generating enzymes. In contrast to its inhibitory (toxicological) mitochondrial effects, at lower (physiological) concentrations, H₂S serves as a stimulator of electron transport in mammalian mitochondria, by acting as an electron donor-with sulfide:quinone oxidoreductase (SQR) being the immediate electron acceptor. The mitochondrial roles of H₂S are significant in various cancer cells, many of which exhibit high expression and partial mitochondrial localization of various H₂S producing enzymes. In addition to the stimulation of mitochondrial ATP production, the roles of endogenous H₂S in cancer cells include the maintenance of mitochondrial organization (protection against mitochondrial fission) and the maintenance of mitochondrial DNA repair (via the stimulation of the assembly of mitochondrial DNA repair complexes). The current article overviews the state-of-the-art knowledge regarding the mitochondrial functions of endogenously produced H₂S in cancer cells.