Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics

It is well established that exposure of mammalian cells to hydrogen sulfide (H2S) suppresses mitochondrial function by inhibiting cytochrome-c oxidase (CcOX; complex IV). However, recent experimental data show that administration of H2S to mammalian cells can serve as an electron donor and inorganic source of energy. The aim of our study was to investigate the role of endogenously produced H2S in the regulation of mitochondrial electron transport and oxidative phosphorylation in isolated liver mitochondria and in the cultured murine hepatoma cell line Hepa1c1c7. Low concentrations of H2S (0.1-1 mu M) elicited a significant increase in mitochondrial function, while higher concentrations of H2S (3-30 mu M) were inhibitory. The positive bioenergetic effect of H2S required a basal activity of the Krebs cycle and was most pronounced at intermediate concentrations of succinate. 3-mercaptopyruvate (3-MP), the substrate of the mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) stimulated mitochondrial H2S production and enhanced mitochondrial electron transport and cellular bioenergetics at low concentrations (10-100 nM), while at higher concentrations, it inhibited cellular bioenergetics. SiRNA silencing of 3-MST reduced basal bioenergetic parameters and prevented the stimulating effect of 3-MP on mitochondrial bioenergetics. Silencing of sulfide quinone oxidoreductase (SQR) also reduced basal and 3-MP-stimulated bioenergetic parameters. We conclude that an endogenous intramitochondrial H2S-producing pathway, governed by 3-MST, complements and balances the bioenergetic role of Krebs cycle-derived electron donors. This pathway may serve a physiological role in the maintenance of mitochondrial electron transport and cellular bioenergetics.-Modis, K., Coletta, C., Erdelyi, K., Papapetropoulos, A., Szabo, C. Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics. FASEB J. 27, 601-611 (2013). www.fasebj.org