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

Abstract

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.

Keywords: ATP; DNA repair; bioenergetics; gasotransmitters.

Figure 1

Mechanisms by which mitochondrial H₂S (produced by CBS, CSE or 3-MST) can stimulate mitochondrial electron transport and aerobic ATP generation in cancer cells. #1: H₂S acts as a direct electron donor at the level of SQR, which feeds electrons into the electron transport chain at the level of Complex II. #2: H₂S inhibits intramitochondrial cAMP phosphodiesterase; this results in an elevation of intramitochondrial cAMP, which, in turn, phosphorylates electron transport chain proteins via the activation of intramitochondrial cAMP-dependent protein kinases. #3: H₂S acts as direct stimulator of ATP synthase activity via sulfhydration of the α subunit (ATP5A1) at Cys 244 and Cys 294.

Figure 2

Due to the bell-shaped/biphasic pharmacological character of H₂S, pharmacological inhibitors of H₂S biosynthesis (via the removal of the stimulatory effects of endogenously produced, CBS, CSE or 3-MST-derived H₂S) as well as exogenous, pharmacological H₂S donor compounds (via stimulation of multiple cytostatic and cytotoxic mechanisms) can exert anticancer effects.