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

Csaba Szabo

doi:10.3390/cells10020220

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 γ-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.

Highlights

Chair of Pharmacology, Section of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland; Abstract: Hydrogen sulfide (H2 S) has a long history as toxic gas and environmental hazard; inhibition of cytochrome c oxidase is viewed as a primary mode of its cytotoxic action
In 2013, we have discovered that CBS is upregulated and H2 S generation is increased in primary human colon cancer tissues compared to the surrounding tissues [50]
We have demonstrated that H2 S is an inhibitor of the mitochondrial form of cAMP phosphodiesterase (PDE2A), which, in turn, elevates mitochondrial cAMP levels and stimulates mitochondrial electron transport [93]

Summary

Upregulation of Various H2 S-Producing Enzymes in Cancer Cells

In 2013, we have discovered that CBS is upregulated and H2 S generation is increased in primary human colon cancer tissues compared to the surrounding (nominally healthy) tissues [50]. The most recent study (and, to date, the only published report focusing on the role of H2 S in mitochondrial DNA repair in cancer cells) was conducted by our group in A549 lung adenocarcinoma cells [159]. These cells show an increased expression of all 3 H2 S-producing enzymes. Oxidative mitochondrial DNA damage in these cells was increased and/or the efficacy of the DNA repair was impaired when the cells’ H2 S biosynthesis was suppressed (either by treating of the cells with the pharmacological CBS inhibitor AOAA or after siRNA-mediated silencing any of the three major H2 S-producing enzymes). Survivable mutations may even be beneficial to the tumor tissue as a whole ( not necessarily to individual cancer cells), as they might produce clones that are resistant to the body’s own immunological tumor elimination processes or to chemotherapeutic agents [160,161]

Anticancer Effects of Pharmacological H2 S Donation

Additional Mitochondrial Roles of H2 S in Cancer Cells

Conclusions and Implications