Redox Biology of Hydrogen Sulfide: Implications for Physiology, Pathophysiology, and Pharmacology

Abstract

Hydrogen sulfide (H₂S) has emerged as a critical mediator of multiple physiological processes in mammalian systems. The pathways involved in the production, consumption, and mechanism of action of H₂S appear to be sensitive to alterations in the cellular redox state and O₂ tension. Indeed, the catabolism of H₂S through a putative oxidation pathway, the sulfide quinone oxido-reductase system, is highly dependent on O₂ tension. Dysregulation of H₂S homeostasis has also been implicated in numerous pathological conditions and diseases. In this review, the chemistry and the main physiological actions of H₂S are presented. Some examples highlighting the cytoprotective actions of H₂S within the context of cardiovascular disease are also reported. Elucidation of the redox biology of H₂S will enable the development of new pharmacological agents based on this intriguing new redox cellular signal.

Keywords: hydrogen sulfide; mitochondria; oxidative stress; oxygen; redox biology.

Graphical abstract

Fig. 1

The enzymatic production of H₂S. The two primary enzymes responsible for H₂S production, cystathionine-γ-lyase (CGL) and cystathionine-β-synthase (CBS), are found in the cytosol. CBS catalyzes the first step in H₂S production through the transsulfuration of homocysteine to cystathionine. CGL in an elimination reaction catalyzes the formation of cysteine and α-ketobutyrate. Cysteine is the substrate from which H₂S is directly produced either through elimination (CGL) or β-replacement (CBS). Cysteine amino transferase (CAT) catalyzes the formation of 3-mercaptopyruvate, a substrate for the mitochondrial enzyme 3-mercaptopyruvate-S-transferase (3-MST). 3-MST can directly produce H₂S, albeit at lower levels than CBS and CGL, in mitochondria.

Fig. 2

Proposed pathways of H₂S removal in mammalian cells. The physiological steady-state concentration of H₂S in vivo is believed to be maintained in the sub-micromolar range. This steady state concentration is established by the production pathways shown in Fig. 1 and the proposed consumption pathways shown within this figure. H₂S will react non-enzymatically with many biomolecules such as reactive oxygen and nitrogen species, electrophilic lipids like 4-hydroxy-2-nonenal, free heme, and disulfide bonds to form a thiol and perthiol. The catabolism of H₂S can also be catalyzed enzymatically by the sulfide quinone oxido-reductase system (SQR) comprised by sulfur dioxygenase, rhodanese, and sulfur quinone reductase.

Fig. 3

The oxidation of H₂S by the sulfide quinone oxido-reductase system in mitochondria. H₂S reduces the disulfide composed of the vicinal thiols on the sulfide quinone reductase (SQR) forming a thiol and a perthiol. The second sulfur atom on the perthiol, the sulfane sulfur (S⁰), is the substrate for both the sulfur transferase enzyme, rhodanese, and the sulfur dioxygenase enzyme encoded by the gene ETHE1. Rhodanese catalyzes the formation of thiosulfate (S₂O₃⁻²) from sulfite (SO₃⁻²) and S⁰. ETHE1 catalyzes the formation of SO₃⁻². The reduced SQR can then transfer electrons into the ubiquinone (Q) pool, thus coupling the oxidation of H₂S to electron transfer, H⁺ pumping, and ultimately ATP synthesis.

Fig. 4

Interaction of O₂ and H₂S on physiological outcomes. H₂S plays a role in many physiological processes. Additionally, it is capable of acting as a therapeutic agent. The concentration of H₂S, whether endogenously produced or exogenously administered, will dictate the outcome. This can be beneficial at low and intermediate concentrations or harmful at high concentrations. High O₂ can reverse many of the beneficial roles of H₂S seen at lower O₂ concentrations, resulting in, for example, vasoconstriction rather than vasodilation. Additionally, under hypoxic and normoxic conditions, H₂S promotes angiogenesis. However, at higher concentrations of both O₂ and H₂S, an inhibition of cellular proliferation is seen. H₂S has a narrow therapeutic window within which it is cytoprotective. At high concentrations it can be pro-apoptotic and pro-inflammatory. Finally, the larger doses of H₂S necessary to induce a hypometabolic effect, can, if pushed further, result in cardiac and respiratory toxicity.