Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part II. Pathophysiological and therapeutic aspects

Abstract

Emerging work demonstrates the dual regulation of mitochondrial function by hydrogen sulfide (H2S), including, at lower concentrations, a stimulatory effect as an electron donor, and, at higher concentrations, an inhibitory effect on cytochrome C oxidase. In the current article, we overview the pathophysiological and therapeutic aspects of these processes. During cellular hypoxia/acidosis, the inhibitory effect of H2S on complex IV is enhanced, which may shift the balance of H2S from protective to deleterious. Several pathophysiological conditions are associated with an overproduction of H2S (e.g. sepsis), while in other disease states H2S levels and H2S bioavailability are reduced and its therapeutic replacement is warranted (e.g. diabetic vascular complications). Moreover, recent studies demonstrate that colorectal cancer cells up-regulate the H2S-producing enzyme cystathionine β-synthase (CBS), and utilize its product, H2S, as a metabolic fuel and tumour-cell survival factor; pharmacological CBS inhibition or genetic CBS silencing suppresses cancer cell bioenergetics and suppresses cell proliferation and cell chemotaxis. In the last chapter of the current article, we overview the field of H2S-induced therapeutic 'suspended animation', a concept in which a temporary pharmacological reduction in cell metabolism is achieved, producing a decreased oxygen demand for the experimental therapy of critical illness and/or organ transplantation. LINKED ARTICLESThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi. org/10.1111/bph.2014.171.issue-8 Abbreviations 3-MST, 3-mercaptopyruvate sulfurtransferase; AOAA, aminooxyacetic acid; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; H2S, hydrogen sulfide; KATP, ATP-sensitive potassium channel; PAG, propargylglycine; SOU, sulfide-oxidizing unit Introduction H2S, a colourless, flammable, water-soluble gas, is gaining increased attention as an endogenous biological mediator. The distribution and regulation of the three H2S-producing enzymes [cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST)], and the wide range of biological effects of H2S are discussed in separate reviews Szabo, 2007 Snyder, 2010;Kimura, 2010;2013;Predmore and Lefer, 2010;Whiteman and Winyard, 2011;Kimura et al., 2012;Wang, 2012). In a recent article, we have overviewed the dual mitochondrial effects of H2S, which range from stimulatory effects, occurring at lower concentrations, to the suppression of mitochondrial function, which occurs at higher concentrations . The purpose of the current article is to outline the physiological, pathophysiological and therapeutic aspects of this regulation. Similar to our approach in the companion article , in the current article we use the terms 'sulfide' and H2S interchangeably to collectively refer to H2S gas as well as its two ionized forms in solution: HS -and S 2-. H 2 S as a potential inducer of ...

Gaseous Mediators in Temperature Regulation

“…This increased inhibition has been believed to shift the balance of H 2 S from protective to deleterious. Sepsis has been documented to be associated with an overproduction of H 2 S, whereas, conversely, in other disease states H 2 S levels and H 2 S bioavailability have been shown to be diminished (224).…”

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid

“…We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may exert adverse effects on cellular homeostasis (20,21). Given the importance of H 2 S as a vasorelaxant (22)(23)(24)(25)(26)(27)(28)(29), proangiogenic agent (27,(30)(31)(32)(33)(34)(35)(36) and mitochondrial/bioenergetic modulator (20,21,35,(37)(38)(39)(40)(41)(42), here we examined whether the 3-MST/H 2 S system plays physiological regulatory roles in endothelial cells. Next, we examined whether a dysfunction of the 3-MST/H 2 S system develops in hyperglycemia/diabetes and tested whether this dysfunction can be corrected by DL-α-lipoic acid (LA), a known antioxidant and 3-MST cofactor (43)(44)(45).…”

The Therapeutic Potential of Cystathionine β-Synthetase/Hydrogen Sulfide Inhibition in Cancer

“…Although referred to as the prototypical CBS inhibitor, the pharmacology of AOAA is complex (78) and not entirely specific. Its mode of action entails an irreversible binding to the prosthetic group PLP in CBS and therefore other PLPdependent enzymes.…”

“…To see this illustration in color, the reader is referred to the web version of this article at www .liebertpub.com/ars of GOT1 and other essential enzymes in the glutaminolysis pathway have recently been shown to suppress cancer cell metabolism (109). Therefore, we have recently suggested (78) that AOAA may exert its anticancer effects through the simultaneous suppression of the malate/aspartate shuttle, glutaminolysis, and the CBS/H 2 S axis. In effect, through these diverse, but interrelated pharmacological actions in the cancer cell, AOAA can be viewed as an inducer of ''synthetic lethality'' (Fig.…”