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

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.