Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms

Abstract

Until recently, hydrogen sulfide (H 2 S) was exclusively viewed a toxic gas and an environmental hazard, with its toxicity primarily attributed to the inhibition of mitochondrial C omplex IV, resulting in a shutdown of mitochondrial electron transport and cellular ATP generation. Work over the last decade established multiple biological regulatory roles of H 2 S, as an endogenous gaseous transmitter. H 2 S is produced by cystathionine γ‐lyase (CSE), cystathionine β‐synthase (CBS) and 3‐mercaptopyruvate sulfurtransferase (3‐MST). In striking contrast to its inhibitory effect on C omplex IV, recent studies showed that at lower concentrations, H 2 S serves as a stimulator of electron transport in mammalian cells, by acting as a mitochondrial electron donor. Endogenous H 2 S, produced by mitochondrially localized 3‐MST, supports basal, physiological cellular bioenergetic functions; the activity of this metabolic support declines with physiological aging. In specialized conditions (calcium overload in vascular smooth muscle, colon cancer cells), CSE and CBS can also associate with the mitochondria; H 2 S produced by these enzymes, serves as an endogenous stimulator of cellular bioenergetics. The current article overviews the biochemical mechanisms underlying the stimulatory and inhibitory effects of H 2 S on mitochondrial function and cellular bioenergetics and discusses the implication of these processes for normal cellular physiology. The relevance of H 2 S biology is also discussed in the context of colonic epithelial cell physiology: colonocytes are exposed to high levels of sulfide produced by enteric bacteria, and serve as a metabolic barrier to limit their entry into the mammalian host, while, at the same time, utilizing it as a metabolic ‘fuel’. Linked Articles: This 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