Hydrogen Sulfide System in Down Syndrome

Published in "The FEBS Journal doi: 10.1111/febs.15214, 2020" which should be cited to refer to this work. The re-emerging pathophysiological role of the cystathionine-b-synthase - hydrogen sulfide system in Down syndrome Csaba Szabo Chair of Pharmacology, Section of Medicine, University of Fribourg, Switzerland Keywords Down syndrome (DS) is associated with significant perturbances in many bioenergetics; hydrogen sulfide; morphological and biochemical features. Cystathionine-b-synthase (CBS) is metabolism; mitochondria; trisomy one of the key mammalian enzymes that is responsible for the biological production of the gaseous transmitter hydrogen sulfide (H S). When H Sis Correspondence 2 2 C. Szabo, Chair of Pharmacology, Section of overproduced, it can exert detrimental cellular effects, in part due to inhibi- Medicine, University of Fribourg, PER 17, tion of mitochondrial Complex IV activity. An increased expression of Chemin Du Musee 18, Fribourg 1700, CBS and the consequent overproduction of H2S are well documented in Switzerland individuals with DS. Two decades ago, it has been proposed that a toxic Tel: +41 26 300 9409 overproduction of H2S importantly contributes to the metabolic and neu- E-mail: [email protected] rological deficits associated with DS. However, until recently, this hypothesis has not yet been tested experimentally. Recent data generated in human dermal fibroblasts show that DS cells overproduce H2S, which, in turn, suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and ATP generation. Therapeutic CBS inhibition lifts the tonic (and reversible) suppression of Complex IV: This results in the normalization of mitochondrial function in DS cells. H2S may also con- tribute to the cellular dysfunction via several other molecular mechanisms through interactions with various mitochondrial and extramitochondrial molecular targets. The current article provides a historical background of the field, summarizes the recently published data and their potential implications, and outlines potential translational approaches (such as CBS inhibition and H2S neutralization) and future experimental studies in this re-emerging field of pathobiochemistry. http://doc.rero.ch The CBS/H S system: emergence of a 2 regulated fashion, by various mammalian cells and tis- multifunctional endogenous gaseous c mediator sues. Three major enzymes, cystathionine- -lyase (CSE), cystathionine-b-synthase (CBS), and 3-mercap- Over the last decades, various biological regulatory topyruvate sulfurtransferase (3-MST) are responsible roles of a novel endogenous gaseous mediator, hydro- for mammalian H2S biogenesis. CBS and CSE utilize gen sulfide (H2S), emerged (overviewed in Ref. [1–4]). L-cysteine and homocysteine as substrates, while 3- These data demonstrated that H2S is produced, in a MST utilizes 3-mercaptopyruvate (which is also Abbreviations 3-MST, 3-mercaptopyruvate sulfurtransferase; AOAA, aminooxyacetate; CBS, cystathionine-b-synthase; CNS, central nervous system; CSE, cystathionine-c-lyase; DOPA, 3,4-dihydroxyphenylalanine; DS, Down syndrome; GMP, Good Manufacturing Practice; H2S, hydrogen sulfide; O2, oxygen; PLP, pyridoxal phosphate; RAC1, ras-related C3 botulinum toxin substrate 1; ROS, reactive oxygen species. 1 generated from L-cysteine). H2S serves a diverse set of decades, CBS has been mostly studied in the context biological regulatory roles in the cardiovascular, ner- of its inactivating mutations, which are the underlying vous, and immune system (overviewed in Ref. [1–9]). causes of the most common inborn error of sulfur While H2S has many distinct molecular targets and amino acid metabolism called classical homocystinuria can regulate many different proteins and second mes- [22,23]. Based on some ‘mirror image’ features evident senger systems [1–9], one of the key aspects of its bio- in the clinical picture of homocystinuria vs. DS, J. logical role is that it can regulate mitochondrial Lejeune (the French physician who discovered Trisomy function. Similar to its effects on many other biologi- 21 and several other diseases related to chromosomal cal systems, its effects are bell-shaped: H2S exerts abnormalities) already hypothesized in 1975 [24] that mostly regulatory, beneficial, or protective effects at the increased expression of CBS may importantly con- lower concentrations, and deleterious and cytotoxic tribute to the metabolic alterations and overall clinical effects at higher concentrations [1–13]. (The literature picture of DS. published prior to the mid-2000s almost exclusively The hypothesis that CBS-derived overproduction of focuses on the latter aspects, mostly in the context of H2S may be responsible for some of the pathophysio- environmental toxicology [10–13].) logical aspects of DS has been first put forward by At lower concentrations, H2S stimulates mitochon- P. Kamoun almost two decades ago [25], based on drial functions and exerts protective effects in the mito- his own clinical findings demonstrating markedly chondria. As discussed elsewhere [14–17], these effects increased circulating levels of sulfhemoglobin (a pro- involve several different mechanisms, including direct duct of the reaction of hemoglobin with H2S) and electron donation at the level of mitochondrial Complex increased (approximately twofold over healthy con- II, inhibition of mitochondrial protein kinase A, stimu- trols) urinary excretion of thiosulfate (a stable degra- lation of mitochondrial ATP synthase (i.e., mitochon- dation product of H2S) in individuals with DS drial Complex V), formation of an antioxidant ‘cloud’ [26,27]. A later study, using a different H2S detection within the mitochondria, and stimulation of mitochon- method, has also reported increased circulating H2S drial DNA repair via the facilitation of the assembly of levels in DS individuals [28]. According to the mitochondrial DNA repair protein complexes. In con- ‘Kamoun Hypothesis’ [25], excess H2S—at least, in trast, at high concentrations, H2S exerts deleterious part, via inhibition of mitochondrial Complex IV— effects on mitochondrial function. This effect is, to a may be responsible for the metabolic and neu- large extent, due to a direct (but reversible) inhibition ropathological features of DS. Several lines of inde- of Complex IV, a biochemical mechanism that was dis- pendent studies have demonstrated elevated covered in the 70s and has been characterized, in fine expression of CBS in DS cells and tissues, including molecular detail, over the last two decades [18,19]. the brain [28–32]. Moreover, both the footprint of Complex IV inhibition, in fact, is generally accepted in excess CBS (evidenced by low circulating homocys- the environmental toxicological literature as the primary teine levels) [33] and the footprint of inhibition of mode of the deleterious biological actions of H2S toxic- mitochondrial oxidative phosphorylation (evidenced ity (which underlies the H2S-induced metabolic suppres- by the accumulation of Krebs cycle intermediaries) sion, the neurotoxicological effects of H2S, and the have been demonstrated in DS individuals by meta- http://doc.rero.ch lethal actions of severe H2S intoxication) [10–13,20,21]. bolomic analysis [34]. Several lines of independent (The H2S-mediated inhibition of mitochondrial Com- studies have also demonstrated that DS cells exhibit plex IV has many parallels of the inhibition of Complex suppressed mitochondrial function; in some (but not IV by cyanide, with one important difference: The effect all) of these reports, an inhibition of Complex IV of cyanide is irreversible, while the effect of H2Sis activity was noted [35–39]. (Because H2S is a labile reversible [19].) Most of these studies were conducted in gaseous molecule, and the effects of H2S on Complex the field of environmental toxicology, where H2Sis IV are reversible, it is conceivable that methodologi- delivered via the inhalational route. In turn, it dissolves cal aspects have contributed to these differences: A in the bloodstream and distributes to various cells and reversible, H2S-mediated inhibitory effect could be tissues [10–13,20,21]. lifted during sample preparation and would not be expected to be readily demonstratable in Complex IV The ‘Kamoun Hypothesis’ measurements in isolated mitochondrial or mitochondrial fractions.) However, whether endogenous H2S Cystathionine-b-synthase is a key enzyme in the overproduction is directly responsible for the suppres- transsulfuration pathway; it catalyzes the conversion sion of mitochondrial function in DS has not been of homocysteine into cystathionine. For the last three directly tested until recently. 2 Experimental confirmation of the pharmacological H2S donor; the same donor molecule Kamoun Hypothesis also reversed the mitochondrial stimulatory effects of CBS inhibition in DS cells [40]. When the Kamoun Hypothesis was originally pro- The above findings can be conceptualized on a bell- posed (almost two decades ago), it may have been con- shaped curve that represents the pharmacological sidered ‘wild’ or ‘far out’: H2S, at the time, was not effects of low vs. high levels of H2S in terms of mito- generally accepted as an endogenous mammalian bio- chondrial function and cell viability (Fig. 1): in DS logical mediator or regulator. However, work in the cells, high intracellular H2S levels induce Complex IV last two decades has demonstrated the multiple biolog- blockade, suppress cellular bioenergetics, and impair ical roles of this mediator [1–9] and started to distin- proliferation.

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