Altered Sulfide (H2S) Metabolism in Ethylmalonic Encephalopathy

Tiranti, Valeria; Zeviani, Massimo

doi:10.1101/cshperspect.a011437

Cited by 42 publications

(34 citation statements)

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“…overall sulfide‐oxidizing capacities of the animal plus sulfide exhalation). An extreme example illustrates the biological consequences of impaired sulfide elimination: genetic deletion of ETHE1 (encoding for a β‐lactamase‐like, iron‐coordinating metalloprotein, with sulfur dioxygenase activity) in mice results in a severe, toxic accumulation of sulfide, producing a severe inhibition of cytochrome c oxidase activity as well as a severe form of encephalopathy (Tiranti et al ., ; Tiranti and Zeviani, ).…”

Section: Therapeutic Sulfide Administration: Pharmacological and Biocmentioning

confidence: 98%

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

Módis

Bos

Calzia

et al. 2014

British J Pharmacology

136

112

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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 ...

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Section: Therapeutic Sulfide Administration: Pharmacological and Biocmentioning

confidence: 98%

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

Módis

Bos

Calzia

et al. 2014

British J Pharmacology

136

112

View full text Add to dashboard Cite

show abstract

“…Because excess hydrogen sulfide (H 2 S) production or accumulation has been shown to impair mitochondrial cytochrome oxidase activity, short‐chain fatty acid oxidation, and branched‐chain amino acid oxidation in several different experimental models, , we examined cytochrome c oxidase (COX) subunit abundance, mitochondrial and peroxisomal marker protein abundances, and the abundance of enzymes involved in fatty acid metabolism in the liver tissues collected in this study. As shown in Figure , neither peroxisomal nor mitochondrial density in mouse liver appeared to be affected by loss of CDO, on the basis of the absence of any significant differences in the abundance of catalase (peroxisomal enzyme) or in the abundances of mitochondrial marker proteins, succinate dehydrogenase subunit A (SDHA), heat shock protein 60 (HSP60), and pyruvate dehydrogenase catalytic subunit (PDH).…”

Section: Resultsmentioning

confidence: 99%

Effects of a block in cysteine catabolism on energy balance and fat metabolism in mice

Niewiadomski

Zhou

Roman

et al. 2016

Annals of the New York Academy of Sciences

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To gain further insights into the effect of elevated cysteine levels on energy metabolism and the possible mechanisms by which cysteine may have these effects, we conducted studies in cysteine dioxygenase (Cdo1)–null mice. Cysteine dioxygenase (CDO) catalyzes the first step of the major pathway for cysteine catabolism. When CDO is absent, tissue and plasma cysteine levels are elevated, resulting in enhanced flux of cysteine through desulfhydration reactions. When Cdo1-null mice were fed a high-fat diet, they gained more weight than their wild-type controls, regardless of whether the diet was supplemented with taurine. Cdo1-null mice had markedly lower leptin levels, higher feed intakes, and markedly higher abundance of hepatic stearoyl-CoA desaturase 1 (SCD1) compared to wild-type control mice, and these differences were not affected by the fat or taurine content of the diet. Thus, reported associations of elevated cysteine levels with greater weight gain and with elevated hepatic Scd1 expression holds in the Cdo1-null mouse model. Hepatic accumulation of acylcarnitines suggested impaired mitochondrial β-oxidation of fatty acids in Cdo1-null mice. The strong associations of elevated cysteine levels with excess H2S production and impairments in energy metabolism suggest that H2S signaling could be involved.

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“…Persistent anorexia, feeding difficulties, chronic vomiting, failure to thrive, frequent infections, generalized hypotonia and neurological findings in association with chronic diarrhea occur in a wide variety of inborn errors of metabolism. Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) syndrome, menkes disease, congenital disorder of glycosylation, hartnup disease and disorders of cobalamin and folate metabolism and transport are examples of metabolic disorders which also give rise to chronic diarrhea and neurological findings (2)(3)(4). High levels of ethylmalonic acid in the urine may also be observed inshort-chain acyl-CoA dehydrogenase deficiency and glutaric acidemia Type II, but none of these has been associated with the major clinical features of EE.…”

Section: Discussionmentioning

confidence: 99%

“…Ethylmalonic encephalopathy (EE) is an autosomal recessive metabolic disease caused by mutations in the mitochondrial sulfur dioxygenase (ETHE1) gene (1). The disease is characterized by an early onset of neurological degeneration, chronic hemorrhagic diarrhea, recurrent petechiae, orthostatic acrocyanosis and death in the first years of life (2)(3)(4). Biochemically, these patients have increased urinary excretion of ethylmalonic acid, along with 2-methylsuccinate, butyrylglycine and isovalerylglycine.…”

Section: Introductionmentioning

confidence: 99%