Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches

Drousiotou, Anthi; Meo, Ivano Di; Mineri, Rossana; Georgiou, Th; Stylianidou, Goula; Tiranti, Valeria

doi:10.1111/j.1399-0004.2010.01457.x

Cited by 39 publications

(14 citation statements)

References 9 publications

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“…Inhibition of this pathway will prevent H 2 S binding to SQR and enable H 2 S and thiosulfate to accumulate. This has been shown in human and animal models of ETHE1 deficiencies (28,36,46,166).…”

Section: Effectors Of H 2 S Metabolismmentioning

confidence: 63%

Hydrogen sulfide as an oxygen sensor

Olson

2013

Clinical Chemistry and Laboratory Medicine

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Significance: Although oxygen (O 2 )-sensing cells and tissues have been known for decades, the identity of the O 2 -sensing mechanism has remained elusive. Evidence is accumulating that O 2 -dependent metabolism of hydrogen sulfide (H 2 S) is this enigmatic O 2 sensor. Recent Advances: The elucidation of biochemical pathways involved in H 2 S synthesis and metabolism have shown that reciprocal H 2 S/O 2 interactions have been inexorably linked throughout eukaryotic evolution; there are multiple foci by which O 2 controls H 2 S inactivation, and the effects of H 2 S on downstream signaling events are consistent with those activated by hypoxia. H 2 S-mediated O 2 sensing has been demonstrated in a variety of O 2 -sensing tissues in vertebrate cardiovascular and respiratory systems, including smooth muscle in systemic and respiratory blood vessels and airways, carotid body, adrenal medulla, and other peripheral as well as central chemoreceptors. Critical Issues: Information is now needed on the intracellular location and stoichometry of these signaling processes and how and which downstream effectors are activated by H 2 S and its metabolites. Future Directions: Development of specific inhibitors of H 2 S metabolism and effector activation as well as cellular organelle-targeted compounds that release H 2 S in a timeor environmentally controlled way will not only enhance our understanding of this signaling process but also provide direction for future therapeutic applications. Antioxid. Redox Signal. 22, 377-397.

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Section: Effectors Of H 2 S Metabolismmentioning

confidence: 63%

Hydrogen sulfide as an oxygen sensor

Olson

2013

Clinical Chemistry and Laboratory Medicine

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“…4). ETHE1 deficiency in either experimental animals or humans prevents H 2 S binding and is characterized by greatly elevated tissue H 2 S and thiosulfate (3,7,10,41). Because of the O 2 dependency of this reaction, hypoxia would be expected to achieve the same result.…”

Section: H 2 S Thiosulfate and Oxygen Sensingmentioning

confidence: 99%

Thiosulfate: a readily accessible source of hydrogen sulfide in oxygen sensing

Olson

DeLeon

Gao

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

131

125

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H2S derived from organic thiol metabolism has been proposed serve as an oxygen sensor in a variety of systems because of its susceptibility to oxidation and its ability to mimic hypoxic responses in numerous oxygen-sensing tissues. Thiosulfate, an intermediate in oxidative H2S metabolism can alternatively be reduced and regenerate H2S. We propose that this contributes to the H2S-mediated oxygen-sensing mechanism. H2S formation from thiosulfate in buffers and in a variety of mammalian tissues and in lamprey dorsal aorta was examined in real time using a polarographic H2S sensor. Inferences of intracellular H2S production were made by examining hypoxic pulmonary vasoconstriction (HPV) in bovine pulmonary arteries under conditions in which increased H2S production would be expected and in mouse and rat aortas, where reducing conditions should mediate vasorelaxation. In Krebs-Henseleit (mammalian) and Cortland (lamprey) buffers, H2S was generated from thiosulfate in the presence of the exogenous reducing agent, DTT, or the endogenous reductant dihydrolipoic acid (DHLA). Both the magnitude and rate of H2S production were greatly increased by these reductants in the presence of tissue, with the most notable effects occurring in the liver. H2S production was only observed when tissues were hypoxic; exposure to room air, or injecting oxygen inhibited H2S production and resulted in net H2S consumption. Both DTT and DHLA augmented HPV, and DHLA dose-dependently relaxed precontracted mouse and rat aortas. These results indicate that thiosulfate can contribute to H2S signaling under hypoxic conditions and that this is not only a ready source of H2S production but also serves as a means of recycling sulfur and thereby conserving biologically relevant thiols.

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“…Data from patients with defects in mitochondrial sulfide oxidation due to mutations in ETHE1 (ethylmalonic encephalopathy) as well as studies in Ethe1 knockout mice indicate that elevated levels of H 2 S lead to impairments in fatty acid and branchedchain amino acid oxidation in the mitochondria, along with elevated levels of C4-C6 acylcarnitines in the blood and excretion of ethylmalonic acid and thiosulfate in the urine. 23,35,36 Ethe1 encodes a homodimeric persulfide dioxygenase of the mitochondrial matrix that uses molecular oxygen to oxidize the sulfane sulfur of the persulfide generated by action of the inner mitochondrial membrane sulfide:quinone oxidoreductase on H 2 S, resulting in sulfite formation. ETHE1-deficient patients and mice exhibit a loss of tissue COX activity as well as the loss of holoenzyme and abundance of specific COX subunits, such as COX4 and COX5b, all of which are attributed to the toxicity of H 2 S on COX.…”

Section: Discussionmentioning

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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Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches

Cited by 39 publications

References 9 publications

Hydrogen sulfide as an oxygen sensor

Hydrogen sulfide as an oxygen sensor

Thiosulfate: a readily accessible source of hydrogen sulfide in oxygen sensing

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

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