Morphologic evidence of diffuse vascular damage in human and in the experimental model of ethylmalonic encephalopathy

Giordano, Carla; Viscomi, Carlo; Orlandi, Maurizia; Papoff, Paola; Spalice, Alberto; Burlina, Alberto; Meo, Ivano Di; Tiranti, Valeria; Leuzzi, Vincenzo; d’Amati, Giulia; Zeviani, Massimo

doi:10.1007/s10545-011-9408-3

Cited by 37 publications

(26 citation statements)

References 17 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: 64%

Hydrogen Sulfide as an Oxygen Sensor

Olson

2015

Antioxidants & Redox Signaling

111

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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: 64%

Hydrogen Sulfide as an Oxygen Sensor

Olson

2015

Antioxidants & Redox Signaling

111

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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

128

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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“…The primary cause for the disease is a disruption of the mitochondrial sulfide detoxification pathway that oxidizes sulfide to either thiosulfate or sulfate in four steps catalyzed by sulfide:quinone oxidoreductase, ETHE1, a sulfurtransferase, and sulfite oxidase (Hildebrandt and Grieshaber, 2008;Tiranti et al, 2009). Increased sulfide concentrations in the bloodstream severely damage the vascular endothelium and thus cause the main symptoms of ethylmalonic encephalopathy: rapidly progressive necrosis in the brain, chronic diarrhea, and microangiopathy (Giordano et al, 2012). In addition, sulfide interferes with mitochondrial energy metabolism.…”

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confidence: 99%

The Mitochondrial Sulfur Dioxygenase ETHYLMALONIC ENCEPHALOPATHY PROTEIN1 Is Required for Amino Acid Catabolism during Carbohydrate Starvation and Embryo Development in Arabidopsis

et al. 2014

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The sulfur dioxygenase ETHYLMALONIC ENCEPHALOPATHY PROTEIN1 (ETHE1) catalyzes the oxidation of persulfides in the mitochondrial matrix and is essential for early embryo development in Arabidopsis (Arabidopsis thaliana). We investigated the biochemical and physiological functions of ETHE1 in plant metabolism using recombinant Arabidopsis ETHE1 and three transfer DNA insertion lines with 50% to 99% decreased sulfur dioxygenase activity. Our results identified a new mitochondrial pathway catalyzing the detoxification of reduced sulfur species derived from cysteine catabolism by oxidation to thiosulfate. Knockdown of the sulfur dioxygenase impaired embryo development and produced phenotypes of starvation-induced chlorosis during short-day growth conditions and extended darkness, indicating that ETHE1 has a key function in situations of high protein turnover, such as seed production and the use of amino acids as alternative respiratory substrates during carbohydrate starvation. The amino acid profile of mutant plants was similar to that caused by defects in the electron-transfer flavoprotein/electron-transfer flavoprotein: ubiquinone oxidoreductase complex and associated dehydrogenases. Thus, in addition to sulfur amino acid catabolism, ETHE1 also affects the oxidation of branched-chain amino acids and lysine.

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Morphologic evidence of diffuse vascular damage in human and in the experimental model of ethylmalonic encephalopathy

Cited by 37 publications

References 17 publications

Hydrogen Sulfide as an Oxygen Sensor

Hydrogen Sulfide as an Oxygen Sensor

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

The Mitochondrial Sulfur Dioxygenase ETHYLMALONIC ENCEPHALOPATHY PROTEIN1 Is Required for Amino Acid Catabolism during Carbohydrate Starvation and Embryo Development in Arabidopsis

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