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Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway.

ABSTRACT: Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2^kd/kd mice, which only have ~15% residual CoQ concentrations and are clinically affected, showed (i) reduced protein levels of SQR and downstream enzymes, (ii) accumulation of hydrogen sulfides, and (iii) glutathione depletion. These abnormalities were not present in brain, which maintains ~30% residual CoQ and is clinically unaffected. In Pdss2^kd/kd mice, we also observed low levels of plasma and urine thiosulfate and increased blood C4-C6 acylcarnitines. We propose that impairment of the sulfide oxidation pathway induced by decreased levels of CoQ causes accumulation of sulfides and consequent inhibition of short-chain acyl-CoA dehydrogenase and glutathione depletion, which contributes to increased oxidative stress and kidney failure.

SUBMITTER: Ziosi M

PROVIDER: S-EPMC5210092 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway.

Ziosi Marcello M Di Meo Ivano I Kleiner Giulio G Gao Xing-Huang XH Barca Emanuele E Sanchez-Quintero Maria J MJ Tadesse Saba S Jiang Hongfeng H Qiao Changhong C Rodenburg Richard J RJ Scalais Emmanuel E Schuelke Markus M Willard Belinda B Hatzoglou Maria M Tiranti Valeria V Quinzii Catarina M CM

EMBO molecular medicine 20170101 1

Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidne ...[more]

PMID: 27856618

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Project description:Coenzyme Q (CoQ) is a lipid present in all cell membranes. One of the multiple metabolic functions of CoQ is to transport electrons in the reaction catalyzed by sulfide:quinone oxidoreductase (SQOR), the first enzyme of the oxidation pathway of sulfides (hydrogen sulfide, H2S). Early evidence of a defect in the metabolism of H2S in primary CoQ deficiency came from yeast studies in Schizosaccharomyces pombe strains defective for dps1 and ppt1 (homologs of PDSS1 and COQ2, respectively), which have H2S accumulation. Our recent studies in human skin fibroblasts and in murine models of primary CoQ deficiency show that, also in mammals, decreased CoQ levels cause impairment of H2S oxidation. Patient fibroblasts carrying different mutations in genes encoding proteins involved in CoQ biosynthesis show reduced SQOR activity and protein levels proportional to the levels of CoQ. In Pdss2kd/kd mice, kidney, the only organ clinically affected, shows reduced SQOR levels and downstream enzymes, accumulation of H2S, and glutathione depletion. Pdss2kd/kd mice have also low levels of thiosulfate in plasma and urine, and increased C4-C6 acylcarnitines in blood, due to inhibition of short-chain acyl-CoA dehydrogenase. Also in Coq9R239X mice, the symptomatic organ, cerebrum, shows accumulation of H2S, reduced SQOR, increase in thiosulfate sulfurtransferase and sulfite oxidase, and reduction in the levels of glutathione and glutathione enzymes, leading to alteration of the biosynthetic pathways of glutamate, serotonin, and catecholamines. Coq9R239X mice have also reduced blood pressure, possible consequence of H2S-induced vasorelaxation. Since liver is not clinically affected in Pdss2 and Coq9 mutant mice, the effects of the impairment of H2S oxidation in this organ were not investigated, despite its critical role in metabolism. In conclusion, in vitro and in vivo studies of CoQ deficient models provide evidence of tissue-specific H2S oxidation impairment, an additional pathomechanism that should be considered in the understanding and treatment of primary CoQ deficiency.

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Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway.

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Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway.

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