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Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway.
EMBO Mol Med. 2017 01; 9(1):96-111.EM

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 Pdss2kd/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 Pdss2kd/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.

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Authors+Show Affiliations

Ziosi M
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Di Meo I
Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute "Carlo Besta", Milan, Italy.
Kleiner G
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Gao XH
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
Barca E
Department of Neurology, Columbia University Medical Center, New York, NY, USA. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
Sanchez-Quintero MJ
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Tadesse S
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Jiang H
Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY, USA.
Qiao C
Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY, USA.
Rodenburg RJ
Department of Pediatrics, Radboud Center for Mitochondrial Medicine (RCMM), RadboudUMC, Nijmegen, The Netherlands.
Scalais E
Division of Paediatric Neurology, Department of Paediatrics, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg.
Schuelke M
Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Willard B
Mass Spectrometry Laboratory for Protein Sequencing, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Hatzoglou M
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
Tiranti V
Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute "Carlo Besta", Milan, Italy valeria.tiranti@istituto-besta.it cmq2101@cumc.columbia.edu.
Quinzii CM
Department of Neurology, Columbia University Medical Center, New York, NY, USA valeria.tiranti@istituto-besta.it cmq2101@cumc.columbia.edu.

MeSH

Alkyl and Aryl TransferasesAnimalsAtaxiaCells, CulturedFibroblastsHumansMiceMice, KnockoutMitochondrial DiseasesMuscle WeaknessOxidation-ReductionQuinone ReductasesSulfidesUbiquinone

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27856618

Citation

Ziosi, Marcello, et al. "Coenzyme Q Deficiency Causes Impairment of the Sulfide Oxidation Pathway." EMBO Molecular Medicine, vol. 9, no. 1, 2017, pp. 96-111.
Ziosi M, Di Meo I, Kleiner G, et al. Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway. EMBO Mol Med. 2017;9(1):96-111.
Ziosi, M., Di Meo, I., Kleiner, G., Gao, X. H., Barca, E., Sanchez-Quintero, M. J., Tadesse, S., Jiang, H., Qiao, C., Rodenburg, R. J., Scalais, E., Schuelke, M., Willard, B., Hatzoglou, M., Tiranti, V., & Quinzii, C. M. (2017). Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway. EMBO Molecular Medicine, 9(1), 96-111. https://doi.org/10.15252/emmm.201606356
Ziosi M, et al. Coenzyme Q Deficiency Causes Impairment of the Sulfide Oxidation Pathway. EMBO Mol Med. 2017;9(1):96-111. PubMed PMID: 27856618.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway. AU - Ziosi,Marcello, AU - Di Meo,Ivano, AU - Kleiner,Giulio, AU - Gao,Xing-Huang, AU - Barca,Emanuele, AU - Sanchez-Quintero,Maria J, AU - Tadesse,Saba, AU - Jiang,Hongfeng, AU - Qiao,Changhong, AU - Rodenburg,Richard J, AU - Scalais,Emmanuel, AU - Schuelke,Markus, AU - Willard,Belinda, AU - Hatzoglou,Maria, AU - Tiranti,Valeria, AU - Quinzii,Catarina M, PY - 2016/11/20/pubmed PY - 2017/9/26/medline PY - 2016/11/19/entrez KW - SQR KW - CoQ10 KW - Pdss2 KW - coenzyme Q KW - sulfides SP - 96 EP - 111 JF - EMBO molecular medicine JO - EMBO Mol Med VL - 9 IS - 1 N2 - 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 Pdss2kd/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 Pdss2kd/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. SN - 1757-4684 UR - https://www.unboundmedicine.com/medline/citation/27856618/Coenzyme_Q_deficiency_causes_impairment_of_the_sulfide_oxidation_pathway_ L2 - https://doi.org/10.15252/emmm.201606356 DB - PRIME DP - Unbound Medicine ER -