title: 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 Pdss2kd/kdmice, 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/kdmice, 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.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Marcello
authors.initials: M
authors.lastname: Ziosi
authors.affiliation: Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute "Carlo Besta", Milan, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Di Meo
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Kleiner
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Xing-Huang
authors.initials: XH
authors.lastname: Gao
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.|Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Barca
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Sanchez-Quintero
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Saba
authors.initials: S
authors.lastname: Tadesse
authors.affiliation: Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY, USA.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY, USA.
authors.forename: Changhong
authors.initials: C
authors.lastname: Qiao
authors.affiliation: Department of Pediatrics, Radboud Center for Mitochondrial Medicine (RCMM), RadboudUMC, Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Division of Paediatric Neurology, Department of Paediatrics, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Scalais
authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Markus
authors.identifier: 0000-0003-2824-3891
authors.initials: M
authors.lastname: Schuelke
authors.affiliation: Mass Spectrometry Laboratory for Protein Sequencing, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Maria
authors.identifier: 0000-0003-2037-1231
authors.initials: M
authors.lastname: Hatzoglou
authors.affiliation: Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute "Carlo Besta", Milan, Italy valeria.tiranti@istituto-besta.it cmq2101@cumc.columbia.edu.
authors.forename: Valeria
authors.identifier: 0000-0002-3584-7338
authors.initials: V
authors.lastname: Tiranti
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA valeria.tiranti@istituto-besta.it cmq2101@cumc.columbia.edu.
authors.forename: Catarina M
authors.identifier: 0000-0003-3819-1298
authors.initials: CM
authors.lastname: Quinzii
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000172:deficiency; D000818:Animals; D001259:Ataxia / Q000503:physiopathology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000503:physiopathology*; D018908:Muscle Weakness / Q000503:physiopathology*; D010084:Oxidation-Reduction; D011808:Quinone Reductases / Q000032:analysis; D013440:Sulfides / Q000378:metabolism*; D014451:Ubiquinone / Q000172:deficiency*
chemical_list: D013440:Sulfides; D014451:Ubiquinone; D011808:Quinone Reductases; C073412:sulfide quinone reductase; D019883:Alkyl and Aryl Transferases; C573473:prenyl diphosphate synthase subunit 2, mouse
keywords: 
  SQR
  ; CoQ10; Pdss2; coenzyme Q; sulfides