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      Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway

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          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.

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          Most cited references50

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          H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase.

          Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H2S) is now receiving increasing attention. Here we show that H2S is physiologically generated by cystathionine gamma-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H2S formation in response to vascular activation. These findings provide direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure.
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            The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener.

            Hydrogen sulfide (H(2)S) has been traditionally viewed as a toxic gas. It is also, however, endogenously generated from cysteine metabolism. We attempted to assess the physiological role of H(2)S in the regulation of vascular contractility, the modulation of H(2)S production in vascular tissues, and the underlying mechanisms. Intravenous bolus injection of H(2)S transiently decreased blood pressure of rats by 12- 30 mmHg, which was antagonized by prior blockade of K(ATP) channels. H(2)S relaxed rat aortic tissues in vitro in a K(ATP) channel-dependent manner. In isolated vascular smooth muscle cells (SMCs), H(2)S directly increased K(ATP) channel currents and hyperpolarized membrane. The expression of H(2)S-generating enzyme was identified in vascular SMCs, but not in endothelium. The endogenous production of H(2)S from different vascular tissues was also directly measured with the abundant level in the order of tail artery, aorta and mesenteric artery. Most importantly, H(2)S production from vascular tissues was enhanced by nitric oxide. Our results demonstrate that H(2)S is an important endogenous vasoactive factor and the first identified gaseous opener of K(ATP) channels in vascular SMCs.
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              H2S signals through protein S-sulfhydration.

              Hydrogen sulfide (H2S), a messenger molecule generated by cystathionine gamma-lyase, acts as a physiologic vasorelaxant. Mechanisms whereby H2S signals have been elusive. We now show that H2S physiologically modifies cysteines in a large number of proteins by S-sulfhydration. About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. Sulfhydration augments GAPDH activity and enhances actin polymerization. Sulfhydration thus appears to be a physiologic posttranslational modification for proteins.
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                Author and article information

                Contributors
                valeria.tiranti@istituto-besta.it
                cmq2101@cumc.columbia.edu
                Journal
                EMBO Mol Med
                EMBO Mol Med
                10.1002/(ISSN)1757-4684
                EMMM
                embomm
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1757-4676
                1757-4684
                17 November 2016
                January 2017
                : 9
                : 1 ( doiID: 10.1002/emmm.v9.1 )
                : 96-111
                Affiliations
                [ 1 ] Department of NeurologyColumbia University Medical Center New York NYUSA
                [ 2 ] Unit of Molecular NeurogeneticsIRCCS Foundation Neurological Institute “Carlo Besta” MilanItaly
                [ 3 ] Department of Genetics and Genome SciencesCase Western Reserve University Cleveland OHUSA
                [ 4 ] Department of Clinical and Experimental MedicineUniversity of Messina MessinaItaly
                [ 5 ] Irving Institute for Clinical and Translational ResearchColumbia University Medical Center New York NYUSA
                [ 6 ] Department of Pediatrics Radboud Center for Mitochondrial Medicine (RCMM)RadboudUMC NijmegenThe Netherlands
                [ 7 ] Division of Paediatric Neurology Department of PaediatricsCentre Hospitalier de Luxembourg Luxembourg CityLuxembourg
                [ 8 ] Department of Neuropediatrics and NeuroCure Clinical Research CenterCharité‐Universitätsmedizin Berlin BerlinGermany
                [ 9 ] Mass Spectrometry Laboratory for Protein Sequencing Learner Research InstituteCleveland Clinic Cleveland OHUSA
                Author notes
                [*] [* ] Corresponding author. Tel: +39 02 23942633; Fax: +39 02 23942619; E‐mail: valeria.tiranti@ 123456istituto-besta.it

                Corresponding author. Tel: +1 212 305 1637; Fax: +1 212 305 3986; E‐mail: cmq2101@ 123456cumc.columbia.edu

                [†]

                These authors contributed equally to this work

                [‡]

                These authors contributed equally to thus work

                Author information
                http://orcid.org/0000-0003-2824-3891
                http://orcid.org/0000-0003-2037-1231
                http://orcid.org/0000-0002-3584-7338
                http://orcid.org/0000-0003-3819-1298
                Article
                EMMM201606356
                10.15252/emmm.201606356
                5210092
                27856618
                3ad90cac-1fdc-494e-8897-240960bbc16b
                © 2016 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 February 2016
                : 15 September 2016
                : 19 October 2016
                Page count
                Figures: 15, Tables: 1, Pages: 16, Words: 12366
                Funding
                Funded by: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
                Award ID: P01 HD080642‐01
                Funded by: National Institutes of Health
                Award ID: P01 HD080642‐01
                Award ID: 1S10RR031537‐01
                Award ID: UL1TR000040
                Award ID: R37‐DK060596
                Award ID: R01‐DK053307
                Funded by: NIH Clinical Translational Science Award (CTSA)
                Award ID: UL1TR000040
                Funded by: Fondazione Pierfranco e Luisa Mariani
                Funded by: Muscle Dystrophy Association (MDA)
                Funded by: Department of Defense (DOD)
                Funded by: Italian Ministry of Health
                Award ID: 79/GR‐2010‐2306756
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                emmm201606356
                January 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.0 mode:remove_FC converted:04.01.2017

                Molecular medicine
                coenzyme q,coq10,pdss2,sqr,sulfides,genetics, gene therapy & genetic disease,metabolism
                Molecular medicine
                coenzyme q, coq10, pdss2, sqr, sulfides, genetics, gene therapy & genetic disease, metabolism

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