title: Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis.
abstract: Protection against oxidative damage caused by excessive reactive oxygen species (ROS) by an antioxidant network is essential for the health of tissues, especially in the cardiovascular system. Here, we identified a gene with important antioxidant features by analyzing a null allele of zebrafish ubiad1, called barolo (bar). bar mutants show specific cardiovascular failure due to oxidative stress and ROS-mediated cellular damage. Human UBIAD1 is a nonmitochondrial prenyltransferase that synthesizes CoQ10 in the Golgi membrane compartment. Loss of UBIAD1 reduces the cytosolic pool of the antioxidant CoQ10 and leads to ROS-mediated lipid peroxidation in vascular cells. Surprisingly, inhibition of eNOS prevents Ubiad1-dependent cardiovascular oxidative damage, suggesting a crucial role for this enzyme and nonmitochondrial CoQ10 in NO signaling. These findings identify UBIAD1 as a nonmitochondrial CoQ10-forming enzyme with specific cardiovascular protective function via the modulation of eNOS activity.
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy.
authors: Vera
authors: V
authors: Mugoni
authors: Ruben
authors: R
authors: Postel
authors: Valeria
authors: V
authors: Catanzaro
authors: Elisa
authors: E
authors: De Luca
authors: Emilia
authors: E
authors: Turco
authors: Giuseppe
authors: G
authors: Digilio
authors: Lorenzo
authors: L
authors: Silengo
authors: Michael P
authors: MP
authors: Murphy
authors: Claudio
authors: C
authors: Medana
authors: Didier Y R
authors: DY
authors: Stainier
authors: Jeroen
authors: J
authors: Bakkers
authors: Massimo M
authors: MM
authors: Santoro
mesh_terms: D000818:Animals; D004122:Dimethylallyltranstransferase / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006321:Heart / Q000196:embryology; D006801:Humans; D009206:Myocardium / Q000166:cytology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D029961:Zebrafish Proteins; D014451:Ubiquinone; D052250:Nitric Oxide Synthase Type III; D004122:Dimethylallyltranstransferase; C425464:UBIAD1 protein, human; C579268:Ubiad1 protein, zebrafish; C024989:coenzyme Q10
references: Am J Hum Genet. 2006 Feb;78(2):345-9
references: 16400613
references: J Neurochem. 2002 Mar;80(5):780-7
references: 11948241
references: Nature. 2011 Jan 27;469(7331):498-503
references: 21270888
references: Nature. 2000 Nov 9;408(6809):239-47
references: 11089981
references: Antioxid Redox Signal. 2009 Jul;11(7):1699-709
references: 19186981
references: J Biol Chem. 2002 Feb 8;277(6):4277-84
references: 11729179
references: J Genet Genomics. 2011 Jun 20;38(6):225-34
references: 21703546
references: Mitochondrion. 2007 Jun;7 Suppl:S2-7
references: 17446142
references: Mol Vis. 2007 Sep 24;13:1777-82
references: 17960116
references: Sci STKE. 2006 Aug 22;2006(349):re8
references: 16926363
references: Nature. 1996 May 30;381(6581):380-1
references: 8632794
references: Mitochondrion. 2007 Jun;7 Suppl:S154-67
references: 17485243
references: J Biol Chem. 1990 Jan 15;265(2):1158-64
references: 2295606
references: Am J Physiol Cell Physiol. 2006 Nov;291(5):C803-16
references: 16738003
references: Dev Biol. 2007 Jul 1;307(1):29-42
references: 17531218
references: Nature. 1990 Dec 20-27;348(6303):728-30
references: 2259382
references: J Chromatogr A. 2007 Dec 21;1175(2):242-8
references: 17996879
references: Biofactors. 2008;32(1-4):99-111
references: 19096105
references: Neurology. 2005 Aug 23;65(4):606-8
references: 16116126
references: J Clin Invest. 2005 Mar;115(3):509-17
references: 15765132
references: QJM. 2004 Aug;97(8):537-48
references: 15256611
references: Clin Sci (Lond). 2007 Jul;113(2):47-63
references: 17555404
references: Mech Dev. 2009 Aug-Sep;126(8-9):638-49
references: 19539756
references: J Biol Chem. 2001 May 4;276(18):14533-6
references: 11279231
references: Dev Dyn. 2007 Nov;236(11):3088-99
references: 17937395
references: Annu Rev Physiol. 2012;74:403-24
references: 22077215
references: Cell. 2001 Sep 21;106(6):675-83
references: 11572774
references: Biochim Biophys Acta. 2004 Jan 28;1660(1-2):171-99
references: 14757233
references: Cell. 2009 May 15;137(4):736-48
references: 19450519
references: PLoS One. 2007 Aug 01;2(8):e685
references: 17668063
references: Acta Chem Scand B. 1987 Jan;41(1):70-2
references: 3577554
references: Nature. 1961 Jul 8;191:144-8
references: 13771349
references: Dev Cell. 2006 Dec;11(6):845-57
references: 17141159
references: J Cell Sci. 2004 Jan 15;117(Pt 2):143-53
references: 14676270
references: Nat Protoc. 2008;3(4):619-28
references: 18388944
references: Nat Genet. 2002 May;31(1):106-10
references: 11967535
references: Mitochondrion. 2007 Jun;7 Suppl:S41-50
references: 17482888
references: J Clin Invest. 2011 May;121(5):2013-24
references: 21540551
references: Am J Physiol Regul Integr Comp Physiol. 2000 Dec;279(6):R2200-7
references: 11080086
references: Comp Biochem Physiol A Mol Integr Physiol. 2005 Oct;142(2):215-20
references: 15958285
references: Blood. 2011 Oct 13;118(15):4102-10
references: 21849483
references: J Am Coll Nutr. 2001 Dec;20(6):591-8
references: 11771674
references: PLoS One. 2010 May 21;5(5):e10760
references: 20505825
references: Pharmacol Ther. 2009 Dec;124(3):259-68
references: 19638284
references: Circ Res. 2010 Feb 5;106(2):285-96
references: 20133913
references: Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):413-20
references: 14656731
references: Nat Rev Mol Cell Biol. 2005 Feb;6(2):150-66
references: 15688001
references: Nature. 2010 Nov 4;468(7320):117-21
references: 20953171
references: Antioxid Redox Signal. 2010 Dec 15;13(12):1899-910
references: 20698753
references: Mitochondrion. 2007 Jun;7 Suppl:S34-40
references: 17482527
references: Biochem Biophys Res Commun. 2010 May 21;396(1):74-9
references: 20494114
references: Biochem J. 2004 Sep 1;382(Pt 2):519-26
references: 15153069
references: Electrophoresis. 2001 Feb;22(3):386-93
references: 11258743
references: Nat Rev Mol Cell Biol. 2007 Oct;8(10):813-24
references: 17848967
references: Eur Heart J. 2012 Apr;33(7):829-37, 837a-837d
references: 21890489
references: Comp Biochem Physiol C Toxicol Pharmacol. 2004 Jul;138(3):363-73
references: 15533794
references: Curr Opin Cell Biol. 2003 Apr;15(2):247-54
references: 12648682
references: J Biol Chem. 2002 Feb 1;277(5):3101-8
references: 11719508
references: Invest Ophthalmol Vis Sci. 2007 Nov;48(11):5007-12
references: 17962451
references: Nature. 2010 Apr 22;464(7292):1196-200
references: 20364122
references: J Nutr Biochem. 2012 May;23(5):458-68
references: 21684136
references: Antioxid Redox Signal. 2011 Feb 1;14(3):459-68
references: 20649461
references: Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9828-32
references: 1682921
references: Am J Hum Genet. 2009 May;84(5):558-66
references: 19375058
references: J Clin Invest. 2005 Mar;115(3):500-8
references: 15765131
references: Annu Rev Pharmacol Toxicol. 2007;47:629-56
references: 17014364
references: Dev Biol. 2006 Nov 15;299(2):551-62
references: 16999953
references: Nat Genet. 2007 Nov;39(11):1397-402
references: 17934460
references: Curr Opin Neurol. 2011 Oct;24(5):449-56
references: 21844807
references: J Biol Chem. 1993 Jan 15;268(2):1494-9
references: 8419349