title: Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons.
abstract: A variety of observations support the hypothesis that deficiency of complex I [reduced nicotinamide-adenine dinucleotide (NADH):ubiquinone oxidoreductase] of the mitochondrial respiratory chain plays a role in the pathophysiology of Parkinson's disease (PD). However, recent data from a study using mice with knockout of the complex I subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4) has challenged this concept as these mice show degeneration of non-dopamine neurons. In addition, primary dopamine (DA) neurons derived from such mice, reported to lack complex I activity, remain sensitive to toxins believed to act through inhibition of complex I. We tissue-specifically disrupted the Ndufs4 gene in mouse heart and found an apparent severe deficiency of complex I activity in disrupted mitochondria, whereas oxidation of substrates that result in entry of electrons at the level of complex I was only mildly reduced in intact isolated heart mitochondria. Further analyses of detergent-solubilized mitochondria showed the mutant complex I to be unstable but capable of forming supercomplexes with complex I enzyme activity. The loss of Ndufs4 thus causes only a mild complex I deficiency in vivo. We proceeded to disrupt Ndufs4 in midbrain DA neurons and found no overt neurodegeneration, no loss of striatal innervation and no symptoms of Parkinsonism in tissue-specific knockout animals. However, DA homeostasis was abnormal with impaired DA release and increased levels of DA metabolites. Furthermore, Ndufs4 DA neuron knockouts were more vulnerable to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Taken together, these findings lend in vivo support to the hypothesis that complex I deficiency can contribute to the pathophysiology of PD.
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Retzius väg 8, SE-17177 Stockholm, Sweden.
authors.forename: Fredrik H
authors.initials: FH
authors.lastname: Sterky
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Hoffman
authors.forename: Dusanka
authors.initials: D
authors.lastname: Milenkovic
authors.forename: Betty
authors.initials: B
authors.lastname: Bao
authors.forename: Arianna
authors.initials: A
authors.lastname: Paganelli
authors.forename: Daniel
authors.initials: D
authors.lastname: Edgar
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
authors.forename: Lars
authors.initials: L
authors.lastname: Olson
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004795:Enzyme Stability; D006706:Homeostasis; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism
chemical_list: C534449:Ndufs4 protein, mouse; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D004298:Dopamine
references.citation: Nat Genet. 2006 May;38(5):515-7
references.pmid: 16604074
references.citation: Mol Pharmacol. 2008 Oct;74(4):933-40
references.pmid: 18599602
references.citation: J Cereb Blood Flow Metab. 2002 Feb;22(2):232-9
references.pmid: 11823721
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3136-41
references.pmid: 14978272
references.citation: Hum Mol Genet. 2012 Jan 1;21(1):115-20
references.pmid: 21965299
references.citation: Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94
references.pmid: 17911161
references.citation: Neuroscience. 2002;114(2):475-92
references.pmid: 12204216
references.citation: J Neurosci. 2006 May 10;26(19):5256-64
references.pmid: 16687518
references.citation: Proc Natl Acad Sci U S A. 1983 Jul;80(14):4546-50
references.pmid: 6192438
references.citation: Neurosci Lett. 1981 Sep 25;25(3):251-6
references.pmid: 6270601
references.citation: Neuroscience. 2009 Jul 21;161(4):1082-90
references.pmid: 19376196
references.citation: Histochemistry. 1992 Aug;98(1):39-49
references.pmid: 1429016
references.citation: J Neurol. 2008 Aug;255(8):1231-5
references.pmid: 18604467
references.citation: Nat Rev Mol Cell Biol. 2011 Jan;12(1):9-14
references.pmid: 21179058
references.citation: Anat Rec. 1946 Feb;94:239-47
references.pmid: 21015608
references.citation: FASEB J. 2011 Apr;25(4):1333-44
references.pmid: 21233488
references.citation: Anal Biochem. 2002 Dec 15;311(2):139-51
references.pmid: 12470673
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10996-1001
references.pmid: 20534480
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1956-61
references.pmid: 8700866
references.citation: Cell Metab. 2008 Apr;7(4):312-20
references.pmid: 18396137
references.citation: Exp Neurol. 2009 Aug;218(2):235-46
references.pmid: 19303005
references.citation: Lancet. 1989 Jul 1;2(8653):49
references.pmid: 2567823
references.citation: Anal Biochem. 1991 Dec;199(2):223-31
references.pmid: 1812789
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):389-94
references.pmid: 20018672
references.citation: J Cell Biol. 2011 Mar 7;192(5):873-82
references.pmid: 21383081
references.citation: Ann Neurol. 1989 Dec;26(6):719-23
references.pmid: 2557792
references.citation: Parkinsonism Relat Disord. 2002 Sep;8(6):389-93
references.pmid: 12217625
references.citation: Lancet. 2004 Sep 4-10;364(9437):875-82
references.pmid: 15351195
references.citation: Lancet. 1989 Jun 3;1(8649):1269
references.pmid: 2566813
references.citation: Nat Genet. 1992 Dec;2(4):318-23
references.pmid: 1303287
references.citation: Genes Brain Behav. 2010 Mar 1;9(2):173-81
references.pmid: 20002202
references.citation: Annu Rev Neurosci. 1988;11:81-96
references.pmid: 3129982
references.citation: Nat Genet. 1996 Jul;13(3):296-302
references.pmid: 8673128
references.citation: Nat Genet. 1992 Dec;2(4):324-9
references.pmid: 1303288
references.citation: Science. 1983 Feb 25;219(4587):979-80
references.pmid: 6823561
references.citation: Brain Res Mol Brain Res. 2005 Mar 24;134(1):57-66
references.pmid: 15790530
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1325-30
references.pmid: 17227870
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12937-42
references.pmid: 21768369
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15136-41
references.pmid: 18812510
references.citation: J Neurosci. 2007 Jul 25;27(30):8138-48
references.pmid: 17652604
references.citation: Nat Neurosci. 2000 Dec;3(12):1301-6
references.pmid: 11100151