Silencing of PINK1 Expression Affects Mitochondrial DNA and Oxidative Phosphorylation in DOPAMINERGIC Cells 英文参考文献.docVIP

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Silencing of PINK1 Expression Affects Mitochondrial DNA and Oxidative Phosphorylation in DOPAMINERGIC Cells 英文参考文献.doc

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Silencing of PINK1 Expression Affects Mitochondrial DNA and Oxidative Phosphorylation in DOPAMINERGIC Cells 英文参考文献

SilencingofPINK1ExpressionAffectsMitochondrialDNA andOxidativePhosphorylationinDOPAMINERGICCells MatthewE.Gegg,J.MarkCooper,AnthonyH.V.Schapira,Jan-WillemTaanman* DepartmentofClinicalNeurosciences,InstituteofNeurology,UniversityCollegeLondon,QueenSquare,London,UnitedKingdom Abstract Background:MitochondrialdysfunctionhasbeenimplicatedinthepathogenesisofParkinson’sdisease(PD).Impairmentof themitochondrialelectrontransportchain(ETC)andanincreasedfrequencyindeletionsofmitochondrialDNA(mtDNA), whichencodessomeofthesubunitsoftheETC,havebeenreportedinthesubstantianigraofPDbrains.Theidentification ofmutationsinthePINK1gene,whichcauseanautosomalrecessiveformofPD,hassupportedmitochondrialinvolvement in PD. The PINK1 protein is a serine/threonine kinase localized in mitochondria and the cytosol. Its precise function is unknown,butitisinvolvedinneuroprotectionagainstavarietyofstresssignallingpathways. Methodology/Principal Findings: In this report we have investigated the effect of silencing PINK1 expression in human dopaminergicSH-SY5YcellsbysiRNAonmtDNAsynthesisandETCfunction.LossofPINK1expressionresultedinadecrease in mtDNA levels and mtDNA synthesis. We also report a concomitant loss of mitochondrial membrane potential and decreased mitochondrial ATP synthesis, with the activity of complex IV of the ETC most affected. This mitochondrial dysfunction resulted in increased markers of oxidative stress under basal conditions and increased cell death following treatmentwiththefreeradicalgeneratorparaquat. Conclusions: This report highlights a novel function of PINK1 in mitochondrial biogenesis and a role in maintaining mitochondrialETCactivity.DysfunctionofbothhasbeenimplicatedinsporadicformsofPDsuggestingthatthesemaybe keypathwaysinthedevelopmentofthedisease. Citation:GeggME,CooperJM,SchapiraAHV,TaanmanJ-W(2009)SilencingofPINK1ExpressionAffectsMitochondrialDNAandOxidativePhosphorylationin DOPAMINERGICCells.PLoSONE4(3):e4756.doi:10.1371/journal.pone.0004756 Editor:SimonMelov,B