Mutations in PINK1 and Parkin Impair Ubiquitination of Mitofusins in Human Fibroblasts 英文参考文献.docVIP

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Mutations in PINK1 and Parkin Impair Ubiquitination of Mitofusins in Human Fibroblasts 英文参考文献.doc

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Mutations in PINK1 and Parkin Impair Ubiquitination of Mitofusins in Human Fibroblasts 英文参考文献

MutationsinPINK1andParkinImpairUbiquitinationof MitofusinsinHumanFibroblasts AleksandarRakovic1.,AnneGru¨newald1.,JanKottwitz1,NorbertBru¨ggemann1,PeterP.Pramstaller2, KatjaLohmann1,ChristineKlein1* 1SectionofClinicalandMolecularNeurogenetics,DepartmentofNeurology,UniversityofLu¨beck,Lu¨beck,Germany,2InstituteofGeneticMedicine,EuropeanAcademy, Bolzano,Italy Abstract PINK1andParkinmutationscauserecessiveParkinson’sdisease(PD).InDrosophilaandSH-SY5Ycells,Parkinisrecruitedby PINK1todamagedmitochondria,whereitubiquitinatesMitofusinsandconsequentlypromotesmitochondrialfissionand mitophagy. Here, we investigated the impact of mutations in endogenous PINK1 and Parkin on the ubiquitination of mitochondrial fusion and fission factors and the mitochondrial network structure. Treating control fibroblasts with mitochondrialmembranepotential(Dy)inhibitorsorH2O2 resultedinubiquitinationofMfn1/2butnotofOPA1orFis1. Ubiquitination of Mitofusins through the PINK1/Parkin pathway was observed within 1h of treatment. Upon combined inhibition of Dy and the ubiquitin proteasome system (UPS), no ubiquitination of Mitofusins was detected. Regarding morphological changes, we observed a trend towards increased mitochondrial branching in PD patient cells upon mitochondrial stress. For the first time in PD patient-derived cells, we demonstrate that mutations in PINK1 and Parkin impairubiquitinationofMitofusins.InthepresenceofUPSinhibitors,ubiquitinatedMitofusinisdeubiquitinatedbytheUPS butnotdegraded,suggestingthattheUPSisinvolvedinMitofusindegradation. Citation:RakovicA,Gru¨newaldA,KottwitzJ,Bru¨ggemannN,PramstallerPP,etal.(2011)MutationsinPINK1andParkinImpairUbiquitinationofMitofusinsin HumanFibroblasts.PLoSONE6(3):e16746.doi:10.1371/journal.pone.0016746 Editor:MarkCookson,NationalInstitutesofHealth,UnitedStatesofAmerica ReceivedNovember22,2010;AcceptedJanuary11,2011;PublishedMarch8,2011 Copyright: ? 2011 Rakovic et al. This is an open-access article distributed under the terms of the Cr