title: Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis.
abstract: The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Lena F
authors.initials: LF
authors.lastname: Burbulla
authors.forename: Carina
authors.initials: C
authors.lastname: Schelling
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.forename: Doron
authors.initials: D
authors.lastname: Rapaport
authors.forename: Dirk
authors.initials: D
authors.lastname: Woitalla
authors.forename: Carola
authors.initials: C
authors.lastname: Schiesling
authors.forename: Claudia
authors.initials: C
authors.lastname: Schulte
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Stephan
authors.initials: S
authors.lastname: Jung
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
mesh_terms: D000368:Aged; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; C080352:mortalin; D004250:DNA Topoisomerases, Type II
references.citation: Neurochem Int. 2002 Dec;41(6):383-9
references.pmid: 12213225
references.citation: J Neuropathol Exp Neurol. 2008 Feb;67(2):117-24
references.pmid: 18219256
references.citation: Exp Cell Res. 1995 Jan;216(1):101-6
references.pmid: 7813609
references.citation: J Biol Chem. 2007 Feb 23;282(8):5910-8
references.pmid: 17189267
references.citation: Science. 2004 May 21;304(5674):1158-60
references.pmid: 15087508
references.citation: Biochem Biophys Res Commun. 2000 Aug 18;275(1):174-9
references.pmid: 10944461
references.citation: J Neural Transm (Vienna). 2009 Oct;116(10):1289-93
references.pmid: 19657588
references.citation: Cell Stress Chaperones. 2006 Summer;11(2):116-28
references.pmid: 16817317
references.citation: Nature. 1994 Oct 27;371(6500):768-74
references.pmid: 7935837
references.citation: JAMA. 2001 Nov 14;286(18):2239-44
references.pmid: 11710888
references.citation: Ann N Y Acad Sci. 2006 May;1067:220-3
references.pmid: 16803989
references.citation: Ann N Y Acad Sci. 2007 Apr;1100:306-11
references.pmid: 17460192
references.citation: Mol Cell Biochem. 2005 Jan;268(1-2):45-51
references.pmid: 15724436
references.citation: J Med Genet. 2004 Dec;41(12):900-7
references.pmid: 15591275
references.citation: Neurology. 1988 Sep;38(9):1402-6
references.pmid: 3412587
references.citation: Science. 2003 Jan 10;299(5604):256-9
references.pmid: 12446870
references.citation: Am J Physiol Cell Physiol. 2005 Jun;288(6):C1440-50
references.pmid: 15647387
references.citation: Biogerontology. 2008 Dec;9(6):391-403
references.pmid: 18770009
references.citation: Neuropathol Appl Neurobiol. 2008 Jun;34(3):255-71
references.pmid: 18447897
references.citation: Electrophoresis. 1999 Dec;20(18):3551-67
references.pmid: 10612281
references.citation: PLoS One. 2010 Feb 23;5(2):e9367
references.pmid: 20186336
references.citation: Mol Cell Biol. 1987 May;7(5):1906-16
references.pmid: 3037338
references.citation: Hum Mol Genet. 2005 Aug 1;14(15):2099-111
references.pmid: 15961413
references.citation: BMC Bioinformatics. 2008 Mar 26;9:163
references.pmid: 18366760
references.citation: Brain Res Mol Brain Res. 2005 Mar 24;134(1):119-38
references.pmid: 15790536
references.citation: FEBS Lett. 2002 Apr 10;516(1-3):53-7
references.pmid: 11959102
references.citation: Exp Cell Res. 2003 May 15;286(1):96-101
references.pmid: 12729798
references.citation: EMBO J. 1994 Nov 1;13(21):5135-45
references.pmid: 7957078
references.citation: J Cell Sci. 2007 May 15;120(Pt 10):1707-16
references.pmid: 17502481
references.citation: Neurol Sci. 2003 Oct;24(3):159-60
references.pmid: 14598065
references.citation: Nat Genet. 2009 Dec;41(12):1308-12
references.pmid: 19915575
references.citation: Nat Rev Mol Cell Biol. 2004 Jul;5(7):519-30
references.pmid: 15232570
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9103-8
references.pmid: 15181200
references.citation: Free Radic Res. 2005 Oct;39(10):1091-9
references.pmid: 16298734
references.citation: J Mol Biol. 2005 Aug 5;351(1):206-18
references.pmid: 15992824
references.citation: Exp Neurol. 2007 Feb;203(2):370-80
references.pmid: 17010972
references.citation: J Cell Biol. 2008 Dec 1;183(5):795-803
references.pmid: 19029340
references.citation: Proteomics. 2006 Aug;6(15):4300-8
references.pmid: 16819721
references.citation: Mol Cell Proteomics. 2007 May;6(5):845-59
references.pmid: 16854843
references.citation: J Cell Sci. 2001 Oct;114(Pt 19):3565-74
references.pmid: 11682615
references.citation: J Neurosci. 2007 Nov 7;27(45):12413-8
references.pmid: 17989306
references.citation: Parkinsonism Relat Disord. 1999 Dec;5(4):139-43
references.pmid: 18591132
references.citation: J Neural Transm (Vienna). 2000;107(5):553-62
references.pmid: 11072751
references.citation: Science. 2007 Feb 2;315(5812):607-9
references.pmid: 17272709
references.citation: Exp Gerontol. 2007 Apr;42(4):263-74
references.pmid: 17188442
references.citation: Cold Spring Harb Symp Quant Biol. 1995;60:619-27
references.pmid: 8824435
references.citation: DNA Cell Biol. 1994 Dec;13(12):1213-20
references.pmid: 7811387
references.citation: Ann Neurol. 2002 Nov;52(5):549-55
references.pmid: 12402251
references.citation: Exp Cell Res. 2010 Apr 15;316(7):1213-24
references.pmid: 20064504
references.citation: Mol Cell Proteomics. 2006 Jul;5(7):1193-204
references.pmid: 16565515
references.citation: Hum Mol Genet. 2003 Oct 15;12(20):2599-608
references.pmid: 12925570
references.citation: Bioinformatics. 2007 Jan 15;23(2):e191-7
references.pmid: 17237091
references.citation: Ann Neurol. 2004 Sep;56(3):336-41
references.pmid: 15349860
references.citation: Sci Aging Knowledge Environ. 2004 Jun 09;2004(23):pe26
references.pmid: 15190177
references.citation: J Biol Chem. 2008 May 9;283(19):12681-5
references.pmid: 18362145
references.citation: Ann Neurol. 2003 Sep;54(3):283-6
references.pmid: 12953260
references.citation: Brain. 2005 Dec;128(Pt 12):3000-11
references.pmid: 16251215
references.citation: J Neurosci Res. 2009 Jan;87(1):123-9
references.pmid: 18711745
references.citation: Exp Cell Res. 1997 Nov 25;237(1):38-45
references.pmid: 9417864