title: PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility.
abstract: Cells keep their energy balance and avoid oxidative stress by regulating mitochondrial movement, distribution, and clearance. We report here that two Parkinson's disease proteins, the Ser/Thr kinase PINK1 and ubiquitin ligase Parkin, participate in this regulation by arresting mitochondrial movement. PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. Removal of Miro from the mitochondrion also detaches kinesin from its surface. By preventing mitochondrial movement, the PINK1/Parkin pathway may quarantine damaged mitochondria prior to their clearance. PINK1 has been shown to act upstream of Parkin, but the mechanism corresponding to this relationship has not been known. We propose that PINK1 phosphorylation of substrates triggers the subsequent action of Parkin and the proteasome.
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Xinnan
authors.initials: X
authors.lastname: Wang
authors.forename: Dominic
authors.initials: D
authors.lastname: Winter
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Ashrafi
authors.forename: Julia
authors.initials: J
authors.lastname: Schlehe
authors.forename: Yao Liang
authors.initials: YL
authors.lastname: Wong
authors.forename: Dennis
authors.initials: D
authors.lastname: Selkoe
authors.forename: Sarah
authors.initials: S
authors.lastname: Rice
authors.forename: Judith
authors.initials: J
authors.lastname: Steen
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LaVoie
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism; D004331:Drosophila melanogaster; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D020741:rho GTP-Binding Proteins; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C504427:Miro protein, Drosophila; C473124:RHOT1 protein, human; C473125:RHOT2 protein, human
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14503-8
references.pmid: 18799731
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8
references.pmid: 16818890
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43
references.pmid: 18230723
references.citation: J Neurosci. 2007 Nov 7;27(45):12413-8
references.pmid: 17989306
references.citation: Development. 2003 Jun;130(12):2645-56
references.pmid: 12736209
references.citation: PLoS One. 2010 Apr 07;5(4):e10054
references.pmid: 20383334
references.citation: Biochem Biophys Res Commun. 2006 Jun 2;344(2):500-10
references.pmid: 16630562
references.citation: J Bioenerg Biomembr. 2009 Dec;41(6):499-503
references.pmid: 19967438
references.citation: Cell. 2009 Jan 9;136(1):163-74
references.pmid: 19135897
references.citation: J Biol Chem. 2003 Oct 31;278(44):43628-35
references.pmid: 12930822
references.citation: Curr Opin Cell Biol. 2011 Aug;23(4):476-82
references.pmid: 21705204
references.citation: Traffic. 2007 Dec;8(12):1668-1675
references.pmid: 17944806
references.citation: Prog Brain Res. 2010;183:59-77
references.pmid: 20696315
references.citation: Nat Rev Mol Cell Biol. 2011 Jan;12(1):9-14
references.pmid: 21179058
references.citation: Biochemistry. 2009 Mar 10;48(9):2045-52
references.pmid: 19152501
references.citation: J Cell Biol. 2010 Nov 29;191(5):933-42
references.pmid: 21115803
references.citation: Neuron. 2009 Feb 26;61(4):541-55
references.pmid: 19249275
references.citation: Cell. 2011 Mar 4;144(5):689-702
references.pmid: 21376232
references.citation: Am J Physiol Cell Physiol. 2010 Aug;299(2):C477-87
references.pmid: 20445168
references.citation: J Biol Chem. 2005 Apr 15;280(15):14723-32
references.pmid: 15644324
references.citation: Hum Mol Genet. 2005 Sep 1;14(17):2571-86
references.pmid: 16049031
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11364-9
references.pmid: 18687901
references.citation: J Biol Chem. 2004 Apr 30;279(18):18614-22
references.pmid: 14985362
references.citation: J Cell Biol. 2006 May 22;173(4):545-57
references.pmid: 16717129
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20728-33
references.pmid: 19098100
references.citation: Hum Mol Genet. 2009 Nov 15;18(22):4390-404
references.pmid: 19692353
references.citation: Hum Mol Genet. 2011 Mar 1;20(5):867-79
references.pmid: 21138942
references.citation: Mol Cell. 2009 Mar 13;33(5):627-38
references.pmid: 19285945
references.citation: Nature. 2006 Jun 29;441(7097):1162-6
references.pmid: 16672981
references.citation: J Cell Biol. 2008 Dec 1;183(5):795-803
references.pmid: 19029340
references.citation: Nat Cell Biol. 2010 Feb;12(2):119-31
references.pmid: 20098416
references.citation: Nature. 2006 Jun 29;441(7097):1157-61
references.pmid: 16672980
references.citation: Neuron. 2005 Aug 4;47(3):379-93
references.pmid: 16055062
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12022-7
references.pmid: 18687899
references.citation: Methods Enzymol. 2009;457:319-33
references.pmid: 19426876
references.citation: PLoS Biol. 2010 Jan 26;8(1):e1000298
references.pmid: 20126261
references.citation: J Neurosci. 2010 Mar 24;30(12):4232-40
references.pmid: 20335458
references.citation: Biochim Biophys Acta. 2011 Jan;1813(1):269-81
references.pmid: 21034780
references.citation: Mol Biol Cell. 2006 Apr;17(4):2057-68
references.pmid: 16467387
references.citation: Hum Mol Genet. 2009 Nov 15;18(22):4317-28
references.pmid: 19679562
references.citation: Nature. 1998 Apr 9;392(6676):605-8
references.pmid: 9560156
references.citation: Neuron. 2011 Jun 23;70(6):1033-53
references.pmid: 21689593
references.citation: Neuron. 2002 Dec 19;36(6):1063-77
references.pmid: 12495622
references.citation: Hum Mol Genet. 2011 May 1;20(9):1726-37
references.pmid: 21296869
references.citation: Science. 2004 May 21;304(5674):1158-60
references.pmid: 15087508
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5018-23
references.pmid: 20194754
references.citation: Hum Mol Genet. 2011 Mar 1;20(5):927-40
references.pmid: 21147754
references.citation: Trends Mol Med. 2011 Mar;17(3):158-65
references.pmid: 21146459