title: PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy.
abstract: Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential-dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.
authors.affiliation: Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan. matsuda-nr@igakuken.or.jp
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Matsuda
authors.forename: Shigeto
authors.initials: S
authors.lastname: Sato
authors.forename: Kahori
authors.initials: K
authors.lastname: Shiba
authors.forename: Kei
authors.initials: K
authors.lastname: Okatsu
authors.forename: Keiko
authors.initials: K
authors.lastname: Saisho
authors.forename: Clement A
authors.initials: CA
authors.lastname: Gautier
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Sou
authors.forename: Shinji
authors.initials: S
authors.lastname: Saiki
authors.forename: Sumihiro
authors.initials: S
authors.lastname: Kawajiri
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sato
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kimura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012997:Solvents / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D015415:Biomarkers; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D004121:Dimethyl Sulfoxide; D005456:Fluorescent Dyes; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D012997:Solvents; D044767:Ubiquitin-Protein Ligases; D014475:Uncoupling Agents; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8
references.pmid: 16818890
references.citation: J Cell Biol. 2005 May 9;169(3):425-34
references.pmid: 15866887
references.citation: Lancet Neurol. 2008 Jan;7(1):97-109
references.pmid: 18093566
references.citation: J Alzheimers Dis. 2010;19(1):1-9
references.pmid: 20061621
references.citation: Curr Opin Neurobiol. 2007 Jun;17(3):331-7
references.pmid: 17499497
references.citation: J Biol Chem. 2009 May 29;284(22):14978-86
references.pmid: 19339245
references.citation: Nature. 2006 Jun 29;441(7097):1162-6
references.pmid: 16672981
references.citation: Nature. 2006 Jun 29;441(7097):1157-61
references.pmid: 16672980
references.citation: J Neurosci. 2007 Nov 7;27(45):12413-8
references.pmid: 17989306
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12022-7
references.pmid: 18687899
references.citation: PLoS Biol. 2010 Jan 26;8(1):e1000298
references.pmid: 20126261
references.citation: Hum Mol Genet. 2006 Nov 1;15(21):3251-62
references.pmid: 17000703
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5703-8
references.pmid: 15824318
references.citation: J Biol Chem. 2000 Nov 17;275(46):35661-4
references.pmid: 10973942
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83
references.pmid: 19966284
references.citation: Exp Hematol. 2003 Nov;31(11):1007-14
references.pmid: 14585362
references.citation: Nat Genet. 2000 Jul;25(3):302-5
references.pmid: 10888878
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13354-9
references.pmid: 11078524
references.citation: Ann Neurol. 2006 Oct;60(4):389-98
references.pmid: 17068789
references.citation: Neurosci Lett. 2008 Jan 3;430(1):13-7
references.pmid: 18031932
references.citation: Hum Mol Genet. 2006 Jul 1;15(13):2059-75
references.pmid: 16714300
references.citation: Hum Mol Genet. 2005 Nov 15;14(22):3477-92
references.pmid: 16207731
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11364-9
references.pmid: 18687901
references.citation: Oncogene. 2003 Nov 13;22(51):8370-8
references.pmid: 14614460
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. 1998 Apr 9;392(6676):605-8
references.pmid: 9560156
references.citation: Expert Rev Proteomics. 2007 Dec;4(6):769-81
references.pmid: 18067415
references.citation: J Biol Chem. 2003 Nov 28;278(48):48120-8
references.pmid: 12972409
references.citation: Science. 2004 May 21;304(5674):1158-60
references.pmid: 15087508
references.citation: Annu Rev Neurosci. 2005;28:57-87
references.pmid: 16022590
references.citation: J Biol Chem. 2006 Feb 10;281(6):3204-9
references.pmid: 16339143