title: The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway.
abstract: Loss-of-function mutations in the PINK1 or parkin genes result in recessive heritable forms of parkinsonism. Genetic studies of Drosophila orthologs of PINK1 and parkin indicate that PINK1, a mitochondrially targeted serine/threonine kinase, acts upstream of Parkin, a cytosolic ubiquitin-protein ligase, to promote mitochondrial fragmentation, although the molecular mechanisms by which the PINK1/Parkin pathway promotes mitochondrial fragmentation are unknown. We tested the hypothesis that PINK1 and Parkin promote mitochondrial fragmentation by targeting core components of the mitochondrial morphogenesis machinery for ubiquitination. We report that the steady-state abundance of the mitochondrial fusion-promoting factor Mitofusin (dMfn) is inversely correlated with the activity of PINK1 and Parkin in Drosophila. We further report that dMfn is ubiquitinated in a PINK1- and Parkin-dependent fashion and that dMfn co-immunoprecipitates with Parkin. By contrast, perturbations of PINK1 or Parkin did not influence the steady-state abundance of the mitochondrial fission-promoting factor Drp1 or the mitochondrial fusion-promoting factor Opa1, or the subcellular distribution of Drp1. Our findings suggest that dMfn is a direct substrate of the PINK1/Parkin pathway and that the mitochondrial morphological alterations and tissue degeneration phenotypes that derive from mutations in PINK1 and parkin result at least in part from reduced ubiquitin-mediated turnover of dMfn.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Poole
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Thomas
authors.forename: Selina
authors.initials: S
authors.lastname: Yu
authors.forename: Evelyn S
authors.initials: ES
authors.lastname: Vincow
authors.forename: Leo
authors.initials: L
authors.lastname: Pallanck
mesh_terms: D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000473:pathology; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C527117:Marf protein, Drosophila; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C487430:park protein, Drosophila
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 Dec 30;105(52):20567-74
references.pmid: 19074260
references.citation: J Biol Chem. 2009 Aug 21;284(34):22938-51
references.pmid: 19546216
references.citation: Nature. 2006 Jun 29;441(7097):1162-6
references.pmid: 16672981
references.citation: Biochem Biophys Res Commun. 2009 Jan 16;378(3):518-23
references.pmid: 19056353
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83
references.pmid: 12642658
references.citation: Mech Dev. 2002 Aug;116(1-2):213-6
references.pmid: 12128227
references.citation: EMBO J. 2000 Jan 4;19(1):94-102
references.pmid: 10619848
references.citation: J Biol Chem. 2009 May 15;284(20):13843-13855
references.pmid: 19279012
references.citation: EMBO J. 2006 Jul 12;25(13):2966-77
references.pmid: 16778770
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):7070-5
references.pmid: 18443288
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83
references.pmid: 19966284
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5018-23
references.pmid: 20194754
references.citation: Dis Model Mech. 2009 Jul-Aug;2(7-8):336-40
references.pmid: 19553694
references.citation: Nat Genet. 2006 May;38(5):515-7
references.pmid: 16604074
references.citation: Hum Mol Genet. 2005 Mar 15;14(6):799-811
references.pmid: 15689351
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. 2005 May 31;102(22):8024-9
references.pmid: 15911761
references.citation: IUBMB Life. 2008 Jul;60(7):448-55
references.pmid: 18465792
references.citation: Int J Biochem Cell Biol. 2009 Oct;41(10):2025-35
references.pmid: 19703660
references.citation: Development. 1993 Sep;119(1):1-17
references.pmid: 8565817
references.citation: NeuroRx. 2005 Jul;2(3):484-94
references.pmid: 16389312
references.citation: J Neurochem. 2009 Dec;111(5):1075-93
references.pmid: 19780902
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43
references.pmid: 18230723
references.citation: Nat Genet. 2006 May;38(5):518-20
references.pmid: 16604072
references.citation: Neuron. 1994 Sep;13(3):507-23
references.pmid: 7917288
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: Cell Death Differ. 2007 Jul;14(7):1261-6
references.pmid: 17464321
references.citation: Neuroscientist. 2002 Jun;8(3):192-7
references.pmid: 12061498
references.citation: Dev Biol. 1996 May 25;176(1):143-8
references.pmid: 8654890
references.citation: J Neurosci. 2007 Nov 7;27(45):12413-8
references.pmid: 17989306
references.citation: Development. 2004 May;131(9):2183-94
references.pmid: 15073152
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: PLoS One. 2009 May 27;4(5):e5701
references.pmid: 19492085
references.citation: Development. 1993 Jun;118(2):401-15
references.pmid: 8223268
references.citation: Cell. 1997 Jul 11;90(1):121-9
references.pmid: 9230308