title: The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila.
abstract: Mutations in PTEN-induced kinase 1 (pink1) or parkin cause autosomal-recessive and some sporadic forms of Parkinson's disease. pink1 acts upstream of parkin in a common genetic pathway to regulate mitochondrial integrity in Drosophila. Mitochondrial morphology is maintained by a dynamic balance between the opposing actions of mitochondrial fusion, controlled by Mitofusin (mfn) and Optic atrophy 1 (opa1), and mitochondrial fission, controlled by drp1. Here, we explore interactions between pink1/parkin and the mitochondrial fusion/fission machinery. Muscle-specific knockdown of the fly homologue of Mfn (Marf) or opa1, or overexpression of drp1, results in significant mitochondrial fragmentation. Mfn-knockdown flies also display altered cristae morphology. Interestingly, knockdown of Mfn or opa1 or overexpression of drp1, rescues the phenotypes of muscle degeneration, cell death, and mitochondrial abnormalities in pink1 or parkin mutants. In the male germline, we also observe genetic interactions between pink1 and the testes-specific mfn homologue fuzzy onion, and between pink1 and drp1. Our data suggest that the pink1/parkin pathway promotes mitochondrial fission and/or inhibits fusion by negatively regulating mfn and opa1 function, and/or positively regulating drp1. However, pink1 and parkin mutant flies show distinct mitochondrial phenotypes from drp1 mutant flies, and flies carrying a heterozygous mutation in drp1 enhance the pink1-null phenotype, resulting in lethality. These results suggest that pink1 and parkin are likely not core components of the drp1-mediated mitochondrial fission machinery. Modification of fusion and fission may represent a novel therapeutic strategy for Parkinson's disease.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Hansong
authors.initials: H
authors.lastname: Deng
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dodson
authors.forename: Haixia
authors.initials: H
authors.lastname: Huang
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D009132:Muscles / Q000201:enzymology / Q000378:metabolism; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics*; D013091:Spermatogenesis / Q000235:genetics; D013737:Testis / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase
chemical_list: D029721:Drosophila Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C487430:park protein, Drosophila
references.citation: Science. 1997 Jun 27;276(5321):2045-7
references.pmid: 9197268
references.citation: Brain. 2006 Jul;129(Pt 7):1720-31
references.pmid: 16702191
references.citation: Curr Opin Neurobiol. 2007 Jun;17(3):331-7
references.pmid: 17499497
references.citation: Hum Mol Genet. 2005 Nov 15;14(22):3477-92
references.pmid: 16207731
references.citation: Science. 2007 Apr 27;316(5824):597-600
references.pmid: 17395794
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: Ann Neurol. 1999 May;45(5):668-72
references.pmid: 10319893
references.citation: Science. 2004 May 21;304(5674):1158-60
references.pmid: 15087508
references.citation: Annu Rev Biochem. 2007;76:751-80
references.pmid: 17362197
references.citation: Neuron. 2003 Sep 11;39(6):889-909
references.pmid: 12971891
references.citation: Neuron. 2005 Aug 4;47(3):365-78
references.pmid: 16055061
references.citation: PLoS Genet. 2008 Jan;4(1):e6
references.pmid: 18193945
references.citation: J Cell Biol. 2000 Oct 16;151(2):367-80
references.pmid: 11038183
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8
references.pmid: 16818890
references.citation: Dev Cell. 2001 Oct;1(4):515-25
references.pmid: 11703942
references.citation: Science. 2003 Oct 31;302(5646):841
references.pmid: 14593171
references.citation: J Cell Sci. 2002 Apr 15;115(Pt 8):1663-74
references.pmid: 11950885
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43
references.pmid: 18230723
references.citation: J Biol Chem. 1998 Aug 7;273(32):20150-5
references.pmid: 9685359
references.citation: Hum Mol Genet. 2008 Jan 15;17(2):293-302
references.pmid: 17947293
references.citation: Neuroscientist. 2002 Jun;8(3):192-7
references.pmid: 12061498
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):870-9
references.pmid: 17928812
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: Trends Mol Med. 2006 Nov;12(11):521-8
references.pmid: 17027339
references.citation: Annu Rev Genet. 2005;39:503-36
references.pmid: 16285870
references.citation: Nat Cell Biol. 1999 Sep;1(5):298-304
references.pmid: 10559943
references.citation: Nature. 1998 Apr 9;392(6676):605-8
references.pmid: 9560156
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83
references.pmid: 12642658
references.citation: Dev Biol. 2007 Mar 1;303(1):108-20
references.pmid: 17123504
references.citation: Mech Dev. 2002 Aug;116(1-2):213-6
references.pmid: 12128227
references.citation: Science. 1983 Feb 25;219(4587):979-80
references.pmid: 6823561
references.citation: Ann Neurol. 2004 Sep;56(3):336-41
references.pmid: 15349860
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
references.citation: Neurology. 2005 Jul 12;65(1):87-95
references.pmid: 16009891
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5703-8
references.pmid: 15824318