Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.
Vyšlo v časopise: Parkinson's Disease–Associated Kinase PINK1 Regulates Miro Protein Level and Axonal Transport of Mitochondria. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002537 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002537
1. KitadaTAsakawaSHattoriNMatsumineHYamamuraY 1998 Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392 605 608
2. ValenteEMAbou-SleimanPMCaputoVMuqitMMHarveyK 2004 Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304 1158 1160
3. ParkJLeeSBLeeSKimYSongS 2006 Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441 1157 1161
4. ClarkIEDodsonMWJiangCCaoJHHuhJR 2006 Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441 1162 1166
5. YangYGehrkeSImaiYHuangZOuyangY 2006 Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc Natl Acad Sci U S A 103 10793 10798
6. WangDQianLXiongHLiuJNeckameyerWS 2006 Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc Natl Acad Sci U S A 103 13520 13525
7. YangYOuyangYYangLBealMFMcQuibbanA 2008 Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci U S A 105 7070 7075
8. PooleACThomasREAndrewsLAMcBrideHMWhitworthAJ 2008 The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A 105 1638 1643
9. DengHDodsonMWHuangHGuoM 2008 The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci U S A 105 14503 14508
10. LuBVogelH 2009 Drosophila models of neurodegenerative diseases. Annu Rev Pathol 4 315 342
11. WhitworthAJPallanckLJ 2009 The PINK1/Parkin pathway: a mitochondrial quality control system? J Bioenerg Biomembr 41 499 503
12. YuWSunYGuoSLuB 2011 The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons. Hum Mol Genet 20 3227 3240
13. NarendraDTanakaASuenDFYouleRJ 2008 Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183 795 803
14. GeislerSHolmstromKMSkujatDFieselFCRothfussOC 2010 PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12 119 131
15. YouleRJNarendraDP 2011 Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12 9 14
16. ChuCT 2010 A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease. Hum Mol Genet 19 R28 37
17. ImaiYLuB 2011 Mitochondrial dynamics and mitophagy in Parkinson's disease: disordered cellular power plant becomes a big deal in a major movement disorder. Curr Opin Neurobiol 21 935 941
18. TassinJDurrAde BrouckerTAbbasNBonifatiV 1998 Chromosome 6-linked autosomal recessive early-onset Parkinsonism: linkage in European and Algerian families, extension of the clinical spectrum, and evidence of a small homozygous deletion in one family. The French Parkinson's Disease Genetics Study Group, and the European Consortium on Genetic Susceptibility in Parkinson's Disease. Am J Hum Genet 63 88 94
19. BonifatiVRoheCFBreedveldGJFabrizioEDe MariM 2005 Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65 87 95
20. AbbruzzeseGPigulloSSchenoneABelloneEMarcheseR 2004 Does parkin play a role in the peripheral nervous system? A family report. Mov Disord 19 978 981
21. BalohRH 2008 Mitochondrial dynamics and peripheral neuropathy. Neuroscientist 14 12 18
22. DuncanJEGoldsteinLS 2006 The genetics of axonal transport and axonal transport disorders. PLoS Genet 2 e124 doi:10.1371/journal.pgen.0020124
23. ZuchnerSVanceJM 2006 Mechanisms of disease: a molecular genetic update on hereditary axonal neuropathies. Nat Clin Pract Neurol 2 45 53
24. EbnethAGodemannRStamerKIllenbergerSTrinczekB 1998 Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. J Cell Biol 143 777 794
25. MagraneJManfrediG 2009 Mitochondrial function, morphology, and axonal transport in amyotrophic lateral sclerosis. Antioxid Redox Signal 11 1615 1626
26. Kim-HanJSAntenor-DorseyJAO'MalleyKL 2011 The Parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons. J Neurosci 31 7212 7221
27. SterkyFHLeeSWibomROlsonLLarssonNG 2011 Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo. Proc Natl Acad Sci U S A 108 12937 12942
28. HirokawaN 1998 Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 279 519 526
29. HollenbeckPJSaxtonWM 2005 The axonal transport of mitochondria. J Cell Sci 118 5411 5419
30. FranssonARuusalaAAspenstromP 2003 Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J Biol Chem 278 6495 6502
31. GuoXMacleodGTWellingtonAHuFPanchumarthiS 2005 The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron 47 379 393
32. StowersRSMegeathLJGorska-AndrzejakJMeinertzhagenIASchwarzTL 2002 Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 36 1063 1077
33. LiuWAcin-PerezRGeghmanKDManfrediGLuB 2011 Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission. Proc Natl Acad Sci U S A 108 12920 12924
34. WangXWinterDAshrafiGSchleheJWongYL 2011 PINK1 and Parkin Target Miro for Phosphorylation and Degradation to Arrest Mitochondrial Motility. Cell 147 893 906
35. LiuSLuB 2010 Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in Drosophila melanogaster. PLoS Genet 6 e1001237 doi:10.1371/journal.pgen.1001237
36. WeihofenAThomasKJOstaszewskiBLCooksonMRSelkoeDJ 2009 Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry 48 2045 2052
37. PillingADHoriuchiDLivelyCMSaxtonWM 2006 Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons. Mol Biol Cell 17 2057 2068
38. RussoGJLouieKWellingtonAMacleodGTHuF 2009 Drosophila Miro is required for both anterograde and retrograde axonal mitochondrial transport. J Neurosci 29 5443 5455
39. NarendraDPJinSMTanakaASuenDFGautierCA 2010 PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin. PLoS Biol 8 e1000298 doi:10.1371/journal.pbio.1000298
40. ChanNCSalazarAMPhamAHSweredoskiMJKolawaNJ 2011 Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 20 1726 37
41. YoshiiSRKishiCIshiharaNMizushimaN 2011 Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane. J Biol Chem 286 19630 19640
42. ImaiYKanaoTSawadaTKobayashiYMoriwakiY 2010 The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila. PLoS Genet 6 e1001229 doi:10.1371/journal.pgen.1001229
43. GautierCAKitadaTShenJ 2008 Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A 105 11364 11369
44. SatoSHattoriN 2011 Genetic mutations and mitochondrial toxins shed new light on the pathogenesis of Parkinson's disease. Parkinsons Dis 2011 979231
45. ExnerNTreskeBPaquetDHolmstromKSchieslingC 2007 Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci 27 12413 12418
46. Van LaarVSArnoldBCassadySJChuCTBurtonEA 2011 Bioenergetics of neurons inhibit the translocation response of Parkin following rapid mitochondrial depolarization. Hum Mol Genet 20 927 940
47. KitadaTPisaniAPorterDRYamaguchiHTscherterA 2007 Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A 104 11441 11446
48. Wood-KaczmarAGandhiSYaoZAbramovAYMiljanEA 2008 PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE 3 e2455 doi:10.1371/journal.pone.0002455
49. WangHLChouAHWuASChenSYWengYH 2011 PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons. Biochimica et biophysica acta 1812 674 684
50. AkundiRSHuangZEasonJPandyaJDZhiL 2011 Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS ONE 6 e16038 doi:10.1371/journal.pone.0016038
51. TanakaAClelandMMXuSNarendraDPSuenDF 2010 Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191 1367 1380
52. Di BartolomeoSCorazzariMNazioFOliverioSLisiG 2010 The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol 191 155 168
53. GreeneJCWhitworthAJAndrewsLAParkerTJPallanckLJ 2005 Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum Mol Genet 14 799 811
54. FernandesCRaoY 2011 Genome-wide screen for modifiers of Parkinson's disease genes in Drosophila. Mol Brain 4 17
55. SuzukiYImaiYNakayamaHTakahashiKTakioK 2001 A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8 613 621
56. MatsudaNSatoSShibaKOkatsuKSaishoK 2010 PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189 211 221
57. PridgeonJWOlzmannJAChinLSLiL 2007 PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1. PLoS Biol 5 e172 doi:10.1371/journal.pbio.0050172
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
