#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in


Mutations in PINK1 and Parkin cause familial, early onset Parkinson's disease. In Drosophila melanogaster, PINK1 and Parkin mutants show similar phenotypes, such as swollen and dysfunctional mitochondria, muscle degeneration, energy depletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrial fusion/fission pathway, and PINK1 and Parkin were recently proposed to form a mitochondrial quality control system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/fusion, and autophagy remain unclear; and other cellular events critical for PINK1 pathogenesis remain to be identified. Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. Induction of autophagy by Atg1 overexpression also rescued PINK1 mutant phenotypes, even in the presence of activated S6K. Downregulation of translation and activation of autophagy were already manifested in PINK1 mutant, suggesting that they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably serving to conserve energy. Interestingly, the enhanced PINK1 mutant phenotype in the presence of activated S6K could be fully rescued by Parkin, apparently in an autophagy-independent manner. Our results reveal complex cellular responses to PINK1 inactivation and suggest novel therapeutic strategies through manipulation of the compensatory responses.


Vyšlo v časopise: Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in. PLoS Genet 6(12): e32767. doi:10.1371/journal.pgen.1001237
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001237

Souhrn

Mutations in PINK1 and Parkin cause familial, early onset Parkinson's disease. In Drosophila melanogaster, PINK1 and Parkin mutants show similar phenotypes, such as swollen and dysfunctional mitochondria, muscle degeneration, energy depletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrial fusion/fission pathway, and PINK1 and Parkin were recently proposed to form a mitochondrial quality control system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/fusion, and autophagy remain unclear; and other cellular events critical for PINK1 pathogenesis remain to be identified. Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. Induction of autophagy by Atg1 overexpression also rescued PINK1 mutant phenotypes, even in the presence of activated S6K. Downregulation of translation and activation of autophagy were already manifested in PINK1 mutant, suggesting that they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably serving to conserve energy. Interestingly, the enhanced PINK1 mutant phenotype in the presence of activated S6K could be fully rescued by Parkin, apparently in an autophagy-independent manner. Our results reveal complex cellular responses to PINK1 inactivation and suggest novel therapeutic strategies through manipulation of the compensatory responses.


Zdroje

1. ValenteEM

Abou-SleimanPM

CaputoV

MuqitMM

HarveyK

2004 Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304 1158 1160

2. KitadaT

AsakawaS

HattoriN

MatsumineH

YamamuraY

1998 Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392 605 608

3. GandhiS

MuqitMM

StanyerL

HealyDG

Abou-SleimanPM

2006 PINK1 protein in normal human brain and Parkinson's disease. Brain 129 1720 1731

4. ZhouC

HuangY

ShaoY

MayJ

ProuD

2008 The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci U S A 105 12022 12027

5. YangY

GehrkeS

ImaiY

HuangZ

OuyangY

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. ParkJ

LeeSB

LeeS

KimY

SongS

2006 Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441 1157 1161

7. ClarkIE

DodsonMW

JiangC

CaoJH

HuhJR

2006 Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441 1162 1166

8. YangY

OuyangY

YangL

BealMF

McQuibbanA

2008 Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci U S A 105 7070 7075

9. PooleAC

ThomasRE

AndrewsLA

McBrideHM

WhitworthAJ

2008 The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A 105 1638 1643

10. DengH

DodsonMW

HuangH

GuoM

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

11. NarendraD

TanakaA

SuenDF

YouleRJ

2008 Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183 795 803

12. NarendraDP

JinSM

TanakaA

SuenDF

GautierCA

2010 PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin. PLoS Biol 8 e1000298 doi:10.1371/journal.pbio.1000298

13. ZivianiE

TaoRN

WhitworthAJ

2010 Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin. Proc Natl Acad Sci U S A 107 5018 5023

14. GeislerS

HolmstromKM

SkujatD

FieselFC

RothfussOC

2010 PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12 119 131

15. WullschlegerS

LoewithR

HallMN

2006 TOR signaling in growth and metabolism. Cell 124 471 484

16. CardenasC

MillerRA

SmithI

BuiT

MolgoJ

2010 Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell 142 270 283

17. HardieDG

2007 AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8 774 785

18. DingWX

NiHM

LiM

LiaoY

ChenX

2010 Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J Biol Chem 285 27879 27890

19. ImaiY

GehrkeS

WangHQ

TakahashiR

HasegawaK

2008 Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. Embo J 27 2432 2443

20. JefferiesHB

FumagalliS

DennisPB

ReinhardC

PearsonRB

1997 Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k. Embo J 16 3693 3704

21. BarceloH

StewartMJ

2002 Altering Drosophila S6 kinase activity is consistent with a role for S6 kinase in growth. Genesis 34 83 85

22. PearsonRB

DennisPB

HanJW

WilliamsonNA

KozmaSC

1995 The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. Embo J 14 5279 5287

23. HanJW

PearsonRB

DennisPB

ThomasG

1995 Rapamycin, wortmannin, and the methylxanthine SQ20006 inactivate p70s6k by inducing dephosphorylation of the same subset of sites. J Biol Chem 270 21396 21403

24. RaughtB

GingrasAC

SonenbergN

2000 Regulation of Ribosomal Recruitment in Eukaryotes.

SonenbergN

HersheyJWB

MathewsMB

Translational Control of Gene Expression Cold Spring Harbor Cold Spring Harbor Laboratory Press 245 293

25. HennigKM

NeufeldTP

2002 Inhibition of cellular growth and proliferation by dTOR overexpression in Drosophila. Genesis 34 107 110

26. ScottRC

JuhaszG

NeufeldTP

2007 Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. Curr Biol 17 1 11

27. BerryDL

BaehreckeEH

2007 Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131 1137 1148

28. ChangYY

NeufeldTP

2009 An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol Biol Cell 20 2004 2014

29. WhitworthAJ

TheodoreDA

GreeneJC

BenesH

WesPD

2005 Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc Natl Acad Sci U S A 102 8024 8029

30. TainLS

MortiboysH

TaoRN

ZivianiE

BandmannO

2009 Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat Neurosci 12 129 135

31. RuvinskyI

MeyuhasO

2006 Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci 31 342 348

32. LindstromMS

ZhangY

2008 Ribosomal protein S9 is a novel B23/NPM-binding protein required for normal cell proliferation. J Biol Chem 283 15568 15576

33. NakatogawaH

SuzukiK

KamadaY

OhsumiY

2009 Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10 458 467

34. LeeSB

KimS

LeeJ

ParkJ

LeeG

2007 ATG1, an autophagy regulator, inhibits cell growth by negatively regulating S6 kinase. EMBO Rep 8 360 365

35. LinMT

BealMF

2006 Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443 787 795

36. SchmidtEV

1999 The role of c-myc in cellular growth control. Oncogene 18 2988 2996

37. KapahiP

ZidBM

HarperT

KosloverD

SapinV

2004 Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14 885 890

38. ChaturvediRK

BealMF

2008 Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 1147 395 412

39. MizushimaN

LevineB

CuervoAM

KlionskyDJ

2008 Autophagy fights disease through cellular self-digestion. Nature 451 1069 1075

40. TwigG

ElorzaA

MolinaAJ

MohamedH

WikstromJD

2008 Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. Embo J 27 433 446

41. KurodaY

MitsuiT

KunishigeM

ShonoM

AkaikeM

2006 Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 15 883 895

42. CortiO

HampeC

KoutnikovaH

DariosF

JacquierS

2003 The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. Hum Mol Genet 12 1427 1437

43. DagdaRK

CherraSJ3rd

KulichSM

TandonA

ParkD

2009 Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 284 13843 13855

44. Friggi-GrelinF

CoulomH

MellerM

GomezD

HirshJ

2003 Targeted gene expression in Drosophila dopaminergic cells using regulatory sequences from tyrosine hydroxylase. J Neurobiol 54 618 627

45. PesahY

PhamT

BurgessH

MiddlebrooksB

VerstrekenP

2004 Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131 2183 2194

46. DavisRJ

TavsanliBC

DittrichC

WalldorfU

MardonG

2003 Drosophila retinal homeobox (drx) is not required for establishment of the visual system, but is required for brain and clypeus development. Dev Biol 259 272 287

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2010 Číslo 12
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#