The Yeast Complex I Equivalent NADH Dehydrogenase Rescues Mutants

English version České info

Pink1 is a mitochondrial kinase involved in Parkinson's disease, and loss of Pink1 function affects mitochondrial morphology via a pathway involving Parkin and components of the mitochondrial remodeling machinery. Pink1 loss also affects the enzymatic activity of isolated Complex I of the electron transport chain (ETC); however, the primary defect in pink1 mutants is unclear. We tested the hypothesis that ETC deficiency is upstream of other pink1-associated phenotypes. We expressed Saccaromyces cerevisiae Ndi1p, an enzyme that bypasses ETC Complex I, or sea squirt Ciona intestinalis AOX, an enzyme that bypasses ETC Complex III and IV, in pink1 mutant Drosophila and find that expression of Ndi1p, but not of AOX, rescues pink1-associated defects. Likewise, loss of function of subunits that encode for Complex I–associated proteins displays many of the pink1-associated phenotypes, and these defects are rescued by Ndi1p expression. Conversely, expression of Ndi1p fails to rescue any of the parkin mutant phenotypes. Additionally, unlike pink1 mutants, fly parkin mutants do not show reduced enzymatic activity of Complex I, indicating that Ndi1p acts downstream or parallel to Pink1, but upstream or independent of Parkin. Furthermore, while increasing mitochondrial fission or decreasing mitochondrial fusion rescues mitochondrial morphological defects in pink1 mutants, these manipulations fail to significantly rescue the reduced enzymatic activity of Complex I, indicating that functional defects observed at the level of Complex I enzymatic activity in pink1 mutant mitochondria do not arise from morphological defects. Our data indicate a central role for Complex I dysfunction in pink1-associated defects, and our genetic analyses with heterologous ETC enzymes suggest that Ndi1p-dependent NADH dehydrogenase activity largely acts downstream of, or in parallel to, Pink1 but upstream of Parkin and mitochondrial remodeling.

Vyšlo v časopise: The Yeast Complex I Equivalent NADH Dehydrogenase Rescues Mutants. PLoS Genet 8(1): e32767. doi:10.1371/journal.pgen.1002456
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002456

Souhrn

Zdroje

1. DauerWPrzedborskiS 2003 Parkinson's disease: mechanisms and models. Neuron 39 889 909

2. MoraisVADe StrooperB 2010 Mitochondria dysfunction and neurodegenerative disorders: cause or consequence. J Alzheimers Dis 20 Suppl 2 S255 263

3. MandemakersWMoraisVADe StrooperB 2007 A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases. J Cell Sci 120 1707 1716

4. WinklhoferKFHaassC 2009 Mitochondrial dysfunction in Parkinson's disease. Biochim Biophys Acta 1802 29 44

5. PanovADikalovSShalbuyevaNTaylorGShererT 2005 Rotenone model of Parkinson disease: multiple brain mitochondria dysfunctions after short term systemic rotenone intoxication. J Biol Chem 280 42026 42035

6. ShererTBBetarbetRGreenamyreJT 2002 Environment, mitochondria, and Parkinson's disease. Neuroscientist 8 192 197

7. ParkerWDJrSwerdlowRH 1998 Mitochondrial dysfunction in idiopathic Parkinson disease. Am J Hum Genet 62 758 762

8. 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

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

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

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

12. GreeneJCWhitworthAJKuoIAndrewsLAFeanyMB 2003 Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci U S A 100 4078 4083

13. MeulenerMWhitworthAJArmstrong-GoldCERizzuPHeutinkP 2005 Drosophila DJ-1 mutants are selectively sensitive to environmental toxins associated with Parkinson's disease. Curr Biol 15 1572 1577

14. HaoLYGiassonBIBoniniNM 2010 DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function. Proc Natl Acad Sci U S A 107 9747 9752

15. MoraisVAVerstrekenPRoethigASmetJSnellinxA 2009 Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function. EMBO Mol Med 1 99 111

16. VerstrekenPLyCVVenkenKJKohTWZhouY 2005 Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47 365 378

17. 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

18. NarendraDPJinSMTanakaASuenDFGautierCA 2010 PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8 e1000298 doi:10.1371/journal.pbio.1000298

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

20. Vives-BauzaCZhouCHuangYCuiMde VriesRL 2010 PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A 107 378 383

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

22. ParkJLeeGChungJ 2009 The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process. Biochem Biophys Res Commun 378 518 523

23. 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

24. ParkJKimYChoiSKohHLeeSH 2010 Drosophila Porin/VDAC affects mitochondrial morphology. PLoS ONE 5 e13151 doi:10.1371/journal.pone.0013151

25. GrahamBHLiZAlesiiEPVerstekenPLeeC 2010 Neurologic dysfunction and male infertility in Drosophila porin mutants: a new model for mitochondrial dysfunction and disease. J Biol Chem 285 11143 11153

26. IchishitaRTanakaKSugiuraYSayanoTMiharaK 2008 An RNAi screen for mitochondrial proteins required to maintain the morphology of the organelle in Caenorhabditis elegans. J Biochem 143 449 454

27. SeoBBKitajima-IharaTChanEKSchefflerIEMatsuno-YagiA 1998 Molecular remedy of complex I defects: rotenone-insensitive internal NADH-quinone oxidoreductase of Saccharomyces cerevisiae mitochondria restores the NADH oxidase activity of complex I-deficient mammalian cells. Proc Natl Acad Sci U S A 95 9167 9171

28. BaiYHajekPChomynAChanESeoBB 2001 Lack of complex I activity in human cells carrying a mutation in MtDNA-encoded ND4 subunit is corrected by the Saccharomyces cerevisiae NADH-quinone oxidoreductase (NDI1) gene. J Biol Chem 276 38808 38813

29. JuszczukIMRychterAM 2003 Alternative oxidase in higher plants. Acta Biochim Pol 50 1257 1271

30. BahadoraniSChoJLoTContrerasHLawalHO 2010 Neuronal expression of a single-subunit yeast NADH-ubiquinone oxidoreductase (Ndi1) extends Drosophila lifespan. Aging Cell 9 191 202

31. SanzASoikkeliMPortero-OtinMWilsonAKemppainenE 2010 Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction. Proc Natl Acad Sci U S A 107 9105 9110

32. Fernandez-AyalaDJSanzAVartiainenSKemppainenKKBabusiakM 2009 Expression of the Ciona intestinalis alternative oxidase (AOX) in Drosophila complements defects in mitochondrial oxidative phosphorylation. Cell Metab 9 449 460

33. DeCorbyAGaskovaDSaylesLCLemireBD 2007 Expression of Ndi1p, an alternative NADH:ubiquinone oxidoreductase, increases mitochondrial membrane potential in a C. elegans model of mitochondrial disease. Biochim Biophys Acta 1767 1157 1163

34. MarellaMSeoBBNakamaru-OgisoEGreenamyreJTMatsuno-YagiA 2008 Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease. PLoS ONE 3 e1433 doi:10.1371/journal.pone.0001433

35. KuromiHKidokoroY 2000 Tetanic stimulation recruits vesicles from reserve pool via a cAMP-mediated process in Drosophila synapses. Neuron 27 133 143

36. BetzWJMaoFSmithCB 1996 Imaging exocytosis and endocytosis. Curr Opin Neurobiol 6 365 371

37. VerstrekenPOhyamaTBellenHJ 2008 FM 1–43 labeling of synaptic vesicle pools at the Drosophila neuromuscular junction. Methods Mol Biol 440 349 369

38. ReersMSmithTWChenLB 1991 J-aggregate formation of a carbocyanine as a quantitative fluorescent indicator of membrane potential. Biochemistry 30 4480 4486

39. ZivianiETaoRNWhitworthAJ 2010 Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci U S A 107 5018 5023

40. PooleACThomasREYuSVincowESPallanckL 2010 The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS ONE 5 e10054 doi:10.1371/journal.pone.0010054

41. Plun-FavreauHKlupschKMoisoiNGandhiSKjaerS 2007 The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat Cell Biol 9 1243 1252

42. PridgeonJWOlzmannJAChinLSLiL 2007 PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5 e172 doi:10.1371/journal.pbio.0050172

43. RustinPJacobsHT 2009 Respiratory chain alternative enzymes as tools to better understand and counteract respiratory chain deficiencies in human cells and animals. Physiol Plant 137 362 370

44. LutzAKExnerNFettMESchleheJSKloosK 2009 Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem 284 22938 22951

45. KoopmanWJVerkaartSVischHJvan der WesthuizenFHMurphyMP 2005 Inhibition of complex I of the electron transport chain causes O2-. -mediated mitochondrial outgrowth. Am J Physiol Cell Physiol 288 C1440 1450

46. ExnerNTreskeBPaquetDHolmstromKSchieslingC 2007 Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci 27 12413 12418

47. SandebringAThomasKJBeilinaAvan der BrugMClelandMM 2009 Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLoS ONE 4 e5701 doi:10.1371/journal.pone.0005701

48. ChaGHKimSParkJLeeEKimM 2005 Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. Proc Natl Acad Sci U S A 102 10345 10350

49. DietzlGChenDSchnorrerFSuKCBarinovaY 2007 A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448 151 156

50. VenkenKJHeYHoskinsRABellenHJ 2006 P[acman]: a BAC transgenic platform for targeted insertion of large DNA fragments in D. melanogaster. Science 314 1747 1751