#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Drosophila phosphatidylinositol-4 kinase fwd promotes mitochondrial fission and can suppress Pink1/parkin phenotypes


Autoři: Ana Terriente-Felix aff001;  Emma L. Wilson aff002;  Alexander J. Whitworth aff001
Působiště autorů: MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom aff001;  Department of Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom aff002
Vyšlo v časopise: Drosophila phosphatidylinositol-4 kinase fwd promotes mitochondrial fission and can suppress Pink1/parkin phenotypes. PLoS Genet 16(10): e32767. doi:10.1371/journal.pgen.1008844
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008844

Souhrn

Balanced mitochondrial fission and fusion play an important role in shaping and distributing mitochondria, as well as contributing to mitochondrial homeostasis and adaptation to stress. In particular, mitochondrial fission is required to facilitate degradation of damaged or dysfunctional units via mitophagy. Two Parkinson’s disease factors, PINK1 and Parkin, are considered key mediators of damage-induced mitophagy, and promoting mitochondrial fission is sufficient to suppress the pathological phenotypes in Drosophila Pink1/parkin mutants. We sought additional factors that impinge on mitochondrial dynamics and which may also suppress Pink1/parkin phenotypes. We found that the Drosophila phosphatidylinositol 4-kinase IIIβ homologue, Four wheel drive (Fwd), promotes mitochondrial fission downstream of the pro-fission factor Drp1. Previously described only as male sterile, we identified several new phenotypes in fwd mutants, including locomotor deficits and shortened lifespan, which are accompanied by mitochondrial dysfunction. Finally, we found that fwd overexpression can suppress locomotor deficits and mitochondrial disruption in Pink1/parkin mutants, consistent with its function in promoting mitochondrial fission. Together these results shed light on the complex mechanisms of mitochondrial fission and further underscore the potential of modulating mitochondrial fission/fusion dynamics in the context of neurodegeneration.


Zdroje

1. Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62(3):341–60. doi: 10.1042/EBC20170104 30030364

2. Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012;148(6):1145–59. doi: 10.1016/j.cell.2012.02.035 22424226

3. Nagashima S, Tabara LC, Tilokani L, Paupe V, Anand H, Pogson JH, et al. Golgi-derived PI(4)P-containing vesicles drive late steps of mitochondrial division. Science (New York, NY. 2020;367(6484):1366–71.

4. Twig G, Hyde B, Shirihai OS. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta. 2008;1777(9):1092–7. doi: 10.1016/j.bbabio.2008.05.001 18519024

5. Twig G, Shirihai OS. The interplay between mitochondrial dynamics and mitophagy. Antioxid Redox Signal. 2011;14(10):1939–51. doi: 10.1089/ars.2010.3779 21128700

6. McWilliams TG, Muqit MM. PINK1 and Parkin: emerging themes in mitochondrial homeostasis. Curr Opin Cell Biol. 2017;45:83–91. doi: 10.1016/j.ceb.2017.03.013 28437683

7. Nguyen TN, Padman BS, Lazarou M. Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. Trends Cell Biol. 2016;26(10):733–44. doi: 10.1016/j.tcb.2016.05.008 27291334

8. Pickrell AM, Youle RJ. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. Neuron. 2015;85(2):257–73. doi: 10.1016/j.neuron.2014.12.007 25611507

9. Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(7):4078–83. doi: 10.1073/pnas.0737556100 12642658

10. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. The Journal of biological chemistry. 2004;279(18):18614–22. doi: 10.1074/jbc.M401135200 14985362

11. Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006;441(7097):1157–61. doi: 10.1038/nature04788 16672980

12. Mortiboys H, Thomas KJ, Koopman WJ, Klaffke S, Abou-Sleiman P, Olpin S, et al. Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol. 2008;64(5):555–65. doi: 10.1002/ana.21492 19067348

13. Exner N, Treske B, Paquet D, Holmstrom K, Schiesling C, Gispert S, et al. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci. 2007;27(45):12413–8. doi: 10.1523/JNEUROSCI.0719-07.2007 17989306

14. Gautier CA, Kitada T, Shen J. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(32):11364–9. doi: 10.1073/pnas.0802076105 18687901

15. Flinn L, Mortiboys H, Volkmann K, Koster RW, Ingham PW, Bandmann O. Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). Brain. 2009;132(Pt 6):1613–23. doi: 10.1093/brain/awp108 19439422

16. Morais VA, Verstreken P, Roethig A, Smet J, Snellinx A, Vanbrabant M, et al. Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function. EMBO Mol Med. 2009;1(2):99–111. doi: 10.1002/emmm.200900006 20049710

17. Grunewald A, Gegg ME, Taanman JW, King RH, Kock N, Klein C, et al. Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and morphology. Exp Neurol. 2009;219(1):266–73. doi: 10.1016/j.expneurol.2009.05.027 19500570

18. Deng H, Dodson MW, Huang H, Guo M. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci USA. 2008;105(38):14503–8. doi: 10.1073/pnas.0803998105 18799731

19. Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ. The PINK1/Parkin pathway regulates mitochondrial morphology. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(5):1638–43. doi: 10.1073/pnas.0709336105 18230723

20. Yang Y, Ouyang Y, Yang L, Beal MF, McQuibban A, Vogel H, et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc Natl Acad Sci USA. 2008;105(19):7070–5. doi: 10.1073/pnas.0711845105 18443288

21. Park J, Lee G, Chung J. The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process. Biochem Biophys Res Commun. 2009;378(3):518–23. doi: 10.1016/j.bbrc.2008.11.086 19056353

22. Burman JL, Yu S, Poole AC, Decal RB, Pallanck L. Analysis of neural subtypes reveals selective mitochondrial dysfunction in dopaminergic neurons from parkin mutants. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(26):10438–43. doi: 10.1073/pnas.1120688109 22691499

23. Vilain S, Esposito G, Haddad D, Schaap O, Dobreva MP, Vos M, et al. The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants. PLoS genetics. 2012;8(1):e1002456. doi: 10.1371/journal.pgen.1002456 22242018

24. Fernandes C, Rao Y. Genome-wide screen for modifiers of Parkinson's disease genes in Drosophila. Mol Brain. 2011;4:17. doi: 10.1186/1756-6606-4-17 21504582

25. Pogson JH, Ivatt RM, Sanchez-Martinez A, Tufi R, Wilson E, Mortiboys H, et al. The Complex I Subunit NDUFA10 Selectively Rescues Drosophila pink1 Mutants through a Mechanism Independent of Mitophagy. PLoS genetics. 2014;10(11):e1004815. doi: 10.1371/journal.pgen.1004815 25412178

26. Giansanti MG, Belloni G, Gatti M. Rab11 is required for membrane trafficking and actomyosin ring constriction in meiotic cytokinesis of Drosophila males. Mol Biol Cell. 2007;18(12):5034–47. doi: 10.1091/mbc.e07-05-0415 17914057

27. Giansanti MG, Farkas RM, Bonaccorsi S, Lindsley DL, Wakimoto BT, Fuller MT, et al. Genetic dissection of meiotic cytokinesis in Drosophila males. Mol Biol Cell. 2004;15(5):2509–22. doi: 10.1091/mbc.e03-08-0603 15004238

28. Brill JA, Hime GR, Scharer-Schuksz M, Fuller MT. A phospholipid kinase regulates actin organization and intercellular bridge formation during germline cytokinesis. Development. 2000;127(17):3855–64. 10934029

29. Polevoy G, Wei HC, Wong R, Szentpetery Z, Kim YJ, Goldbach P, et al. Dual roles for the Drosophila PI 4-kinase four wheel drive in localizing Rab11 during cytokinesis. J Cell Biol. 2009;187(6):847–58. doi: 10.1083/jcb.200908107 19995935

30. Forrest S, Chai A, Sanhueza M, Marescotti M, Parry K, Georgiev A, et al. Increased levels of phosphoinositides cause neurodegeneration in a Drosophila model of amyotrophic lateral sclerosis. Hum Mol Genet. 2013;22(13):2689–704. doi: 10.1093/hmg/ddt118 23492670

31. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006;441(7097):1162–6. doi: 10.1038/nature04779 16672981

32. Perkins LA, Holderbaum L, Tao R, Hu Y, Sopko R, McCall K, et al. The Transgenic RNAi Project at Harvard Medical School: Resources and Validation. Genetics. 2015;201(3):843–52. doi: 10.1534/genetics.115.180208 26320097

33. Landis GN, Bhole D, Tower J. A search for doxycycline-dependent mutations that increase Drosophila melanogaster life span identifies the VhaSFD, Sugar baby, filamin, fwd and Cctl genes. Genome Biol. 2003;4(2):R8. doi: 10.1186/gb-2003-4-2-r8 12620118

34. Godi A, Pertile P, Meyers R, Marra P, Di Tullio G, Iurisci C, et al. ARF mediates recruitment of PtdIns-4-OH kinase-beta and stimulates synthesis of PtdIns(4,5)P2 on the Golgi complex. Nature cell biology. 1999;1(5):280–7. doi: 10.1038/12993 10559940

35. Di Paolo G, De Camilli P. Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006;443(7112):651–7. doi: 10.1038/nature05185 17035995

36. Vincow ES, Thomas RE, Merrihew GE, Shulman NJ, Bammler TK, MacDonald JW, et al. Autophagy accounts for approximately one-third of mitochondrial protein turnover and is protein selective. Autophagy. 2019;15(9):1592–605. doi: 10.1080/15548627.2019.1586258 30865561

37. Vincow ES, Merrihew G, Thomas RE, Shulman NJ, Beyer RP, MacCoss MJ, et al. The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(16):6400–5. doi: 10.1073/pnas.1221132110 23509287

38. McWilliams TG, Prescott AR, Montava-Garriga L, Ball G, Singh F, Barini E, et al. Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand. Cell metabolism. 2018;27(2):439–49 e5. doi: 10.1016/j.cmet.2017.12.008 29337137

39. Lee JJ, Sanchez-Martinez A, Zarate AM, Beninca C, Mayor U, Clague MJ, et al. Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin. J Cell Biol. 2018;217(5):1613–22. doi: 10.1083/jcb.201801044 29500189

40. Whitworth AJ, Pallanck LJ. PINK1/Parkin mitophagy and neurodegeneration-what do we really know in vivo? Curr Opin Genet Dev. 2017;44:47–53. doi: 10.1016/j.gde.2017.01.016 28213158

41. Kim YY, Um JH, Yoon JH, Kim H, Lee DY, Lee YJ, et al. Assessment of mitophagy in mt-Keima Drosophila revealed an essential role of the PINK1-Parkin pathway in mitophagy induction in vivo. FASEB J. 2019;33(9):9742–51. doi: 10.1096/fj.201900073R 31120803

42. Cornelissen T, Vilain S, Vints K, Gounko N, Verstreken P, Vandenberghe W. Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila. Elife. 2018;7.

43. Sandoval H, Yao CK, Chen K, Jaiswal M, Donti T, Lin YQ, et al. Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production. Elife. 2014;3.

44. Vagnoni A, Bullock SL. A simple method for imaging axonal transport in aging neurons using the adult Drosophila wing. Nature protocols. 2016;11(9):1711–23. doi: 10.1038/nprot.2016.112 27560175

45. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nature protocols. 2008;3(6):1101–8. doi: 10.1038/nprot.2008.73 18546601


Článek vyšel v časopise

PLOS Genetics


2020 Číslo 10
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#