Skip to main content
Springer Nature Link
Log in

Mitochondrial Respiratory Dysfunction in Familiar Parkinsonism Associated with PINK1 Mutation

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

In the present study mitochondrial respiratory function of fibroblasts from a patient affected by early-onset Parkinsonism carrying the homozygous W437X nonsense mutation in the PINK1 gene has been thoroughly characterized. When compared with normal fibroblasts, the patient’s fibroblast mitochondria exhibited a lower respiratory activity and a decreased respiratory control ratio with cellular ATP supply relying mainly on enhanced glycolytic production. The quantity, specific activity and subunit pattern of the oxidative phosphorylation complexes were normal. However, a significant decrease of the cellular cytochrome c content was observed and this correlated with a reduced cytochrome c oxidase in situ-activity. Measurement of ROS revealed in mitochondria of the patient’s fibroblasts enhanced O •−2 and H2O2 production abrogated by inhibition of complex I. No change in the glutathione-based redox buffering was, however, observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Lang AE, Lozano AM (1998) Parkinson’s disease. First of two parts. N Engl J Med 339:1044–1053

    Article  PubMed  CAS  Google Scholar 

  2. Farrer MJ (2006) Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 7:306–318

    Article  PubMed  CAS  Google Scholar 

  3. Dekker MCJ, Bonifati V, van Duijn CM (2003) Parkinson’s disease: piecing together a genetic jigsaw. Brain 126:1722–1733

    Article  PubMed  CAS  Google Scholar 

  4. Gasser T (2005) Genetics of Parkinson’s disease. Curr Opin Neurol 18:363–369

    Article  PubMed  CAS  Google Scholar 

  5. Valente EM et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160

    Article  PubMed  CAS  Google Scholar 

  6. Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, Romito L, Albanese A, Dallapiccola B, Bentivoglio AR (2004) PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 56:336–441

    Article  PubMed  CAS  Google Scholar 

  7. Lücking CB, Dürr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denèfle P, Wood NW, Agid Y, Brice A, French Parkinson’s Disease Genetics Study Group; European Consortium on Genetic Susceptibility in Parkinson’s Disease (2000) Association between early-onset Parkinson’s disease and mutations in the Parkin gene. N Engl J Med 342:1560–1567

    Google Scholar 

  8. Bonifati V et al (2005) Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65:87–95

    Article  PubMed  CAS  Google Scholar 

  9. Hedrich K, Hagenah J, Djarmati A, Hiller A, Lohnau T, Lasek K, Grünewald A, Hilker R, Steinlechner S, Boston H, Kock N, Schneider-Gold C, Kress W, Siebner H, Binkofski F, Lencer R, Münchau A, Klein C (2006) Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit? Arch Neurol 63:833–838

    Article  PubMed  Google Scholar 

  10. Gandhi S, Muqit MM, Stanyer L, Healy DG, Abou-Sleiman PM, Hargreaves I, Heales S, Ganguly M, Parsons L, Lees AJ, Latchman DS, Holton JL, Wood NW, Revesz T (2006) PINK1 protein in normal human brain and Parkinson’s disease. Brain 129:1720–1731

    Article  PubMed  CAS  Google Scholar 

  11. Petit A, Kawarai T, Paitel E, Sanjo N, Maj M, Scheid M, Chen F, Gu Y, Hasegawa H, Salehi-Rad S, Wang L, Rogaeva E, Fraser P, Robinson B, St George-Hyslop P, Tandon A (2005) Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem 280:34025–34032

    Article  PubMed  CAS  Google Scholar 

  12. Pridgeon JW, Olzmann JA, Chin LS, Li L (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5:e172

    Article  PubMed  CAS  Google Scholar 

  13. Criscuolo C, Volpe G, De Rosa A, Varrone A, Marongiu R, Mancini P, Salvatore E, Dallapiccola B, Filla A, Valente EM, De Michele G (2006) PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism. Mov Disord 21:1265–1267

    Article  PubMed  Google Scholar 

  14. Marongiu R, Brancati F, Antonini A, Ialongo T, Ceccarini C, Scarciolla O, Capalbo A, Benti R, Pezzoli G, Dallapiccola B, Goldwurm S, Valente EM (2007) Whole gene deletion and splicing mutations expand the PINK1 genotypic spectrum. Hum Mutat 28:98

    Article  PubMed  Google Scholar 

  15. Sim CH, Lio DS, Mok SS, Masters CL, Hill AF, Culvenor JG, Cheng HC (2006) C-terminal truncation and Parkinson’s disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum Mol Genet 15:3251–3262

    Article  PubMed  CAS  Google Scholar 

  16. Piccoli C, Scacco S, Bellomo F, Signorile A, Iuso A, Boffoli D, Scrima R, Capitanio N, Papa S (2006) cAMP controls oxygen metabolism in mammalian cells. FEBS Lett 580:4539–4543

    Article  PubMed  CAS  Google Scholar 

  17. Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA (2004) Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res 64:985–993

    Article  PubMed  CAS  Google Scholar 

  18. Gottlieb RA, Adachi S (2000) Nitrogen cavitation for cell disruption to obtain mitochondria from cultured cells. Methods Enzymol 322:213–221

    Article  PubMed  CAS  Google Scholar 

  19. Boffoli D, Scacco SC, Vergari R, Persio MT, Solarino G, Laforgia R, Papa S (1996) Ageing is associated in females with a decline in the content and activity on the b-c1 complex in skeletal muscle mitochondria. Biochim Biophys Acta 1315:66–72

    PubMed  Google Scholar 

  20. Papa S, Guerrieri F, Izzo G (1986) Cooperative proton-transfer reactions in the respiratory chain: redox bohr effects. Methods Enzymol 126:331–343

    Article  PubMed  CAS  Google Scholar 

  21. Scacco S, Vergari R, Scarpulla RC, Technikova-Dobrova Z, Sardanelli A, Lambo R, Lorusso V, Papa S (2000) cAMP-dependent phosphorylation of the nuclear encoded 18-kDa (IP) subunit of respiratory complex I and activation of the complex in serum-starved mouse fibroblast cultures. J Biol Chem 275:17578–17582

    Article  PubMed  CAS  Google Scholar 

  22. Wheeler CR, Salzman JA, Elsayed NM, Omaye ST, Korte DW (1990) Automated assays for superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Anal Biochem 184:193–199

    Article  PubMed  CAS  Google Scholar 

  23. Yang NC, Ho WM, Chen YH, Hu ML (2002) A convenient one-step extraction of cellular ATP using boiling water for the luciferin–luciferase assay of ATP. Anal Biochem 306:323–327

    Article  PubMed  CAS  Google Scholar 

  24. Bellomo F, Piccoli C, Cocco T, Scacco S, Papa F, Gaballo A, Boffoli D, Signorile A, D’Aprile A, Scrima R, Sardanelli AM, Capitanio N, Papa S (2006) Regulation by the cAMP cascade of oxygen free radical balance in Mammalian cell. Antioxid Redox Sign 8:495–502

    Article  CAS  Google Scholar 

  25. Iuso A, Scacco S, Piccoli C, Bellomo F, Petruzzella V, Trentadue R, Minuto M, Ripoli M, Capitanio N, Zeviani M, Papa S (2006) Dysfunctions of cellular oxidative metabolism in patients with mutations in the NDUFS1 and NDUFS4 genes of complex I. J Biol Chem 281:10374–10380

    Article  PubMed  CAS  Google Scholar 

  26. Johnson DK, Schillinger KJ, Kwait DM, Hughes CV, McNamara EJ, Ishmael F, O’Donnell RW, Chang MM, Hogg MG, Dordick JS, Santhanam L, Ziegler LM, Holland JA (2002) Inhibition of NADPH oxidase activation in endothelial cells by ortho-methoxy-substituted catechols. Endothelium 9:191–203

    Article  PubMed  CAS  Google Scholar 

  27. Majander A, Finel M, Wikstrom M (1994) Diphenyleneiodonium inhibits reduction of iron–sulfur clusters in the mitochondrial NADH-ubiquinone oxidoreductase (Complex I). J Biol Chem 269:21037–21042

    PubMed  CAS  Google Scholar 

  28. Chen Q, Lesnefsky EJ (2006) Depletion of cardiolipin and cytochrome c during ischemia increases hydrogen peroxide production from the electron transport chain. Free Radic Biol Med 40:976–982

    Article  PubMed  CAS  Google Scholar 

  29. Lin MT, Beal F (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  PubMed  CAS  Google Scholar 

  30. Hoepken HH, Gispert S, Morales B, Wingerter O, Del Turco D, Mülsch A, Nussbaum RL, Müller K, Dröse S, Brandt U, Deller T, Wirth B, Kudin AP, Kunz WS, Auburger G (2007) Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol Dis 25:401–411

    Article  PubMed  CAS  Google Scholar 

  31. Wang HL, Chou AH, Yeh TH, Li AH, Chen YL, Kuo YL, Tsai SR, Yu ST (2007) PINK1 mutants associated with recessive Parkinson’s disease are defective in inhibiting mitochondrial release of cytochrome c. Neurobiol Dis 28:216–226

    Article  PubMed  CAS  Google Scholar 

  32. Burke WJ (2004) Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases. Neurotoxicology 25:101–115

    Article  PubMed  CAS  Google Scholar 

  33. Abou-Sleiman PM, Muqit MM, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7:207–219

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Research Funds 2006 University of Bari, University of Foggia; Foundation of Cassa di Risparmio di Puglia; The National Project on “Molecular Mechanisms, Physiology and Pathology of Membrane Bioenergetics Systems”, MIUR 2005, Italy.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, University of Foggia, Foggia, Italy

    Claudia Piccoli, Rosella Scrima, Maria Ripoli, Giovanni Quarato, Annamaria D’Aprile, Domenico Boffoli & Nazzareno Capitanio

  2. Department of Medical Biochemistry, Biology and Physics, University of Bari, Piazza G. Cesare, 70100, Bari, Italy

    Annamaria Sardanelli, Francesco Bellomo, Salvatore Scacco, Arcangela Iuso & Sergio Papa

  3. Department of Neurological Sciences, Federico II University, Naples, Italy

    Giuseppe De Michele & Alessandro Filla

  4. Institute of Biomembranes and Bioenergetics, Italian Research Council, Bari, Italy

    Sergio Papa

Authors
  1. Claudia Piccoli
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Annamaria Sardanelli
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Rosella Scrima
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Maria Ripoli
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Giovanni Quarato
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Annamaria D’Aprile
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Francesco Bellomo
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Salvatore Scacco
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Giuseppe De Michele
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Alessandro Filla
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Arcangela Iuso
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Domenico Boffoli
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Nazzareno Capitanio
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Sergio Papa
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Sergio Papa.

Additional information

Special issue article in honor of Anna Maria Giuffrida-Stella.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Piccoli, C., Sardanelli, A., Scrima, R. et al. Mitochondrial Respiratory Dysfunction in Familiar Parkinsonism Associated with PINK1 Mutation. Neurochem Res 33, 2565–2574 (2008). https://doi.org/10.1007/s11064-008-9729-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-008-9729-2

Keywords