Display options
Cite
Zanellati MC, Monti V, Barzaghi C, et al. Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts. Front Genet. 2015;6:78doi: 10.3389/fgene.2015.00078.
Zanellati, M. C., Monti, V., Barzaghi, C., Reale, C., Nardocci, N., Albanese, A., Valente, E. M., Ghezzi, D., & Garavaglia, B. (2015). Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts. Frontiers in genetics, 678. https://doi.org/10.3389/fgene.2015.00078
Zanellati, Maria C, et al. "Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts." Frontiers in genetics vol. 6 (2015): 78. doi: https://doi.org/10.3389/fgene.2015.00078
Zanellati MC, Monti V, Barzaghi C, Reale C, Nardocci N, Albanese A, Valente EM, Ghezzi D, Garavaglia B. Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts. Front Genet. 2015 Mar 11;6:78. doi: 10.3389/fgene.2015.00078. eCollection 2015. PMID: 25815004; PMCID: PMC4356157.
Copy Download .nbib Format: NLM
Share it on

Front Genet. 2015 Mar 11;6:78. doi: 10.3389/fgene.2015.00078. eCollection 2015.

Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts.

Frontiers in genetics

Maria C Zanellati, Valentina Monti, Chiara Barzaghi, Chiara Reale, Nardo Nardocci, Alberto Albanese, Enza M Valente, Daniele Ghezzi, Barbara Garavaglia

Affiliations

  1. Unit of Molecular Neurogenetics - Pierfranco and Luisa Mariani Center for the Study of Mitochondrial Disorders in Children, Foundation of the Carlo Besta Neurological Institute IRCCS, Milan, Italy.
  2. Unit of Child Neurology, Foundation of the Carlo Besta Neurological Institute IRCCS, Milan, Italy.
  3. Neurology Unit, Foundation of the Carlo Besta Neurological Institute IRCCS, Milan, Italy.
  4. Casa Sollievo Della Sofferenza Hospital, Mendel Institute Rome, Italy.

PMID: 25815004 PMCID: PMC4356157 DOI: 10.3389/fgene.2015.00078

Abstract

Mutations in PARK2, encoding Parkin, cause an autosomal recessive form of juvenile Parkinson Disease (JPD). The aim of the present study was to investigate the impact of PARK2 mutations on mitochondrial function and morphology in human skin fibroblasts. We analyzed cells obtained from four patients clinically characterized by JPD, harboring recessive mutations in PARK2. By quantitative PCR we found a reduction (<50%) of PARK2 transcript in all patients but one; however Western Blot analysis demonstrated the virtual absence of Parkin protein in all mutant fibroblasts. Respiration assays showed an increment of oxygen consumption, which was uncoupled to ATP cellular levels. This finding was probably due to presence of altered mitochondrial membrane potential (ΔΨm), confirmed by JC-1 analysis. The mitochondrial network was comparable between mutant and control cells but, interestingly, a "chain-like" network was found only in mutant fibroblasts. Dissipation of ΔΨm usually leads to mitochondrial fragmentation in healthy cells and eventually to mitophagy; however, this behavior was not observed in patients' fibroblasts. The absence of mitochondrial fragmentation in mutant Parkin fibroblasts could results in accumulation of damaged mitochondria not targeted to mitophagy. This condition should increase the oxidative stress and lead to cellular dysfunction and death. Our results suggest that PARK2 mutations cause mitochondrial impairment, in particular reduction in ATP cellular levels and alteration of ΔΨm, even in non-neuronal cells and confirm the hypothesis that Parkin holds a pivotal role in pro-fission events.

Keywords: PARK2; mitochondrial dynamics; mitochondrial membrane potential; oxygen consumption; parkin

References

  1. PLoS One. 2010 Sep 27;5(9):e12962 - PubMed
  2. Hum Mol Genet. 2011 May 1;20(9):1726-37 - PubMed
  3. Cell Metab. 2014 Apr 1;19(4):630-41 - PubMed
  4. Mov Disord. 2004 May;19(5):544-8 - PubMed
  5. Neurosci Biobehav Rev. 2012 Oct;36(9):2034-43 - PubMed
  6. Nature. 1998 Apr 9;392(6676):605-8 - PubMed
  7. Biochem Biophys Res Commun. 2014 May 2;447(2):334-40 - PubMed
  8. Hum Mol Genet. 2011 Aug 15;20(16):3227-40 - PubMed
  9. Cell Biosci. 2014 Mar 27;4(1):16 - PubMed
  10. PLoS One. 2012;7(4):e34748 - PubMed
  11. Biochim Biophys Acta. 2011 Aug;1812(8):1041-53 - PubMed
  12. Biochim Biophys Acta. 2012 Dec;1823(12 ):2297-310 - PubMed
  13. Brain. 2012 May;135(Pt 5):1387-94 - PubMed
  14. Mov Disord. 2010;25 Suppl 1:S32-9 - PubMed
  15. J Cell Biol. 2014 Sep 1;206(5):655-70 - PubMed
  16. Rejuvenation Res. 2005 Spring;8(1):3-5 - PubMed
  17. Life Sci. 1985 Jul 1;36(26):2503-8 - PubMed
  18. Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):865-77 - PubMed
  19. J Cell Sci. 2014 May 15;127(Pt 10):2313-25 - PubMed
  20. EMBO J. 2008 Jan 23;27(2):433-46 - PubMed
  21. J Cell Biol. 2008 Dec 1;183(5):795-803 - PubMed
  22. J Biol Chem. 2013 Jan 25;288(4):2223-37 - PubMed
  23. Biochim Biophys Acta. 2014 Sep;1843(9):2012-26 - PubMed
  24. Ann Neurol. 2008 Nov;64(5):555-65 - PubMed
  25. Cell. 2011 Nov 11;147(4):893-906 - PubMed
  26. Science. 1983 Feb 25;219(4587):979-80 - PubMed
  27. Mitochondrion. 2012 Mar;12(2):328-35 - PubMed

Publication Types

Grant support