Mitochondrial defect and PGC-1α dysfunction in parkin-associated familial Parkinson's disease

Consiglia Pacelli, Domenico De Rasmo, Anna Signorile, Ignazio Grattagliano, Giuseppe di Tullio, Andria D'Orazio, Beatrice Nico, Giacomo Pietro Comi, Dario Ronchi, Ermanno Ferranini, Domenico Pirolo, Peter Seibel, Susanna Schubert, Antonio Gaballo, Gaetano Villani, Tiziana Cocco

Research output: Contribution to journalArticlepeer-review


Mutations in the s parkin gene are expected to play an essential role in autosomal recessive Parkinson's disease. Recent studies have established an impact of parkin mutations on mitochondrial function and autophagy. In primary skin fibroblasts from two patients affected by an early onset Parkinson's disease, we identified a hitherto unreported compound heterozygous mutation del exon2-3/del exon3 in the parkin gene, leading to the complete loss of the full-length protein. In both patients, but not in their heterozygous parental control, we observed severe ultrastructural abnormalities, mainly in mitochondria. This was associated with impaired energy metabolism, deregulated reactive oxygen species (ROS) production, resulting in lipid oxidation, and peroxisomal alteration. In view of the involvement of parkin in the mitochondrial quality control system, we have investigated upstream events in the organelles' biogenesis. The expression of the peroxisome proliferator-activated receptor gamma-coactivator 1-alpha (PGC-1α), a strong stimulator of mitochondrial biogenesis, was remarkably upregulated in both patients. However, the function of PGC-1α was blocked, as revealed by the lack of its downstream target gene induction. In conclusion, our data confirm the role of parkin in mitochondrial homeostasis and suggest a potential involvement of the PGC-1α pathway in the pathogenesis of Parkinson's disease. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

Original languageEnglish
Pages (from-to)1041-1053
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number8
Publication statusPublished - Aug 2011


  • Mitochondria
  • Oxidative stress
  • Parkin
  • Parkinson's disease
  • Peroxisome
  • PGC-1α

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine


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