PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia

PLoS One. 2010 Apr 7;5(4):e10025. doi: 10.1371/journal.pone.0010025.


Background: Cells from individuals with Friedreich's ataxia (FRDA) show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARgamma) Coactivator 1-alpha (PGC-1alpha), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models.

Methodology/principal findings: We used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse) to determine basal superoxide dismutase 2 (SOD2) levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1alpha. Compared to control cells, PGC-1alpha and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1alpha direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1alpha activation with the PPARgamma agonist (Pioglitazone) or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord.

Conclusions/significance: PGC-1alpha down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARgamma agonists, suggesting a potential therapeutic approach for FRDA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Case-Control Studies
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases
  • Down-Regulation / genetics*
  • Friedreich Ataxia / metabolism
  • Friedreich Ataxia / pathology*
  • Heat-Shock Proteins / genetics*
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Mice
  • Mice, Knockout
  • Oxidative Stress
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Superoxide Dismutase / analysis
  • Transcription Factors / genetics*


  • Antioxidants
  • Heat-Shock Proteins
  • PPAR gamma
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Transcription Factors
  • Hydrogen Peroxide
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Cyclic AMP-Dependent Protein Kinases