Peroxisome proliferator-activated receptor (PPAR) γ and PPARα agonists modulate mitochondrial fusion-fission dynamics: relevance to reactive oxygen species (ROS)-related neurodegenerative disorders?

PLoS One. 2013 May 13;8(5):e64019. doi: 10.1371/journal.pone.0064019. Print 2013.

Abstract

Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of Aβ from the brain of transgenic mice model of Alzheimer's disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPARγ co-activator 1α (PGC-1α), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPARγ agonist (ciglitazone) and a PPARα agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC-1α and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dynamins / genetics
  • Dynamins / metabolism
  • Embryo, Mammalian
  • Gene Expression Regulation
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics / drug effects*
  • Mitochondrial Dynamics / genetics
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Oxidative Stress
  • PPAR alpha / agonists*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Primary Cell Culture
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Thiazolidinediones / pharmacology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Fis1 protein, rat
  • Mitochondrial Proteins
  • PPAR alpha
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • Pyrimidines
  • Reactive Oxygen Species
  • Thiazolidinediones
  • Transcription Factors
  • pirinixic acid
  • Dnm1l protein, rat
  • Dynamins
  • ciglitazone

Grant support

This work was supported by grants from the Basal Centre for Excellence in Science and Technology (PFB 12/2007) and Fondecyt N° 1120156 to NCI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.