title: Peroxisome proliferator-activated receptor (PPAR) γ and PPARα agonists modulate mitochondrial fusion-fission dynamics: relevance to reactive oxygen species (ROS)-related neurodegenerative disorders?
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.
authors.affiliation: Departamento de Biología, Facultad de Ciencias, Universidad de Tarapacá, Arica, Chile.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Zolezzi
authors.forename: Carmen
authors.initials: C
authors.lastname: Silva-Alvarez
authors.forename: Daniela
authors.initials: D
authors.lastname: Ordenes
authors.forename: Juan A
authors.initials: JA
authors.lastname: Godoy
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Carvajal
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Santos
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
mesh_terms: D000818:Animals; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D061251:Primary Cell Culture; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C503403:Fis1 protein, rat; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D014157:Transcription Factors; C006253:pirinixic acid; C519851:Dnm1l protein, rat; D034281:Dynamins; C039671:ciglitazone