Perfluorooctanoic acid stimulated mitochondrial biogenesis and gene transcription in rats.
Perfluorooctanoic acid (PFOA), used in the production of non-stick surface compounds, exhibits a worldwide distribution in the serum of humans and wildlife. In rodents PFOA transactivates PPARalpha and PPARgamma nuclear receptors and increases mitochondrial DNA (mtDNA) copy number, which may be critical to the altered metabolic state of affected animals. A key regulator of mitochondrial biogenesis and transcription of mitochondrial genes is the PPARgamma coactivator-1alpha (Pgc-1alpha) protein. The purpose of this study was to determine if Pgc-1alpha is implicated in the stimulation of mitochondrial biogenesis that occurs following the treatment of rats with PFOA. Livers from adult male Sprague-Dawley rats that received a 30 mg/kg daily oral dose of PFOA for 28 days were used for all experiments. Analysis of mitochondrial replication and transcription was performed by real time PCR, and proteins were detected using western blotting. PFOA treatment caused a transcriptional activation of the mitochondrial biogenesis pathway leading to a doubling of mtDNA copy number. Further, transcription of OXPHOS genes encoded by mtDNA was 3-4 times greater than that of nuclear encoded genes, suggestive of a preferential induction of mtDNA transcription. Western blot analysis revealed an increase in Pgc-1alpha, unchanged Tfam and decreased Cox II and Cox IV subunit protein expression. We conclude that PFOA treatment in rats induces mitochondrial biogenesis at the transcriptional level with a preferential stimulation of mtDNA transcription and that this occurs by way of activation of the Pgc-1alpha pathway. Implication of the Pgc-1alpha pathway is consistent with PPARgamma transactivation by PFOA and reveals new understanding and possibly new critical targets for assessing or averting the associated metabolic disease.
Walters
M W
MW
Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, MN 55812, USA. walt0121@d.umn.edu
Bjork
J A
JA
Wallace
K B
KB
D000818:Animals; D015153:Blotting, Western; D002210:Caprylates / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000302:isolation & purification; D004579:Electron Transport / Q000187:drug effects; D005466:Fluorocarbons / Q000494:pharmacology*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D051266:Nuclear Respiratory Factor 1 / Q000096:biosynthesis / Q000235:genetics; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D016601:RNA-Binding Proteins / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*
D002210:Caprylates; D004272:DNA, Mitochondrial; D005466:Fluorocarbons; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D051266:Nuclear Respiratory Factor 1; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; C489030:Tfam protein, rat; D014157:Transcription Factors; D012313:RNA; C023036:perfluorooctanoic acid; D011451:Prostaglandin-Endoperoxide Synthases