title: Frataxin deficiency increases cyclooxygenase 2 and prostaglandins in cell and animal models of Friedreich's ataxia.
abstract: An inherited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia (FRDA); the mechanism by which this deficiency triggers neuro- and cardio-degeneration is unclear. Microarrays of neural tissue of animal models of the disease showed decreases in antioxidant genes, and increases in inflammatory genes. Cyclooxygenase (COX)-derived oxylipins are important mediators of inflammation. We measured oxylipin levels using tandem mass spectrometry and ELISAs in multiple cell and animal models of FRDA. Mass spectrometry revealed increases in concentrations of prostaglandins, thromboxane B2, 15-HETE and 11-HETE in cerebellar samples of knockin knockout mice. One possible explanation for the elevated oxylipins is that frataxin deficiency results in increased COX activity. While constitutive COX1 was unchanged, inducible COX2 expression was elevated over 1.35-fold (P < 0.05) in two Friedreich's mouse models and Friedreich's lymphocytes. Consistent with higher COX2 expression, its activity was also increased by 58% over controls. COX2 expression is driven by multiple transcription factors, including activator protein 1 and cAMP response element-binding protein, both of which were elevated over 1.52-fold in cerebella. Taken together, the results support the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin synthesis stimulated by increases in transcription factors that respond to increased reactive oxygen species. These findings support a neuroinflammatory mechanism in FRDA, which has both pathomechanistic and therapeutic implications.
authors.affiliation: Department of Molecular Biosciences and.
authors.forename: Genki
authors.initials: G
authors.lastname: Hayashi
authors.affiliation: Department of Molecular Biosciences and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: USDA, ARS, Western Human Nutrition Research Center, 430 West Health Sciences Dr, Davis, CA 95616, USA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Pedersen
authors.affiliation: Department of Nutrition, University of California, Davis, CA 95616, USA USDA, ARS, Western Human Nutrition Research Center, 430 West Health Sciences Dr, Davis, CA 95616, USA West Coast Metabolomics Center, University of California Davis Genome Center, Davis, CA 95616, USA and.
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.affiliation: Department of Biosciences, Brunel University, Uxbridge, Middlesex, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Pook
authors.affiliation: Department of Molecular Biosciences and gcortopassi@ucdavis.edu.
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D005621:Friedreich Ataxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054883:Oxylipins / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013929:Thromboxane B2 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D000096923:Frataxin
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D006893:Hydroxyeicosatetraenoic Acids; D033862:Iron-Binding Proteins; D008565:Membrane Proteins; D054883:Oxylipins; D011453:Prostaglandins; D017382:Reactive Oxygen Species; D013929:Thromboxane B2; D018808:Transcription Factor AP-1; D000096923:Frataxin; C027356:11-hydroxy-5,8,12,14-eicosatetraenoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C077623:Ptgs2 protein, mouse; C496512:Ptgs1 protein, mouse
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