title: Oxidative Stress, Disrupted Energy Metabolism, and Altered Signaling Pathways in Glutaryl-CoA Dehydrogenase Knockout Mice: Potential Implications of Quinolinic Acid Toxicity in the Neuropathology of Glutaric Acidemia Type I.
abstract: We investigated the effects of an acute intrastriatal QUIN administration on cellular redox and bioenergetics homeostasis, as well as on important signaling pathways in the striatum of wild-type (Gcdh+/+, WT) and knockout mice for glutaryl-CoA dehydrogenase (Gcdh-/-) fed a high lysine (Lys, 4.7 %) chow. QUIN increased lactate release in both Gcdh+/+and Gcdh-/-mice and reduced the activities of complex IV and creatine kinase only in the striatum of Gcdh-/-mice. QUIN also induced lipid and protein oxidative damage and increased the generation of reactive nitrogen species, as well as the activities of the antioxidant enzymes glutathione peroxidase, superoxide dismutase 2, and glutathione-S-transferase in WT and Gcdh-/-animals. Furthermore, QUIN induced DCFH oxidation (reactive oxygen species production) and reduced GSH concentrations (antioxidant defenses) in Gcdh-/-. An early increase of Akt and phospho-Erk 1/2 in the cytosol and Nrf2 in the nucleus was also observed, as well as a decrease of cytosolic Keap1caused by QUIN, indicating activation of the Nrf2 pathway mediated by Akt and phospho-Erk 1/2, possibly as a compensatory protective mechanism against the ongoing QUIN-induced toxicity. Finally, QUIN increased NF-κB and diminished IκBα expression, evidencing a pro-inflammatory response. Our data show a disruption of energy and redox homeostasis associated to inflammation induced by QUIN in the striatum of Gcdh-/-mice submitted to a high Lys diet. Therefore, it is presumed that QUIN may possibly contribute to the pathophysiology of striatal degeneration in children with glutaric aciduria type I during inflammatory processes triggered by infections or vaccinations.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Rafael Teixeira
authors.initials: RT
authors.lastname: Ribeiro
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Marília Danyelle Nunes
authors.initials: MDN
authors.lastname: Rodrigues
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, SSA, México, DF, México.
authors.forename: Ana Laura
authors.initials: AL
authors.lastname: Colín-González
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, SSA, México, DF, México.
authors.forename: Abel
authors.initials: A
authors.lastname: Santamaría
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil. mwajner@ufrgs.br.|Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. mwajner@ufrgs.br.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001928:Brain Diseases, Metabolic / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D004032:Diet; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D018345:Mice, Knockout; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017378:Quinolinic Acid / Q000008:administration & dosage / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D003576:Electron Transport Complex IV; D048049:Extracellular Signal-Regulated MAP Kinases; D005452:Fluoresceins; D050770:Glutaryl-CoA Dehydrogenase; D005978:Glutathione; D005979:Glutathione Peroxidase; D007773:Lactates; D008315:Malondialdehyde; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D051057:Proto-Oncogene Proteins c-akt; D017378:Quinolinic Acid; D013438:Sulfhydryl Compounds; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C495636:Nfe2l2 protein, mouse; C065013:2',7'-dichlorodihydrofluorescein
keywords: Energy metabolism; Glutaric acidemia; Inflammatory response; Quinolinic acid; Redox homeostasis; Signaling pathways