2-methylcitric Acid Impairs Glutamate Metabolism And Induces Permeability Transition In Brain Mitochondria

dc.creatorAmaral
dc.creatorAlexandre Umpierrez; Cecatto
dc.creatorCristiane; Castilho
dc.creatorRoger Frigerio; Wajner
dc.creatorMoacir
dc.date2016
dc.dateabr
dc.date2017-11-13T11:32:47Z
dc.date2017-11-13T11:32:47Z
dc.date.accessioned2018-03-29T05:47:20Z
dc.date.available2018-03-29T05:47:20Z
dc.identifierJournal Of Neurochemistry. Wiley-blackwell, v. 137, p. 62 - 75, 2016.
dc.identifier0022-3042
dc.identifier1471-4159
dc.identifierWOS:000372980100006
dc.identifier10.1111/jnc.13544
dc.identifierhttp://onlinelibrary-wiley-com.ez88.periodicos.capes.gov.br/doi/10.1111/jnc.13544/full
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/326137
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1363143
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionAccumulation of 2-methylcitric acid (2MCA) is observed in methylmalonic and propionic acidemias, which are clinically characterized by severe neurological symptoms. The exact pathogenetic mechanisms of brain abnormalities in these diseases are poorly established and very little has been reported on the role of 2MCA. In the present work we found that 2MCA markedly inhibited ADP-stimulated and uncoupled respiration in mitochondria supported by glutamate, with a less significant inhibition in pyruvate plus malate respiring mitochondria. However, no alterations occurred when -ketoglutarate or succinate was used as respiratory substrates, suggesting a defect on glutamate oxidative metabolism. It was also observed that 2MCA decreased ATP formation in glutamate plus malate or pyruvate plus malate-supported mitochondria. Furthermore, 2MCA inhibited glutamate dehydrogenase activity at concentrations as low as 0.5mM. Kinetic studies revealed that this inhibitory effect was competitive in relation to glutamate. In contrast, assays of osmotic swelling in non-respiring mitochondria suggested that 2MCA did not significantly impair mitochondrial glutamate transport. Finally, 2MCA provoked a significant decrease in mitochondrial membrane potential and induced swelling in Ca2+-loaded mitochondria supported by different substrates. These effects were totally prevented by cyclosporine A plus ADP or ruthenium red, indicating induction of mitochondrial permeability transition. Taken together, our data strongly indicate that 2MCA behaves as a potent inhibitor of glutamate oxidation by inhibiting glutamate dehydrogenase activity and as a permeability transition inducer, disturbing mitochondrial energy homeostasis. We presume that 2MCA-induced mitochondrial deleterious effects may contribute to the pathogenesis of brain damage in patients affected by methylmalonic and propionic acidemias.
dc.description137
dc.description1
dc.description62
dc.description75
dc.descriptionCNPq [470236/2012-4]
dc.descriptionFAPERGS [10/0031-1]
dc.descriptionFAPESP [11/50400-0]
dc.descriptionPROPESQ/UFRGS [PIBIC 27613]
dc.descriptionFINEP/IBN-Net [01.06.0842-00]
dc.descriptionINCT-EN [573677/2008-5]
dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.languageEnglish
dc.publisherWiley-Blackwell
dc.publisherHoboken
dc.relationJournal of Neurochemistry
dc.rightsfechado
dc.sourceWOS
dc.subject2-methylcitric Acid
dc.subjectGlutamate Dehydrogenase
dc.subjectGlutamate Oxidative Metabolism
dc.subjectMitochondrial Permeability Transition
dc.subjectMitochondrial Respiration
dc.title2-methylcitric Acid Impairs Glutamate Metabolism And Induces Permeability Transition In Brain Mitochondria
dc.typeArtículos de revistas


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