Methylmalonate Impairs Mitochondrial Respiration Supported By Nadh-linked Substrates: Involvement Of Mitochondrial Glutamate Metabolism.

dc.creatorMelo, Daniela R
dc.creatorMirandola, Sandra R
dc.creatorAssunção, Nilson A
dc.creatorCastilho, Roger F
dc.date2012-Jun
dc.date2015-11-27T13:28:24Z
dc.date2015-11-27T13:28:24Z
dc.date.accessioned2018-03-29T01:15:10Z
dc.date.available2018-03-29T01:15:10Z
dc.identifierJournal Of Neuroscience Research. v. 90, n. 6, p. 1190-9, 2012-Jun.
dc.identifier1097-4547
dc.identifier10.1002/jnr.23020
dc.identifierhttp://www.ncbi.nlm.nih.gov/pubmed/22488725
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/199958
dc.identifier22488725
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1300191
dc.descriptionThe neurodegeneration that occurs in methylmalonic acidemia is proposed to be associated with impairment of mitochondrial oxidative metabolism resulting from methylmalonate (MMA) accumulation. The present study evaluated the effects of MMA on oxygen consumption by isolated rat brain mitochondria in the presence of NADH-linked substrates (α-ketoglutarate, citrate, isocitrate, glutamate, malate, and pyruvate). Respiration supported either by glutamate or glutamate plus malate was significantly inhibited by MMA (1-10 mM), whereas no inhibition was observed when a cocktail of NADH-linked substrates was used. Measurements of glutamate transport revealed that the inhibitory effect of MMA on respiration maintained by this substrate is not due to inhibition of its mitochondrial uptake. In light of this result, the effect of MMA on the activity of relevant enzymes involved in mitochondrial glutamate metabolism was investigated. MMA had minor inhibitory effects on glutamate dehydrogenase and aspartate aminotransferase, whereas α-ketoglutarate dehydrogenase was significantly inhibited by this metabolite (K(i) = 3.65 mM). Moreover, measurements of α-ketoglutarate transport and mitochondrial MMA accumulation indicated that MMA/α-ketoglutarate exchange depletes mitochondria from this substrate, which may further contribute to the inhibition of glutamate-sustained respiration. To study the effect of chronic in vivo MMA treatment on mitochondrial function, young rats were intraperitoneally injected with MMA. No significant difference was observed in respiration between isolated brain mitochondria from control and MMA-treated rats, indicating that in vivo MMA treatment did not lead to permanent mitochondrial respiratory defects. Taken together, these findings indicate that the inhibitory effect of MMA on mitochondrial oxidative metabolism can be ascribed to concurrent inhibition of specific enzymes and lower availability of respiratory substrates.
dc.description90
dc.description1190-9
dc.languageeng
dc.relationJournal Of Neuroscience Research
dc.relationJ. Neurosci. Res.
dc.rightsfechado
dc.rightsCopyright © 2012 Wiley Periodicals, Inc.
dc.sourcePubMed
dc.subjectAmino Acid Transport System X-ag
dc.subjectAnalysis Of Variance
dc.subjectAnimals
dc.subjectAnimals, Newborn
dc.subjectCarboxy-lyases
dc.subjectCitrate (si)-synthase
dc.subjectDose-response Relationship, Drug
dc.subjectGlutamate Dehydrogenase
dc.subjectGlutamic Acid
dc.subjectKetoglutarate Dehydrogenase Complex
dc.subjectKetoglutaric Acids
dc.subjectMethylmalonic Acid
dc.subjectMitochondria
dc.subjectMultienzyme Complexes
dc.subjectOxygen Consumption
dc.subjectProsencephalon
dc.subjectRats
dc.subjectRats, Wistar
dc.titleMethylmalonate Impairs Mitochondrial Respiration Supported By Nadh-linked Substrates: Involvement Of Mitochondrial Glutamate Metabolism.
dc.typeArtículos de revistas


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