Home > Publications Database > Methylmalonate impairs mitochondrial respiration supported by NADH-linked substrates: involvement of mitochondrial glutamate metabolism. > print

001     141163
005     20250416155201.0
024 7 _ |a 10.1002/jnr.23020
|2 doi
024 7 _ |a pmid:22488725
|2 pmid
024 7 _ |a 0360-4012
|2 ISSN
024 7 _ |a 1097-4547
|2 ISSN
037 _ _ |a DZNE-2020-07485
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Melo, Daniela R
|0 P:(DE-HGF)0
|b 0
245 _ _ |a Methylmalonate impairs mitochondrial respiration supported by NADH-linked substrates: involvement of mitochondrial glutamate metabolism.
260 _ _ |a New York, NY [u.a.]
|c 2012
|b Wiley-Liss
264 _ 1 |3 online
|2 Crossref
|b Wiley
|c 2012-02-20
264 _ 1 |3 print
|2 Crossref
|b Wiley
|c 2012-06-01
336 7 _ |a article
|2 DRIVER
336 7 _ |a Output Types/Journal article
|2 DataCite
336 7 _ |a Journal Article
|b journal
|m journal
|0 PUB:(DE-HGF)16
|s 1744811482_3460
|2 PUB:(DE-HGF)
336 7 _ |a ARTICLE
|2 BibTeX
336 7 _ |a JOURNAL_ARTICLE
|2 ORCID
336 7 _ |a Journal Article
|0 0
|2 EndNote
520 _ _ |a The 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.
536 _ _ |a 341 - Molecular Signaling (POF3-341)
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|c POF3-341
|f POF III
|x 0
542 _ _ |i 2015-09-01
|2 Crossref
|u http://doi.wiley.com/10.1002/tdm_license_1.1
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 7 |a Amino Acid Transport System X-AG
|2 NLM Chemicals
650 _ 7 |a Ketoglutaric Acids
|2 NLM Chemicals
650 _ 7 |a Multienzyme Complexes
|2 NLM Chemicals
650 _ 7 |a Glutamic Acid
|0 3KX376GY7L
|2 NLM Chemicals
650 _ 7 |a Methylmalonic Acid
|0 8LL8S712J7
|2 NLM Chemicals
650 _ 7 |a Ketoglutarate Dehydrogenase Complex
|0 EC 1.2.4.2
|2 NLM Chemicals
650 _ 7 |a Glutamate Dehydrogenase
|0 EC 1.4.1.2
|2 NLM Chemicals
650 _ 7 |a Citrate (si)-Synthase
|0 EC 2.3.3.1
|2 NLM Chemicals
650 _ 7 |a Carboxy-Lyases
|0 EC 4.1.1.-
|2 NLM Chemicals
650 _ 7 |a aspartate 4-decarboxylase
|0 EC 4.1.1.12
|2 NLM Chemicals
650 _ 2 |a Amino Acid Transport System X-AG: metabolism
|2 MeSH
650 _ 2 |a Analysis of Variance
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Animals, Newborn
|2 MeSH
650 _ 2 |a Carboxy-Lyases: metabolism
|2 MeSH
650 _ 2 |a Citrate (si)-Synthase: metabolism
|2 MeSH
650 _ 2 |a Dose-Response Relationship, Drug
|2 MeSH
650 _ 2 |a Glutamate Dehydrogenase: metabolism
|2 MeSH
650 _ 2 |a Glutamic Acid: metabolism
|2 MeSH
650 _ 2 |a Ketoglutarate Dehydrogenase Complex: metabolism
|2 MeSH
650 _ 2 |a Ketoglutaric Acids: metabolism
|2 MeSH
650 _ 2 |a Methylmalonic Acid: metabolism
|2 MeSH
650 _ 2 |a Methylmalonic Acid: pharmacology
|2 MeSH
650 _ 2 |a Mitochondria: drug effects
|2 MeSH
650 _ 2 |a Mitochondria: metabolism
|2 MeSH
650 _ 2 |a Multienzyme Complexes: metabolism
|2 MeSH
650 _ 2 |a Oxygen Consumption: drug effects
|2 MeSH
650 _ 2 |a Prosencephalon: drug effects
|2 MeSH
650 _ 2 |a Prosencephalon: ultrastructure
|2 MeSH
650 _ 2 |a Rats
|2 MeSH
650 _ 2 |a Rats, Wistar
|2 MeSH
700 1 _ |a Mirandola, Sandra R
|0 P:(DE-2719)2730352
|b 1
|u dzne
700 1 _ |a Assunção, Nilson A
|0 P:(DE-HGF)0
|b 2
700 1 _ |a Castilho, Roger F
|0 P:(DE-HGF)0
|b 3
|e Corresponding author
773 1 8 |a 10.1002/jnr.23020
|b : Wiley, 2012-02-20
|n 6
|p 1190-1199
|3 journal-article
|2 Crossref
|t Journal of Neuroscience Research
|v 90
|y 2012
|x 0360-4012
773 _ _ |a 10.1002/jnr.23020
|g Vol. 90, no. 6, p. 1190 - 1199
|0 PERI:(DE-600)1474904-X
|n 6
|q 90:6<1190 - 1199
|p 1190-1199
|t Journal of neuroscience research
|v 90
|y 2012
|x 0360-4012
856 4 _ |u https://pub.dzne.de/record/141163/files/DZNE-2020-07485_Restricted.pdf
856 4 _ |u https://pub.dzne.de/record/141163/files/DZNE-2020-07485_Restricted.pdf?subformat=pdfa
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909 C O |p VDB
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
|0 I:(DE-588)1065079516
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913 1 _ |a DE-HGF
|b Gesundheit
|l Erkrankungen des Nervensystems
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|3 G:(DE-HGF)POF3
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914 1 _ |y 2012
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