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@ARTICLE{Melo:141163,
      author       = {Melo, Daniela R and Mirandola, Sandra R and Assunção,
                      Nilson A and Castilho, Roger F},
      title        = {{M}ethylmalonate impairs mitochondrial respiration
                      supported by {NADH}-linked substrates: involvement of
                      mitochondrial glutamate metabolism.},
      journal      = {Journal of neuroscience research},
      volume       = {90},
      number       = {6},
      issn         = {0360-4012},
      address      = {New York, NY [u.a.]},
      publisher    = {Wiley-Liss},
      reportid     = {DZNE-2020-07485},
      pages        = {1190-1199},
      year         = {2012},
      abstract     = {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.},
      keywords     = {Amino Acid Transport System X-AG: metabolism / Analysis of
                      Variance / Animals / Animals, Newborn / Carboxy-Lyases:
                      metabolism / Citrate (si)-Synthase: metabolism /
                      Dose-Response Relationship, Drug / Glutamate Dehydrogenase:
                      metabolism / Glutamic Acid: metabolism / Ketoglutarate
                      Dehydrogenase Complex: metabolism / Ketoglutaric Acids:
                      metabolism / Methylmalonic Acid: metabolism / Methylmalonic
                      Acid: pharmacology / Mitochondria: drug effects /
                      Mitochondria: metabolism / Multienzyme Complexes: metabolism
                      / Oxygen Consumption: drug effects / Prosencephalon: drug
                      effects / Prosencephalon: ultrastructure / Rats / Rats,
                      Wistar / Amino Acid Transport System X-AG (NLM Chemicals) /
                      Ketoglutaric Acids (NLM Chemicals) / Multienzyme Complexes
                      (NLM Chemicals) / Glutamic Acid (NLM Chemicals) /
                      Methylmalonic Acid (NLM Chemicals) / Ketoglutarate
                      Dehydrogenase Complex (NLM Chemicals) / Glutamate
                      Dehydrogenase (NLM Chemicals) / Citrate (si)-Synthase (NLM
                      Chemicals) / Carboxy-Lyases (NLM Chemicals) / aspartate
                      4-decarboxylase (NLM Chemicals)},
      cin          = {AG Alamoudi},
      ddc          = {570},
      cid          = {I:(DE-2719)1013012},
      pnm          = {341 - Molecular Signaling (POF3-341)},
      pid          = {G:(DE-HGF)POF3-341},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:22488725},
      doi          = {10.1002/jnr.23020},
      url          = {https://pub.dzne.de/record/141163},
}