TY  - JOUR
AU  - Melo, Daniela R
AU  - Mirandola, Sandra R
AU  - Assunção, Nilson A
AU  - Castilho, Roger F
TI  - Methylmalonate impairs mitochondrial respiration supported by NADH-linked substrates: involvement of mitochondrial glutamate metabolism.
JO  - Journal of neuroscience research
VL  - 90
IS  - 6
SN  - 0360-4012
CY  - New York, NY [u.a.]
PB  - Wiley-Liss
M1  - DZNE-2020-07485
SP  - 1190-1199
PY  - 2012
AB  - 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.
KW  - Amino Acid Transport System X-AG: metabolism
KW  - Analysis of Variance
KW  - Animals
KW  - Animals, Newborn
KW  - Carboxy-Lyases: metabolism
KW  - Citrate (si)-Synthase: metabolism
KW  - Dose-Response Relationship, Drug
KW  - Glutamate Dehydrogenase: metabolism
KW  - Glutamic Acid: metabolism
KW  - Ketoglutarate Dehydrogenase Complex: metabolism
KW  - Ketoglutaric Acids: metabolism
KW  - Methylmalonic Acid: metabolism
KW  - Methylmalonic Acid: pharmacology
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Multienzyme Complexes: metabolism
KW  - Oxygen Consumption: drug effects
KW  - Prosencephalon: drug effects
KW  - Prosencephalon: ultrastructure
KW  - Rats
KW  - Rats, Wistar
KW  - Amino Acid Transport System X-AG (NLM Chemicals)
KW  - Ketoglutaric Acids (NLM Chemicals)
KW  - Multienzyme Complexes (NLM Chemicals)
KW  - Glutamic Acid (NLM Chemicals)
KW  - Methylmalonic Acid (NLM Chemicals)
KW  - Ketoglutarate Dehydrogenase Complex (NLM Chemicals)
KW  - Glutamate Dehydrogenase (NLM Chemicals)
KW  - Citrate (si)-Synthase (NLM Chemicals)
KW  - Carboxy-Lyases (NLM Chemicals)
KW  - aspartate 4-decarboxylase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22488725
DO  - DOI:10.1002/jnr.23020
UR  - https://pub.dzne.de/record/141163
ER  -