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Amaral 2016 J Neurochem
Additional label 2016-03  +
Coupling states LEAK  + , OXPHOS  + , ET  +
Diseases Neurodegenerative  +
Has abstract Accumulation of 2-methylcitric acid (2MCA)
Accumulation 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 α-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 (GDH) activity at concentrations as low as 0.5 mM. 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 of mitochondrial membrane potential and induced swelling in Ca<sup>2+</sup> -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 (PT). Taken together, our data strongly indicate that 2MCA behaves as a potent inhibitor of glutamate oxidation by inhibiting GDH activity and as a PT 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. This article is protected by copyright. All rights reserved.
otected by copyright. All rights reserved.  +
Has info [ PMID: 26800654]  +
Has publicationkeywords 2-methylcitric acid; glutamate dehydrogenase; glutamate oxidative metabolism  + , Mitochondrial permeability transition  + , Mitochondrial respiration  +
Has title Amaral AU, Cecatto C, Castilho RF, Wajner M (2016) 2-methylcitric acid impairs glutamate metabolism and induces permeability transition in brain mitochondria. J Neurochem 137:62-75.  +
Instrument and method Oxygraph-2k  +
Mammal and model Rat  +
MiP area Respiration  + , mt-Membrane  + , Pharmacology;toxicology  +
Pathways N  + , S  + , NS  +
Preparation Isolated mitochondria  +
Respiration and regulation Inhibitor  +
Tissue and cell Nervous system  +
Was published in journal J Neurochem +
Was published in year 2016  +
Was written by Amaral AU + , Cecatto C + , Castilho RF + , Wajner M +
Categories Publications
Modification date
"Modification date" is a predefined property that corresponds to the date of the last modification of a subject and is provided by Semantic MediaWiki.
14:39:04, 9 November 2017  +
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