2-Methylcitric acid impairs glutamate metabolism and induces permeability transition in brain mitochondria

Journal of Neurochemistry
Alexandre Umpierrez AmaralMoacir Wajner

Abstract

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 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 in mitochondrial membrane pot...Continue Reading

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Citations

May 24, 2019·Journal of Inherited Metabolic Disease·Hanneke A HaijesPeter M van Hasselt
Sep 3, 2019·Hemodialysis International·Jun KidoKimitoshi Nakamura
Mar 28, 2019·Nature Reviews. Neurology·Moacir Wajner
May 24, 2019·Journal of Inherited Metabolic Disease·Hanneke A HaijesNanda M Verhoeven-Duif
Jun 22, 2017·American Journal of Physiology. Endocrinology and Metabolism·Kirkland A WilsonGuo-Fang Zhang
Oct 26, 2020·Archives of Biochemistry and Biophysics·Moacir WajnerAlexandre Umpierrez Amaral

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