title: Ethylmalonic acid impairs brain mitochondrial succinate and malate transport.
abstract: Tissue accumulation and high urinary excretion of ethylmalonic acid (EMA) occur in ethylmalonic encephalopathy (EE) and short chain acyl-CoA dehydrogenase deficiency (SCADD). Although these autosomal recessive disorders are clinically characterized by neurological abnormalities, the mechanisms underlying the brain damage are poorly known. Considering that little is known about the neurotoxicity of EMA and that hyperlacticacidemia occurs in EE and SCADD, we evaluated the effects of this metabolite on important parameters of oxidative metabolism in isolated rat brain mitochondria. EMA inhibited either ADP-stimulated or uncoupled mitochondrial respiration supported by succinate and malate, but not by glutamate plus malate. In addition, EMA mildly stimulated oxygen consumption by succinate-respiring mitochondria in resting state. Methylmalonic acid (MMA), malonic acid (MA) and butylmalonic acid (BtMA) had a similar effect on ADP-stimulated or uncoupled respiration. Furthermore, EMA-, MMA- and BtMA-induced inhibitory effects on succinate oxidation were significantly minimized by nonselective permeabilization of the mitochondrial membranes by alamethicin, whereas MA inhibitory effect was not altered. In addition, MA was the only tested compound that reduced succinate dehydrogenase activity. We also observed that EMA markedly inhibited succinate and malate transport through the mitochondrial dicarboxylate carrier. Mitochondrial membrane potential was also reduced by EMA and MA, but not by MMA, using succinate as electron donor, whereas none of these compounds was able to alter the membrane potential using glutamate plus malate as electron donors. Taken together, our results strongly indicate that EMA impairs succinate and malate uptake through the mitochondrial dicarboxylate carrier.
authors: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Alexandre Umpierrez
authors: AU
authors: Amaral
authors: Cristiane
authors: C
authors: Cecatto
authors: Estela Natasha Brandt
authors: EN
authors: Busanello
authors: César Augusto João
authors: CA
authors: Ribeiro
authors: Daniela Rodrigues
authors: DR
authors: Melo
authors: Guilhian
authors: G
authors: Leipnitz
authors: Roger Frigério
authors: RF
authors: Castilho
authors: Moacir
authors: M
authors: Wajner
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D029382:Dicarboxylic Acid Transporters / Q000378:metabolism; D008293:Malates / Q000378:metabolism*; D008314:Malonates / Q000494:pharmacology*; D008764:Methylmalonic Acid / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D019802:Succinic Acid / Q000378:metabolism*
chemical_list: D029382:Dicarboxylic Acid Transporters; D008293:Malates; D008314:Malonates; C038080:ethylmalonic acid; C006860:2-n-butylmalonate; C030298:malic acid; D008764:Methylmalonic Acid; D019802:Succinic Acid