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.