BRAIN MITOCHONDRIAL CITRATE SYNTHASE AND GLUTAMATE-DEHYDROGENASE - DIFFERENTIAL INHIBITION BY FATTY ACYL-COENZYME A DERIVATIVES

Organic acidemia is found in several metabolic encephalopathies (e.g., hepatic and valproate encephalopathies, Reye's syndrome, and heredita ry organic acidemias). Although fatty acids are known to be neurotoxic , the underlying mechanisms have not been fully elucidated. It has bee n hypothesized that one mechanism underlying fatty acid neurotoxicity is the selective inhibition of rate-limiting and/or regulated tricarbo xylic acid (TCA) cycle and related enzymes by fatty acyl-coenzyme A (C oA) derivatives. To test the hypothesis, this study has examined the e ffects of several fatty acyl-CoAs on citrate synthase (CS) and glutama te dehydrogenase (GDH) in brain mitochondria. At levels higher than 10 0 mu M, butyryl-CoA (BCoA; a short-chain acyl-CoA; IC50 similar to 640 mu M), octanoyl-CoA (OCoA; a medium-chain acyl-CoA; IC50 similar to 3 80 mu M), n-decanoyl-CoA (DCoA; a medium-chain acyl-CoA; IC50 similar to 436 PM), and palmitoyl-CoA (PCoA; a long-chain acyl-CoA; IC50 simil ar to 340 mu M) inhibited brain mitochondrial CS activity in a concent ration-related manner. However, these fatty acyl-CoAs were less effect ive inhibitors (IC50 values for OCoA, DCoA, and PCoA being similar to 1260, 420, and 720 mu M, respectively) of brain mitochondrial GDH acti vity. Compared to the other three acyl-CoAs investigated, BCoA was a v ery poor inhibitor of GDH. These results demonstrate that fatty acyl-C oAs are inhibitors of brain mitochondrial CS and GDH activities only a t pathological/toxicological levels. Thus, the fatty acyl-CoA inhibiti on of brain mitochondrial CS and GDH is unlikely to assume major patho physiological and/or pathogenetic importance. Nevertheless, the result s are consistent with the hypothesis that one mechanism underlying fat ty acid neurotoxicity is the selective inhibition of rate-limiting and /or regulated tricarboxylic acid (TCA) cycle and related enzymes by fa tty acyl-CoAs.