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 hereditary organic acidemias). Although fatty acids are known to be neurotoxic, the underlying mechanisms have not been fully elucidated. It has been hypothesized that one mechanism underlying fatty acid neurotoxicity is the selective inhibition of rate-limiting and/or regulated tricarboxylic acid (TCA) cycle and related enzymes by fatty acyl-coenzyme A (CoA) derivatives. To test the hypothesis, this study has examined the effects of several fatty acyl-CoAs on citrate synthase (CS) and glutamate dehydrogenase (GDH) in brain mitochondria. At levels higher than 100 microM, butyryl-CoA (BCoA; a short-chain acyl-CoA; IC50 approximately 640 microM), octanoyl-CoA (OCoA; a medium-chain acyl-CoA; IC50 approximately 380 microM), n-decanoyl-CoA (DCoA; a medium-chain acyl-CoA; IC50 approximately 436 microM), and palmitoyl-CoA (PCoA; a long-chain acyl-CoA; IC50 approximately 340 microM) inhibited brain mitochondrial CS activity in a concentration-related manner. However, these fatty acyl-CoAs were less effective inhibitors (IC50 values for OCoA, DCoA, and PCoA being approximately 1260, 420, and 720 microM, respectively) of brain mitochondrial GDH activity. Compared to the other three acyl-CoAs investigated, BCoA was a very poor inhibitor of GDH. These results demonstrate that fatty acyl-CoAs are inhibitors of brain mitochondrial CS and GDH activities only at pathological/toxicological levels. Thus, the fatty acyl-CoA inhibition of brain mitochondrial CS and GDH is unlikely to assume major pathophysiological and/or pathogenetic importance.(ABSTRACT TRUNCATED AT 250 WORDS)
Lai
J C
JC
Department of Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello 93209-8334.
Liang
B B
BB
Zhai
S
S
Jarvi
E J
EJ
Lu
D R
DR
D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors*; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors*; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000214:Acyl Coenzyme A; D005969:Glutamate Dehydrogenase; D002950:Citrate (si)-Synthase