ISSN:
1573-7365
Keywords:
neurotoxicity of fatty acids
;
fatty acyl-CoA inhibition of mitochondrial enzymes
;
brain mitochondria
;
organic acidemia
;
metabolic encephalopathies
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract 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 µM, butyryl-CoA (BCoA; a short-chain acyl-CoA; IC50 ∼ 640 µM), octanoyl-CoA (OCoA; a medium-chain acyl-CoA; IC50 ∼ 436 µM), and palmitoyl-CoA (PCoA; a long-chain acyl-CoA; IC50 ∼ 340 µM) 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 ∼ 1260, 420, and 720 µM, 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. Nevertheless, the results are consistent with the hypothesis 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-CoAs.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF01999767
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