Brain mitochondrial citrate synthase and glutamate dehydrogenase: Differential inhibition by fatty acyl coenzyme a derivatives

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 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)

Glucose-fatty acid cycle to inhibit glucose utilization and oxidation is not operative in fatty acid-cultured islets.

“…These changes in citrate and G-6-P are opposite to those expected from the glucose-fatty acid cycle. The inhibitory effect of FA on citrate synthase is not unique to islets, but has been reported in brain and lymphoid tissue (47,48); hence, some other tissues may be resistant to a glucose-fatty acid cycle mechanism in a similar manner. The most important consequence of these enzyme and metabolite changes caused by chronic FA exposure in the pancreatic ␤-cell is probably the increased basal secretion of insulin.…”

Age-related changes in mitochondrial respiration and oxidative damage in the cerebral cortex of the Fischer 344 rat

“…The present study evaluated possible age-related changes in bioenergetics of synaptic and extrasynaptic mitochondria separately, since several groups have reported heterogeneity in the these two fractions (Dennis, Lai et al 1977; Lai, Walsh et al 1977; Deshmukh, Owen et al 1980; Deshmukh and Patel 1980; Villa, Gorini et al 1989; Lai, Liang et al 1994; Davey and Clark 1996; Davey, Peuchen et al 1998; Brown, Sullivan et al 2006; Naga, Sullivan et al 2007). Several complex 1- and 2-driven respiration parameters were quantified from cortical synaptic and extrasynaptic mitochondria.…”