Differential inhibitory effect of long-chain acyl-CoA esters on succinate and glutamate transport into rat liver mitochondria and its possible implications for long-chain fatty acid oxidation defects.
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Ventura FV, Ruiter J, Ijlst L, de Almeida IT, Wanders RJ
Differential inhibitory effect of long-chain acyl-CoA esters on succinate and glutamate transport into rat liver mitochondria and its possible implications for long-chain fatty acid oxidation defects.
Mol Genet Metab. 2005 Nov;86(3):344-52. Epub 2005 Sep 19.
- PubMed ID
- 16176879 [ View in PubMed]
- Abstract
Long-chain fatty acid beta-oxidation defects are associated with a series of clinical and biochemical abnormalities, including accumulation of long-chain acyl-CoA esters which have been shown to inhibit several enzymes and transport systems that may disturb energy metabolism. Using isolated rat liver mitochondria incubated under state 3 conditions, we observed that long-chain acyl-CoA esters and their beta-oxidation intermediates inhibit ATP synthesis and oxygen consumption, both with succinate (plus rotenone) and l-glutamate as respiratory substrates. When an uncoupler (2,4-dinitrophenol) was used instead of ADP, to stimulate respiration maximally, the various CoA esters showed differential effects on the oxidation of succinate and l-glutamate, respectively. With succinate as substrate, there was a strong inhibition of oxygen consumption by palmitoyl-CoA, 2,3-unsaturated, 3-hydroxy, and 3-keto-palmitoyl-CoA, in coupled as well as uncoupled mitochondria. On the other hand, with l-glutamate as substrate, inhibition was only observed under coupled conditions. The finding that acyl-CoA esters inhibit the uncoupler-induced respiration with succinate as substrate but not with glutamate, indicates that the observed inhibitory effect is most probably at the level of the transport of succinate across the mitochondrial membrane as mediated by the mitochondrial dicarboxylate carrier. This conclusion was substantiated by mitochondrial swelling studies, which showed inhibition of succinate transport by the different CoA esters whereas no effect was observed on the phosphate/hydroxyl and glutamate/hydroxyl carriers. Furthermore, long-chain acyl-CoA esters were found to potentiate the inhibitory effect of N-butylmalonate, a known inhibitor of the dicarboxylate carrier, upon oxygen consumption driven by succinate (plus rotenone). We conclude that the inhibitory effects of long-chain acyl-CoA esters on oxidative phosphorylation are dependent on the type of substrate used with the ATP/ADP carrier and the dicarboxylate carrier as targets for inhibition.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Succinic acid Mitochondrial dicarboxylate carrier Protein Humans UnknownLigandDetails