Mitochondrial dysfunction is central to the pathophysiology of Reye's Syndrome (RS). RS serum incubated with isolated mitochondria stimulates respiration, uncouples oxidative phosphorylation and induces ultrastructural changes. These phenomena are induced by the free fatty acids in the serum, particularly dicarboxylic fatty acid (DCAs) and can be reproduced by the addition of long chain DCAs to control serum. Long chain DCAs comprise as much as 55% of the total serum free fatty acids in RS. RS is the first disease in which long chain DCAs have been noted. Since long chain DCA formation is a striking feature, possibly unique to RS, which has the potential for generalized effects on mitochondrial function, an impairment of beta-oxidation and/or the stimulation of omega-oxidation of fatty acids may be important in RS. DCAs probably in combination with monocarboxylic fatty acids could accumulate intracellularly in sufficient concentration to act as uncouplers of oxidative phosphorylation and produce a generalized impairment of mitochondrial function. The central questions addressed are: 1) Is a defect in fatty acid oxidation primary in RS and is long chain DCA formation a consequence of beta-oxidation disruption, or 2.) Is long chain DCA formation primary and will the long chain DCAs have toxic effects on the metabolism of whole cells.
The aims are to: 1) Determine whether uncoupling of oxidative phosphorylation, modulation of beta-oxidation, or stimulation of microsomal enzymes is sufficient to induce long chain DCAs in cultured hepatoma cells. DCA formation will be measured in extracted cell lipid by gas chromatography. 2.) Determine what physiologic effects long chain DCAs have on fatty acid oxidation, glucose utilization, urea synthesis and ATP formation in cultured hepatoma cells. 3.) Evaluate the metabolism of long chain DCAs including their binding to albumin and fatty acid binding protein and the extent to which 14C-labeled DCAs are oxidized in hepatoma cells.
| Tonsgard, J H; Stephens, J K; Rhead, W J et al. (1991) Defect in fatty acid oxidation: laboratory and pathologic findings in a patient. Pediatr Neurol 7:125-30 |
| Tonsgard, J H; Meredith, S C (1991) Characterization of the binding sites for dicarboxylic acids on bovine serum albumin. Biochem J 276 ( Pt 3):569-75 |
| Tonsgard, J H (1989) Effect of Reye's syndrome serum on the ultrastructure of isolated liver mitochondria. Lab Invest 60:568-73 |
| Tonsgard, J H; Mendelson, S A; Meredith, S C (1988) Binding of straight-chain saturated dicarboxylic acids to albumin. J Clin Invest 82:1567-73 |
