DICARBOXYLIC ACIDS AS UNCOUPLERS IN REYE'S SYNDROME

Abstract

A general impairment of liver mitochondrial enzymes is central to Reye's Syndrome(RS). The effect of RS serum from 8 patients in profound coma on respiration of isolated liver mitochondria was measured with 2.5mg of mitochondrial protein, 3mM substrates, and 5x concentrated serum. RS serum stimulates respiration(1.05± .14 nmol O2/min/mg protein, control .30± .08). This effect is due to: 1.)oxidation of uric acid by microsomes contaminating the preparation, 2.)fatty acids providing substrate, 3.)uncoupling of oxidative phosphorylation by 30-40%. The amount of uncoupling is additive, correlates with the amount of free fatty acids in the serum but is not inhibited by 1% defatted albumin as is oleate added to normal serum. The degree of stimulation/mcg of fatty acid is distinct from that of oleate or octanoate added to normal serum. RS serum stimulates respiration in the presence of antimycin and 3mM ascorbate by 80-149%: oleate+ normal serum causes a 0-10% increase. 3mM medium chain dicarboxylic acids are not readily bound to 1% albumin and induce a 90-105% increase in antimycin/ascorbate respiration; they require intact mitochondria and exogenous substrate. Dicarboxylic acids are markedly elevated (1-3mg/mg creatinine, N=12; controls<.10, N=40) in urine from our RS patients and unusual long and unsaturated dicarboxylic acids were reported in the serum of 2 RS patients (Amer. Soc. Mass. Spec. 31:98, 1983). Thus, dicarboxylic acids act as uncouplers and may be important in the general impairment of mitochondrial function in RS and other disorders where large amounts of dicarboxylic acids are present.