Carnitine is a required cofactor for the transport of long chain fatty acids across the inner mitochondrial membrane and is proposed to have a role in the metabolism of short and medium chain acyl groups. Primary carnitine deficiency is a heterogenous syndrome whose symptoms include weakness, cardiomyopathy, hypoglycemia acidosis, and hyperammonemia. Carnitine deficiency has been seen in association with other disorders (renal dialysis prematurity, methylmalonic aciduria, propionic acidemia and valproic acid administration). The mechanism of the development of secondary carnitine deficiency is largely unknown, as its relationship to the symptomatology of the primary disorders. It is proposed to study normal carnitine metabolism and the relationship between carnitine and the metabolism of organic acids important in human disease. The mechanism of carnitine's epithelial transport will be investigated in rat kidney slices and intestinal mucosa. Rats will be given 1-14C or 14CH3-carnitine and turnover rates calculated. Differences in turnover rates between the radioisomers will be assessed. Appearance of label in possible degradation products (respiratory CO2, quaternary ammonium compounds, methionine and glycine) will be measured. The relationships between carnitine, free and acyl CoA's and organic acid toxicity will be studied. A unifying hypothesis that several of the effects of carnitine deficiency and of organic acidoses are due to disruption of the normal free:acyl CoA balance and that carnitine can restore that balance will be tested in animal models and humans. The effect of organic acids which accumulate as CoA esters on plasma and urine carnitine levels will be compared with the effect of those which accumulate as the free acids. The effect of carnitine on citrulline synthesis and N-acetylglutamate levels in rat liver mitochondria will be assessed. Rats will be made carnitine deficient by feeding them a synthetic lysine-deficient diet. Carbamoylglutamate or carnitine will be given, and the response of plasma ammonia levels to an alanine load measured. A model of organic acidosis in intact rats and liver mitochondria will be used to delineate the effect of carnitine on CoA levels, glycine cleavage complex activity and ammonia metabolism.
