The relationship between intramitochondrial N-acetylglutamate and activity of carbamoyl-phosphate synthetase (ammonia). The effect of glucagon.

1. The relationship between urea synthesis, intracellular N-acetylglutamate and the capacity of rat-liver mitochondria to synthesize citrulline was investigated. 2. Treatment of rats with glucagon prior to killing results not only in an increased intramitochondrial ATP concentration and an increased capacity of the mitochondria to synthesize citrulline, but also in an increased concentration of intramitochondrial N-acetylglutamate. 3. Comparison of the rate of citrulline synthesis in mitochondria from glucagon-treated and from control rats, incubated under different conditions, shows that the increased N-acetylglutamate concentration after glucagon treatment is at least in part responsible for the observed increased capacity of the mitochondria to synthesize citrulline. 4. Ureogenic flux in isolated hepatocytes under different incubation conditions correlated with the intracellular concentration of N-acetylglutamate and with the capacity of the mitochondria to synthesize citrulline. 5. When isolated hepatocytes were incubated with NH3, ornithine, lactate and oleate, intracellular N-acetylglutamate increased about eightfold in the first 10 min; during this period the rate of urea synthesis increased considerably. 6. It is concluded that the concentration of intramitochondrial N-acetylglutamate plays an important role in the short-term control of flux through the urea cycle under different nutritional and hormonal conditions.