Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice

Background/Aims: Mutations in SLC25A13, encoding the mitochondrial aspartate-glutamate carrier citrin, cause adult-onset type II citrullinemia (CTLN2) in humans. We have previously reported that although citrin-knockout (Ctrn(-/-)) mice fail to display symptoms of CTLN2, liver perfusion revealed a deficit in ureogenesis from ammonia accompanied by an increase in the perfusate lactate-to-pyruvate (L/P) ratio. The present study explores the effects of pyruvate, aspartate and citrate on improving the abnormalities observed in the Ctrn(-/-) liver. Methods: We measured the rate of ureogenesis from ammonium chloride using the liver-perfusion system. Results: Pyruvate infusion lowered the UP ratio and corrected the deficit in ureogenesis in the Ctrn(-/-) liver. This effect was found to be dose-dependent in both instances. Phenazine methosulfate, a cytosolic oxidant, also improved the rate of ureogenesis in the Ctrn(-/-) liver and led to a fall in the UP ratio. The addition of aspartate or citrate did not change either the rate of ureogenesis or the UP ratio in the Ctrn(-/-) liver. Conclusions: Citrin deficiency disturbs urea synthesis primarily as a result of an elevated cytosolic NADH/NAD(+) ratio owing to limited reoxidation of reducing equivalents. Clinically, pyruvate may have a therapeutic benefit for CTLN2 patients. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.