Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice.
OBJECTIVE
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 L/P 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 L/P ratio. The addition of aspartate or citrate did not change either the rate of ureogenesis or the L/P 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.
Moriyama
Mitsuaki
M
Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan.
Li
Meng Xian
MX
Kobayashi
Keiko
K
Sinasac
David S
DS
Kannan
Yukiko
Y
Iijima
Mikio
M
Horiuchi
Masahisa
M
Tsui
Lap-Chee
LC
Tanaka
Masashi
M
Nakamura
Yoichi
Y
Saheki
Takeyori
T
D000596:Amino Acids / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001224:Aspartic Acid / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000235:genetics*; D019343:Citric Acid / Q000494:pharmacology; D020159:Citrullinemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D022124:Hyperammonemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000235:genetics*; D010084:Oxidation-Reduction; D010477:Perfusion; D019289:Pyruvic Acid / Q000494:pharmacology*; D014508:Urea / Q000378:metabolism*
D000596:Amino Acids; D000925:Anticoagulants; D002135:Calcium-Binding Proteins; D027361:Organic Anion Transporters; C008822:citrin; D019343:Citric Acid; D001224:Aspartic Acid; D000641:Ammonia; D019289:Pyruvic Acid; D014508:Urea