Aspartate-glutamate carrier 2 (citrin): a role in glucose and amino acid metabolism in the liver
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Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrialcarrier expressed in the liver that transports aspartate from mitochondriainto the cytosol in exchange for glutamate. The AGC2is the main component of the malate-aspartate shuttle (MAS)that ensures indirect transport of NADH produced in the cytosolduring glycolysis, lactate oxidation to pyruvate, and ethanoloxidation to acetaldehyde into mitochondria. Through MAS,AGC2 is necessary to maintain intracellular redox balance,mitochondrial respiration, and ATP synthesis. Through elevatedcytosolic Ca2+ level, the AGC2 is stimulated by catecholaminesand glucagon during starvation, exercise, and muscle wastingdisorders. In these conditions, AGC2 increases aspartate inputto the urea cycle, where aspartate is a source of one of twonitrogen atoms in the urea molecule (the other is ammonia),and a substrate for the synthesis of fumarate that is graduallyconverted to oxaloacetate, the starting substrate for gluconeogenesis. Furthermore, aspartate is a substrate for the synthesisof asparagine, nucleotides, and proteins. It is concluded thatAGC2 plays a fundamental role in the compartmentalization ofaspartate and glutamate metabolism and linkage of the reactionsof MAS, glycolysis, gluconeogenesis, amino acid catabolism,urea cycle, protein synthesis, and cell proliferation. Targeting ofAGC genes may represent a new therapeutic strategy to fightcancer.
Abstract
Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrialcarrier expressed in the liver that transports aspartate from mitochondriainto the cytosol in exchange for glutamate. The AGC2is the main component of the malate-aspartate shuttle (MAS)that ensures indirect transport of NADH produced in the cytosolduring glycolysis, lactate oxidation to pyruvate, and ethanoloxidation to acetaldehyde into mitochondria. Through MAS,AGC2 is necessary to maintain intracellular redox balance,mitochondrial respiration, and ATP synthesis. Through elevatedcytosolic Ca2+ level, the AGC2 is stimulated by catecholaminesand glucagon during starvation, exercise, and muscle wastingdisorders. In these conditions, AGC2 increases aspartate inputto the urea cycle, where aspartate is a source of one of twonitrogen atoms in the urea molecule (the other is ammonia),and a substrate for the synthesis of fumarate that is graduallyconverted to oxaloacetate, the starting substrate for gluconeogenesis. Furthermore, aspartate is a substrate for the synthesisof asparagine, nucleotides, and proteins. It is concluded thatAGC2 plays a fundamental role in the compartmentalization ofaspartate and glutamate metabolism and linkage of the reactionsof MAS, glycolysis, gluconeogenesis, amino acid catabolism,urea cycle, protein synthesis, and cell proliferation. Targeting ofAGC genes may represent a new therapeutic strategy to fightcancer.
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