Abstract
Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrial carrier expressed in the liver that transports aspartate from mitochondria into cytosol in exchange with glutamate. The AGC2 is the main component of malate-aspartate shuttle (MAS) that ensures indirect transport of NADH produced in cytosol during glycolysis, lactate oxidation to pyruvate, and ethanol oxidation to acetaldehyde into mitochondria.
Through MAS, AGC2 is necessary for maintaining intracellular redox balance, mitochondrial respiration, and ATP synthesis. Through elevated cytosolic Ca2+ level, the AGC2 is stimulated by catecholamines and glucagon during starvation, exercise, and muscle wasting disorders.
In these conditions, AGC2 increases aspartate input to the urea cycle, where aspartate is a source of one of two nitrogen atoms in the urea molecule (the next is ammonia) and a substrate for synthesis of fumarate that is gradually converted to oxaloacetate, the starting substrate for gluconeogenesis. Furthermore, aspartate is a substrate for synthesis of asparagine, nucleotides, and proteins.
It is concluded that AGC2 has a fundamental role in compartmentalization of aspartate and glutamate metabolism and linking the reactions of MAS, glycolysis, gluconeogenesis, amino acid catabolism, urea cycle, protein synthesis, and cell proliferation. Targeting of AGC genes may represent a new therapeutic strategy to fight cancer.