Aspartate-glutamate carrier 2 (citrin): a role in glucose and amino acid metabolism in the liver

Abstract

Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrial carrier expressed in the liver that transports aspartate from mitochondria into the cytosol in exchange for glutamate. The AGC2 is the main component of the malate-aspartate shuttle (MAS) that ensures indirect transport of NADH produced in the cytosol during glycolysis, lactate oxidation to pyruvate, and ethanol oxidation to acetaldehyde into mitochondria. Through MAS, AGC2 is necessary to maintain intracellular redox balance, mitochondrial respiration, and ATP synthesis. Through elevated cytosolic Ca 2+ 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 other is ammonia), and a substrate for the synthesis of fumarate that is gradually converted to oxaloacetate, the starting substrate for gluconeogenesis. Furthermore, aspartate is a substrate for the synthesis of asparagine, nucleotides, and proteins. It is concluded that AGC2 plays a fundamental role in the compartmentalization of aspartate and glutamate metabolism and linkage of 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.

Aspartic Acid in Health and Disease

“…Although AGC1 and AGC2 have the same role in the mitochondrial membrane, their physiological roles differ due to the different functions of the tissues in which they are found. Specifically, AGC1 plays a unique role in PNC, whereas AGC2 does so in the urea cycle and gluconeogenesis [ 5 ].…”

“…Aspartate exists in two isoforms; the main form is L-aspartic acid (L-Asp), and D-aspartic acid (D-Asp) is present in much smaller amounts: This narrative review aims to examine the origin and pathways of aspartate metabolism in physiological and various pathological conditions, the therapeutic potential of targeting pathways of aspartate metabolism, and the use of aspartate and aspartate-containing substances as nutritional supplements. The focus is on the role of mitochondrial carriers in the compartmentalization of L-Asp and glutamate metabolic pathways between mitochondria and cytosol [2][3][4][5] and new insights into the role of aspartate in cell-to-cell interactions and neurotransmission in the brain, cell proliferation, glycolysis, gluconeogenesis, diabetes, psychiatric and neurologic disorders, liver cirrhosis, and cancer [6][7][8][9][10][11][12][13][14][15][16][17][18].…”