Mitochondrial di-/tricarboxylate and glutamate carriers (SLC25A1 citrate, SLC25A10 dicarboxylate, SLC25A21 oxodicarboxylate, SLC25A22 glutamate)

The tricarboxylic-acid (TCA) cycle both consumes and generates carbon skeletons that must move between the mitochondrial matrix and the cytosol for anabolism (lipogenesis, gluconeogenesis) and amino-acid metabolism. A set of SLC25 mitochondrial carriers exchanges these di- and tricarboxylate intermediates and related amino acids across the impermeable inner membrane. This module groups four such carriers. The citrate carrier SLC25A1 (CIC/CTP) exports matrix citrate in exchange for cytosolic malate, feeding cytosolic citrate lysis into acetyl-CoA (and NADPH) for fatty-acid and cholesterol synthesis. The dicarboxylate carrier SLC25A10 (DIC) exchanges malate or succinate for inorganic phosphate, supplying dicarboxylates for gluconeogenesis and lipogenesis and linking to sulfur metabolism. The oxodicarboxylate carrier SLC25A21 (ODC) transports the C5-C7 2-oxodicarboxylates 2-oxoadipate and 2-oxoglutarate, serving the mitochondrial steps of lysine and tryptophan degradation. The glutamate carrier SLC25A22 (GC1) imports L-glutamate in symport with a proton, feeding glutamate catabolism and ammonia handling (and, in neurons, glutamate metabolism). Loss-of-function causes distinct metabolic diseases: SLC25A1 — combined D-2- and L-2-hydroxyglutaric aciduria and a congenital myasthenic syndrome; SLC25A22 — early infantile epileptic encephalopathy with migrating partial seizures; and SLC25A21 has been linked to a 2-oxoadipate/2-oxoglutarate-dehydrogenase-related phenotype.