Calcium-binding mitochondrial carrier protein Aralar2 (Citrin) (SLC25A13)

Citrin, also known as the calcium-binding mitochondrial carrier protein Aralar2 or SLC25A13, is a calcium-dependent mitochondrial solute transporter primarily expressed in the liver, kidneys, and heart [1, 3]. It functions as an electrogenic aspartate-glutamate carrier (AGC2) in the inner mitochondrial membrane, facilitating the export of mitochondrial aspartate to the cytosol in exchange for cytosolic glutamate and a proton [1, 10]. This exchange is a fundamental component of the malate-aspartate shuttle, which is essential for maintaining the NAD+/NADH redox balance between the cytosol and mitochondria, thereby supporting the urea cycle, gluconeogenesis, and aerobic glycolysis [3, 11, 14]. Mutations in the SLC25A13 gene lead to citrin deficiency, a condition that manifests as neonatal intrahepatic cholestasis (NICCD) or adult-onset type II citrullinemia (CTL2), characterized by hyperammonemia and metabolic distress [1, 7, 20]. While there are currently no direct small-molecule agonists for citrin, therapeutic strategies focus on metabolic bypass using agents like medium-chain triglycerides (MCT) and sodium pyruvate to restore redox balance and provide alternative energy sources [2, 12, 13]. Advanced treatments, including gene therapy and mRNA-based replacement, are under development to restore functional citrin expression in affected tissues [2, 16].

Other names

Aralar2AGC2Solute carrier family 25 member 13Mitochondrial aspartate glutamate carrier 2CMC2CTLN2NICCD

Therapeutic strategies focus on metabolic bypass and redox restoration to compensate for the loss of citrin function. Sodium pyruvate restores the cytosolic NAD+/NADH ratio by consuming NADH during its conversion to lactate, while medium-chain triglycerides (MCT) provide an alternative mitochondrial energy source and promote lipogenesis. L-Arginine is used to facilitate ammonia detoxification through the urea cycle, and experimental gene therapies aim to restore endogenous citrin protein expression.