Citrin Deficiency: Biochemical Mechanisms Underlying a Complex Hepatic Metabolic Disorder

Citrin Deficiency (CD), caused by pathogenic variants in SLC25A13, is a rare inherited metabolic disorder with age-dependent manifestations ranging from neonatal intrahepatic cholestasis to adult-onset citrullinemia. Although the genetic basis of CD is well established, the mechanisms linking loss of the mitochondrial aspartate/glutamate carrier (citrin) to the CD phenotype remain incompletely understood. This review examines current evidence from patients and available cellular and animal models supporting the biochemical mechanisms underlying CD. We discuss how disruption of the malate-aspartate shuttle alters cytosolic redox homeostasis and its consequences for interconnected pathways of carbohydrate, lipid, and nitrogen metabolism, including glycolysis, gluconeogenesis, galactose metabolism, fatty acid oxidation, lipogenesis, and ureagenesis. We also distinguish mechanisms supported by experimental evidence from those that remain hypothetical and highlight major unresolved questions regarding metabolic adaptation, disease progression, and the transition to the adult phenotype.