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Peer-reviewedCC BY 4.0Biomolecules

Citrin Deficiency: Biochemical Mechanisms Underlying a Complex Hepatic Metabolic Disorder

  • Ismael García-Lobo1,2,3
  • Araceli del Arco2,3,4,5
  • Jorgina Satrústegui1,2,3
  • Laura Contreras1,2,3
5 affiliations
  1. 1Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain
  2. 2Instituto Universitario de Biología Molecular (IUBM), Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid, Spain
  3. 3Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Universidad Autónoma de Madrid, 28040 Madrid, Spain
  4. 4Facultad de Ciencias Ambientales y Bioquímica, Universidad de Castilla la Mancha, 45071 Toledo, Spain
  5. 5Centro Regional de Investigaciones Biomédicas and Unidad Asociada de Biomedicina, UCLM-CSIC, Universidad de Castilla la Mancha, 45071 Toledo, Spain
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{garcialobo2026citrin,
  title = {{Citrin Deficiency: Biochemical Mechanisms Underlying a Complex Hepatic Metabolic Disorder}},
  author = {Ismael García-Lobo and Araceli del Arco and Jorgina Satrústegui and Laura Contreras},
  journal = {Biomolecules},
  year = {2026},
  month = oct,
  doi = {10.3390/biom16101460},
  url = {https://www.mdpi.com/2218-273X/16/10/1460},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Citrin Deficiency: Biochemical Mechanisms Underlying a Complex Hepatic Metabolic Disorder
AU  - Ismael García-Lobo
AU  - Araceli del Arco
AU  - Jorgina Satrústegui
AU  - Laura Contreras
PY  - 2026
DA  - 2026/10/01
JO  - Biomolecules
DO  - 10.3390/biom16101460
UR  - https://www.mdpi.com/2218-273X/16/10/1460
AB  - 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.
SN  - 2218-273X
ER  -