Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency

Trends Endocrinol Metab. 2022 Aug;33(8):539-553. doi: 10.1016/j.tem.2022.05.002. Epub 2022 Jun 17.


Citrin deficiency is a pan-ethnic and highly prevalent mitochondrial disease with three different stages: neonatal intrahepatic cholestasis (NICCD), a relatively mild adaptation stage, and type II citrullinemia in adulthood (CTLN2). The cause is the absence or dysfunction of the calcium-regulated mitochondrial aspartate/glutamate carrier 2 (AGC2/SLC25A13), also called citrin, which imports glutamate into the mitochondrial matrix and exports aspartate to the cytosol. In citrin deficiency, these missing transport steps lead to impairment of the malate-aspartate shuttle, gluconeogenesis, amino acid homeostasis, and the urea cycle. In this review, we describe the geological spread and occurrence of citrin deficiency, the metabolic consequences and use our current knowledge of the structure to predict the impact of the known pathogenic mutations on the calcium-regulatory and transport mechanism of citrin.

Keywords: SLC25A12; SLC25A13; calcium regulation; mitochondrial carrier family; transport; urea cycle disorders.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aspartic Acid / genetics
  • Calcium
  • Citrullinemia* / genetics
  • Citrullinemia* / metabolism
  • Glutamates / genetics
  • Humans
  • Infant, Newborn
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mutation


  • Glutamates
  • Mitochondrial Membrane Transport Proteins
  • SLC25A13 protein, human
  • Aspartic Acid
  • Calcium

Supplementary concepts

  • Adult-onset citrullinemia type 2