The mitochondrial ornithine carrier and the HHH syndrome

The mitochondrial ornithine carrier has two isoforms in man (ORC1 and ORC2) encoded by two different genes SLC25A15 and SLC25A2, respectively. Even though both isoforms catalyze the transport of ornithine, lysine, arginine and citrulline, they differ in many respects, such as substrate specificity, kinetic parameters, tissue distribution and expression levels. The ORC fulfils the important function of exchanging cytosolic ornithine and intramitochondrial citrulline, and is therefore an essential component of the urea cycle. This conclusion is strengthened by the demonstration that the SLC25A15 gene coding ORC1 is altered in patients affected by the hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome, an autosomal recessive disorder characterized by growth retardation, periods of lethargy, ataxia, myoclonic seizures and episodes of coma due to hyperammonemia. The co-expression of ORC2 and ORC1 in liver may explain the mild phenotype characteristic of HHH patients, as compared to that caused by defects in any of the other urea cycle enzymes. As well as in ureogenesis, ORC1 and ORC2 may play a role in cell metabolism under various physiological conditions. For instance the net import of lysine, arginine and histidine into the mitochondria is necessary for the synthesis of intramitochondrially translated proteins, whereas the efflux of ornithine from the mitochondria may occur in other metabolic processes, such as the biosynthesis of polyamines that are produced from ornithine in the cytosol.