Minireview
Carnitine Transport by Organic Cation Transporters and Systemic Carnitine Deficiency

https://doi.org/10.1006/mgme.2001.3207Get rights and content

Abstract

The intracellular homeostasis is controlled by different membrane transporters. Organic cation transporters function primarily in the elimination of cationic drugs, endogenous amines, and other xenobiotics in tissues such as the kidney, intestine, and liver. Among these molecules, carnitine is an endogenous amine which is an essential cofactor for mitochondrial β-oxidation. Recently, a new family of transporters, named OCT (organic cation transporters) has been described. In this minireview, we present the recent knowledge about OCT and focus on carnitine transport, more particularly by the OCTN2. The importance of this sodium-dependent carnitine cotransporter, OCTN2, comes from various recently reported mutations in the gene which give rise to the primary systemic carnitine deficiency (SCD; OMIM 212140). The SCD is an autosomal recessive disorder of fatty acid oxidation characterized by skeletal myopathy, progressive cardiomyopathy, hypoglycemia and hyperammonemia. Most of the OCTN2 mutations identified in humans with SCD result in loss of carnitine transport function. Identifying these mutations will allow an easy targeting of the SCD syndrome. The characteristics of the juvenile visceral steatosis (jvs) mouse, an animal model of SCD showing similar symptoms as humans having this genetic disorder, are also described. These mice have a mutation in the gene encoding the mouse carnitine transporter octn2. Although various OCTN carnitine transporters have been identified and functionally characterized, their membrane localization and regulation are still unknown and must be investigated. This knowledge will also help in designing new drugs that regulate carnitine transport activity.

References (57)

  • ME Ganapathy et al.

    β-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter

    J Biol Chem

    (2000)
  • S Sesaki

    Molecular basis of organic anion and cation transport

    Kidney Int

    (2000)
  • AM Lamhonwah et al.

    Carnitine uptake defect: Frameshift mutations in the human plasmalemmal carnitine transporter gene

    Biochem Biophys Res Commun

    (1998)
  • B Burwinkel et al.

    Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: A novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality

    Biochem Biophys Res Commun

    (1999)
  • Y Wang et al.

    Abnormal sodium stimulation of carnitine transport in primary carnitine deficiency

    J Biol Chem

    (2000)
  • AM Lamhonwah et al.

    GFP-human high-affinity carnitine transporter OCTN2 protein: Subcellular localization and functional restoration of carnitine uptake in mutant cell lines with the carnitine transporter defect

    Biochem Biophys Res Commun

    (1999)
  • P Seth et al.

    Mutations in novel organic cation transporter (OCTN2), an organic cation/carnitine transporter, with differential effects on the organic cation transport function and the carnitine transport function

    J Biol Chem

    (1999)
  • K-m Lu et al.

    A missense mutation of mouse OCTN2, a sodium-dependent carnitine cotransporter, in the juvenile visceral steatosis mouse

    Biochem Biophys Res Commun

    (1998)
  • Y Imamura et al.

    Urea cycle disorder in C3H-H-2° mice with juvenile steatosis of viscera

    FEBS Lett

    (1990)
  • M Tomomura et al.

    Abnormal expression of urea cycle enzyme genes in juvenile visceral steatosis (jvs) mice

    Biochim Biophys Acta

    (1992)
  • M Horiuchi et al.

    Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency

    FEBS Lett

    (1993)
  • M Kuwajima et al.

    Animal model of systemic carnitine deficiency: Analysis in C3H-H-2° strain of mouse associated with juvenile visceral steatosis

    Biochem Biophys Res Commun

    (1991)
  • M Horiuchi et al.

    Carnitine administration to juvenile visceral steatosis mice corrects the suppressed expression of urea cycle enzymes by normalizing their transcription

    J Biol Chem

    (1992)
  • M Horiuchi et al.

    Primary defect of juvenile visceral steatosis (jvs) mouse with systemic carnitine deficiency is probably in renal carnitine transport system

    Biochim Biophys Acta

    (1994)
  • M Kuwajima et al.

    Carnitine transport defect in fibroblasts of juvenile visceral steatosis (JVS) mouse

    Biochem Biophys Res Commun

    (1996)
  • N Hashimoto et al.

    Gene-dose effect on carnitine transport activity in embryonic fibroblasts of jvs mice as a model of human carnitine transporter deficiency

    Biochem Pharmacol

    (1998)
  • K Okita et al.

    Definition of the locus responsible for systemic carnitine deficiency within a 1.6cM region of mouse chromosome 11 by detailed linkage analysis

    Genomics

    (1996)
  • L Zhang et al.

    Role of organic cation transporters in drug absorption and elimination

    Annu Rev Pharmacol Toxicol

    (1998)
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