The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation

Monocarboxylates such as lactate and pyruvate play a central role in cellul ar metabolism and metabolic communication between tissues. Essential to the se roles is their rapid transport across the plasma membrane, which is cata lysed by a recently identified family of proton-linked monocarboxylate tran sporters (MCTs). Nine MCT-related sequences have so far been identified in mammals, each having a different tissue distribution, whereas six related p roteins can be recognized in Caenorhabditis elegans and 4 in Saccharomyces cerevisiae. Direct demonstration of proton-linked lactate and pyruvate tran sport has been demonstrated for mammalian MCT1-MCT4, but only for MCT1 and MCT2 have detailed analyses of substrate and inhibitor kinetics been descri bed following heterologous expression in Xenopus oocytes. MCT1 is ubiquitou sly expressed, but is especially prominent in heart and red muscle, where i t is up-regulated in response to increased work, suggesting a special role in lactic acid oxidation. By contrast, MCT4 is most evident in white muscle and other cells with a high glycolytic rate, such as tumour cells and whit e blood cells, suggesting it is expressed where lactic acid efflux predomin ates. MCT2 has a ten-fold higher affinity for substrates than MCT1 and MCT4 and is found in cells where rapid uptake at low substrate concentrations m ay be required, including the proximal kidney tubules, neurons and sperm ta ils. MCT3 is uniquely expressed in the retinal pigment epithelium. The mech anisms involved in regulating the expression of different MCT isoforms rema in to be established. However, there is evidence for alternative splicing o f the 5'- and 3'-untranslated regions and the use of alternative promoters for some isoforms. In addition, MCT1 and MCT4 have been shown to interact s pecifically with OX-47 (CD147), a member of the immunoglobulin superfamily with a single transmembrane helix. This interaction appears to assist MCT e xpression at the cell surface. There is still much work to be done to chara cterize the properties of the different isoforms and their regulation, whic h may have wide-ranging implications for health and disease. In the future- it will be interesting to explore the linkage of genetic diseases to partic ular MCTs through their chromosomal location.