Comprehensive Physiology Wiley Online Library

Monocarboxylic Acid Transport

Full Article on Wiley Online Library



Abstract

Monocarboxylates such as lactate, pyruvate, and the ketone bodies play major roles in metabolism and must be transported across both the plasma membrane and mitochondrial inner membrane. A family of five proton‐linked MonoCarboxylate Transporters (MCTs) is involved in the former and the mitochondrial pyruvate carrier (MPC) mediates the latter. In the intestine and kidney, two Sodium‐coupled MonoCarboxylate Transporters (SMCTs) provide active transport of monocarboxylates across the apical membrane of the epithelial cells with MCTs on the basolateral membrane transporting the accumulated monocarboxylate into the blood. The kinetics and substrate and inhibitor specificities of MCTs, SMCTs, and the MPC have been well characterized and the molecular identity of the MCTs and SMCTs defined unequivocally. The identity of the MPC is less certain. The MCTs have been extensively studied and the three‐dimensional structure of MCT1 has been modeled and a likely catalytic mechanism proposed. MCTs require the binding of a single transmembrane glycoprotein (either embigin or basigin) for activity. Regulation of MCT activity involves both transcriptional and posttranscriptional mechanisms, examples being upregulation of MCT1 by chronic exercise in red muscle (which oxidizes lactate) and in T‐lymphocytes upon stimulation. MCT4 has properties that make it especially suited for lactic acid export by glycolytic cells and is upregulated by hypoxia. Some disease states are associated with modulation of plasma membrane and mitochondrial monocarboxylate transport and MCTs are promising drug targets for cancer chemotherapy. They may also be involved in drug uptake from the intestine and subsequent transport across the blood brain barrier. © 2013 American Physiological Society. Compr Physiol 3:1611‐1643, 2013.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Key metabolic pathways requiring monocarboxylate transport across the plasma and inner mitochondrial membranes. Note that the particular metabolic pathways operating within any cell will depend on the tissue. This Figure does not include monocarboxylate absorption from the lumen of the intestine or reabsorption from the kidney which are illustrated in Figure 10.
Figure 2. Figure 2. Conserved sequence motifs that define membership of the SLCA16 (MCT) family. Family members are defined by the presence of two highly conserved sequences, [D/E]G[G/S][W/F][G/A]W and YFxK[R/K][R/L]xLAx[G/A]xAxAG, which traverse the lead into TM1 and TM5 respectively as well as a conserved R and RP in the lead in to TMs 3 and 6. Sequence variation between different SLC16A family members is greatest in loops between helices and in the N‐ and C‐termini; the TM segments are more conserved. Members of the family known to transport monocarboxylates all contain a lysine (K) on the cytosolic side of TM1 and an aspartate (D but glutamate in MCT7) and arginine (R) in the centre of TM 8. These groups are believed to play a critical role in binding the proton and monocarboxylate anion during the translocation cycle.
Figure 3. Figure 3. Phylogenetic tree of members of the SLC16A family. Both the SLC and MCT nomenclature are given. Only four members are confirmed as proton‐linked monocarboxylate transporters with SCL16A6 (MCT7) the only other member likely to be so. Seven members of the family are currently of unknown function (orphan transporters).
Figure 4. Figure 4. MCTs follow an ordered kinetic mechanism. Transport is show for the lactate anion moving with a proton from the extracellular to the intracellular compartment, but all steps are freely reversible. The conformational change of the protein that translocates the lactate and proton occurs faster for the substrate bound carrier (k1) than the unbound carrier (k2) which accounts for why monocarboxylate exchange is faster than net movement of monocarboxylic acid.
Figure 5. Figure 5. Characterization of the properties of MCTs by expression in Xenopus laevis oocytes.
Figure 6. Figure 6. Schematic diagram showing key structural features of basigin and embigin which are essential ancillary proteins for MCT activity.
Figure 7. Figure 7. Basigin colocalizes with MCT1 in the heart and Islets of Langherhan. Data were obtained using confocal microscopy as described references and , respectively.
Figure 8. Figure 8. The structure of MCT1 derived from molecular modeling is shown in the two conformations representing the two forms, “inside open” and “outside open,” with substrate binding sites on opposite sides of the membrane. The N‐terminal domain is colored red and the C‐terminal domain colored blue, while the intracellular loop connecting the two is not modeled and shown as a connecting line. Cross‐sections of the transporter are rendered with a solvent‐accessible surface. The position of K38 (green) and F360 (yellow) are shown as these are critical residues for the translocation cycle and substrate specificity, respectively. D302 and R306, which are also essential for activity, are not shown for clarity, but line the channel next to F360. Lysine residues (K45, K282, and K413) involved in DIDS binding are rendered magenta. The axis system used for the C‐terminal domain rotations to generate the open model is shown in the centre of the figure. The schematic diagram below the model structures illustrates how individual helices are proposed to move during the transformation between inward and outward facing conformations of MCT1. The Figure is based on the structure reported in Ref. .
Figure 9. Figure 9. Cartoon illustrating the proposed mechanism of lactic acid transport by MCT1. Lactic acid protonates K38 causing the channel to open. Lactate then moves into the open extracellular side of the pore and forms an ion pair with K38. In the next step, the proton on K38 is transferred to aspartate 302 (D‐) neutralizing the aspatate side chain (DH). This is followed by migration of lactate through the pore where it forms an ion pair with R306 (R+). Once K38 is deprotonated and lactate is occupying the specificity filter, the transporter relaxes back toward the closed state and releases lactic acid into the intracellular space. The cartoon is based on the mechanism reported in Ref. .
Figure 10. Figure 10. Monocarboxylate uptake from the intestinal and kidney tubules involves cooperation of SMCTs and MCTs on the apical and basolateral surfaces of epithelial cells. Note that as shown the process would cause the pH of the cell to rise as protons are move with the monocarboxylate across the basolateral membrane and this must be compensated for by pH regulatory mechanisms.
Figure 11. Figure 11. In the brain and muscle MCTs are used to transport lactic and ketone bodies from the blood into the tissue as to shuttle lactic acid between the glycolytic astrocytes and white muscle fibers to the neurons and red fibers that oxidize it. A similar lactic acid shuttle may operate in some tumors where the hypoxic centre of the tumor produces lactic acid that is oxidized by the normoxic peripheral cells.


Figure 1. Key metabolic pathways requiring monocarboxylate transport across the plasma and inner mitochondrial membranes. Note that the particular metabolic pathways operating within any cell will depend on the tissue. This Figure does not include monocarboxylate absorption from the lumen of the intestine or reabsorption from the kidney which are illustrated in Figure 10.


Figure 2. Conserved sequence motifs that define membership of the SLCA16 (MCT) family. Family members are defined by the presence of two highly conserved sequences, [D/E]G[G/S][W/F][G/A]W and YFxK[R/K][R/L]xLAx[G/A]xAxAG, which traverse the lead into TM1 and TM5 respectively as well as a conserved R and RP in the lead in to TMs 3 and 6. Sequence variation between different SLC16A family members is greatest in loops between helices and in the N‐ and C‐termini; the TM segments are more conserved. Members of the family known to transport monocarboxylates all contain a lysine (K) on the cytosolic side of TM1 and an aspartate (D but glutamate in MCT7) and arginine (R) in the centre of TM 8. These groups are believed to play a critical role in binding the proton and monocarboxylate anion during the translocation cycle.


Figure 3. Phylogenetic tree of members of the SLC16A family. Both the SLC and MCT nomenclature are given. Only four members are confirmed as proton‐linked monocarboxylate transporters with SCL16A6 (MCT7) the only other member likely to be so. Seven members of the family are currently of unknown function (orphan transporters).


Figure 4. MCTs follow an ordered kinetic mechanism. Transport is show for the lactate anion moving with a proton from the extracellular to the intracellular compartment, but all steps are freely reversible. The conformational change of the protein that translocates the lactate and proton occurs faster for the substrate bound carrier (k1) than the unbound carrier (k2) which accounts for why monocarboxylate exchange is faster than net movement of monocarboxylic acid.


Figure 5. Characterization of the properties of MCTs by expression in Xenopus laevis oocytes.


Figure 6. Schematic diagram showing key structural features of basigin and embigin which are essential ancillary proteins for MCT activity.


Figure 7. Basigin colocalizes with MCT1 in the heart and Islets of Langherhan. Data were obtained using confocal microscopy as described references and , respectively.


Figure 8. The structure of MCT1 derived from molecular modeling is shown in the two conformations representing the two forms, “inside open” and “outside open,” with substrate binding sites on opposite sides of the membrane. The N‐terminal domain is colored red and the C‐terminal domain colored blue, while the intracellular loop connecting the two is not modeled and shown as a connecting line. Cross‐sections of the transporter are rendered with a solvent‐accessible surface. The position of K38 (green) and F360 (yellow) are shown as these are critical residues for the translocation cycle and substrate specificity, respectively. D302 and R306, which are also essential for activity, are not shown for clarity, but line the channel next to F360. Lysine residues (K45, K282, and K413) involved in DIDS binding are rendered magenta. The axis system used for the C‐terminal domain rotations to generate the open model is shown in the centre of the figure. The schematic diagram below the model structures illustrates how individual helices are proposed to move during the transformation between inward and outward facing conformations of MCT1. The Figure is based on the structure reported in Ref. .


Figure 9. Cartoon illustrating the proposed mechanism of lactic acid transport by MCT1. Lactic acid protonates K38 causing the channel to open. Lactate then moves into the open extracellular side of the pore and forms an ion pair with K38. In the next step, the proton on K38 is transferred to aspartate 302 (D‐) neutralizing the aspatate side chain (DH). This is followed by migration of lactate through the pore where it forms an ion pair with R306 (R+). Once K38 is deprotonated and lactate is occupying the specificity filter, the transporter relaxes back toward the closed state and releases lactic acid into the intracellular space. The cartoon is based on the mechanism reported in Ref. .


Figure 10. Monocarboxylate uptake from the intestinal and kidney tubules involves cooperation of SMCTs and MCTs on the apical and basolateral surfaces of epithelial cells. Note that as shown the process would cause the pH of the cell to rise as protons are move with the monocarboxylate across the basolateral membrane and this must be compensated for by pH regulatory mechanisms.


Figure 11. In the brain and muscle MCTs are used to transport lactic and ketone bodies from the blood into the tissue as to shuttle lactic acid between the glycolytic astrocytes and white muscle fibers to the neurons and red fibers that oxidize it. A similar lactic acid shuttle may operate in some tumors where the hypoxic centre of the tumor produces lactic acid that is oxidized by the normoxic peripheral cells.
References
 1.Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S. Structure and mechanism of the lactose permease of Escherichia coli. Science 301: 610‐615, 2003.
 2.Adijanto J and Philp NJ. The SLC16A family of monocarboxylate transporters (MCTs)‐physiology and function in cellular metabolism, pH homeostasis, fluid transport. Curr Top Membr 70: 275‐312, 2012.
 3.Agrawal SM and Yong VW. The many faces of EMMPRIN ‐ roles in neuroinflammation. Biochim Biophys Acta 1812: 213‐219, 2011.
 4.Anderson CM and Thwaites DT. Hijacking solute carriers for proton‐coupled drug transport. Physiology (Bethesda) 25: 364‐377, 2010.
 5.Baba M, Inoue M, Itoh K, Nishizawa Y. Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism. Biochem Biophys Res Commun 374: 111‐116, 2008.
 6.Babu E, Ramachandran S, CoothanKandaswamy V, Elangovan S, Prasad PD, Ganapathy V, Thangaraju M. Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate. Oncogene 30: 4026‐4037, 2011.
 7.Baker SK, McCullagh KJA, Bonen A. Training intensity‐dependent and tissue‐specific increases in lactate uptake and MCT‐1 in heart and muscle. J Appl Physiol 84: 987‐994, 1998.
 8.Barac‐Nieto M. D(−) 3‐Hydroxybutyrate cotranport with Na in rat renal brush‐border membrane vesicles. Pflugers Arch 408: 321‐327, 1987.
 9.Barac‐Nieto M, Murer H, Kinne R. Lactate‐sodium cotransport in rat renal brush border membrane vesicles. Am J Physiol 239: F496‐F506, 1980.
 10.Barac‐Nieto M, Murer H, Kinne R. Asymetry in the transport of lactate by basolateral and brush border membranes of rat kidney cortex. Pflugers Arch 392: 366‐371, 1982.
 11.Barbara B, Podevin R‐A. Stoichiometry of the renal sodium L‐lactate cotransporter. J Biol Chem 263: 12190‐12193, 1988.
 12.Becker HM, Bröer S, Deitmer JW. Facilitated lactate transport by MCT1 when coexpressed with the sodium bicarbonate cotransporter (NBC) in Xenopus oocytes. Biophys J 86: 235‐247, 2004.
 13.Becker HM, Hirnet D, FecherTrost C, Sultemeyer D, Deitmer JW. Transport activity of MCT1 expressed in Xenopus oocytes is increased by interaction with carbonic anhydrase. J Biol Chem 280: 39882‐39889, 2005.
 14.Becker HM, Klier M, Deitmer JW. Nonenzymatic augmentation of lactate transport via monocarboxylate transporter isoform 4 by carbonic anhydrase II. J Membr Biol 234: 125‐135, 2010.
 15.Belt JA, Thomas JA, Buchsbaum RN, Racker E. Inhibition of lactate transport and glycolysis in Ehrlich ascites tumor cells by bioflavonoids. Biochemistry 19: 3506‐3511, 1979.
 16.Bental M, Deutsch C. Metabolic changes in activated T cells: An NMR study of human peripheral blood lymphocytes. Magn Reson Med 29: 317‐326, 1993.
 17.Benton CR, Campbell SE, Tonouchi M, Hatta H, Bonen A. Monocarboxylate transporters in subsarcolemmal and intermyofibrillar mitochondria. Biochem Biophys Res Commun 323: 249‐253, 2004.
 18.Benton CR, Yoshida Y, Lally J, Han XX, Hatta H, Bonen A. PGC‐1alpha increases skeletal muscle lactate uptake by increasing the expression of MCT1 but not MCT2 or MCT4. Physiol Genomics 35: 45‐54, 2008.
 19.Bergersen L, Waerhaug O, Helm J, Thomas M, Laake P, Davies AJ, Wilson MC, Halestrap AP, Ottersen OP. A novel postsynaptic density protein: The monocarboxylate transporter MCT2 is co‐localized with delta‐glutamate receptors in postsynaptic densities of parallel fiber‐Purkinje cell synapses. Exp Brain Res 136: 523‐534, 2001.
 20.Bergersen LH. Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle. Neuroscience 145: 11‐19, 2007.
 21.Bickham DC, Bentley DJ, LeRossignol PF, CameronSmith D. The effects of short‐term sprint training on MCT expression in moderately endurance‐trained runners. Eur J Appl Physiol 96: 636‐643, 2006.
 22.Bigard X, Sanchez H, Zoll J, Mateo P, Rousseau V, Veksler V, VenturaClapier R. Calcineurin co‐regulates contractile and metabolic components of slow muscle phenotype. J Biol Chem 275: 19653‐19660, 2000.
 23.Birsoy K, Wang T, Possemato R, Yilmaz OH, Koch CE, Chen WW, Hutchins AW, Gultekin Y, Peterson TR, Carette JE, Brummelkamp TR, Clish CB, Sabatini DM. MCT1‐mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nat Genet 45: 104‐108, 2012.
 24.Bogan JS. Regulation of glucose transporter translocation in health and diabetes. Annu Rev Biochem 81: 507‐532, 2012.
 25.Bolli R, Nalecz KA, Azzi A. Monocarboxylate and alpha‐ketoglutarate carriers from bovine heart mitochondria ‐ purification by affinity chromatography on immobilized 2‐cyano‐4‐hydroxycinnamate. J Biol Chem 264: 18024‐18030, 1989.
 26.Bonen A. The expression of lactate transporters (MCT1 and MCT4) in heart and muscle. Eur J Appl Physiol 86: 6‐11, 2001.
 27.Bonen A, McCullagh KJA, Putman CT, Hultman E, Jones NL, Heigenhauser GJF. Short‐term training increases human muscle MCT1 and femoral venous lactate in relation to muscle lactate. Am J Physiol 274: E102‐E107, 1998.
 28.Bonen A, Miskovic D, Tonouchi M, Lemieux K, Wilson MC, Marette A, Halestrap AP. Abundance and subcellular distribution of MCT1 and MCT4 in heart and fast‐twitch skeletal muscles. Am J Physiol 278: E1067‐E1077, 2000.
 29.Bonen A, Tonouchi M, Miskovic D, Heddle C, Heikkila JJ, Halestrap AP. Isoform‐specific regulation of the lactate transporters MCT1 and MCT4 by contractile activity. Am J Physiol 279: E1131‐E1138, 2000.
 30.Brahimi‐Horn MC, Bellot G, Pouyssegur J. Hypoxia and energetic tumor metabolism. Curr Opin Genet Dev 29: 2570‐2578, 2011.
 31.Brailsford MA, Thompson AG, Kaderbhai N, Beechey RB. The extraction and reconstitution of the alpha‐cyanocinnamate‐sensitive pyruvate transporter from castor bean mitochondria. Biochem Biophys Res Commun 140: 1036‐1042, 1986.
 32.Brauchi S, Rauch MC, Alfaro IE, Cea C, Concha II, Benos DJ, Reyes JG. Kinetics, molecular basis, differentiation of L‐lactate transport in spermatogenic cells. Am J Physiol 288: C523‐C534, 2005.
 33.Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, Cox JE, Cardon CM, Van Vranken JG, Dephoure N, Redin C, Boudina S, Gygi SP, Brivet M, Thummel CS, Rutter J. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila and humans. Science 337: 96‐100, 2012.
 34.Brivet M, GarciaCazorla A, Lyonnet S, Dumez Y, Nassogne MC, Slama A, Boutron A, Touati G, Legrand A, Saudubray JM. Impaired mitochondrial pyruvate importation in a patient and a fetus at risk. Mol Genet Metab 78: 186‐192, 2003.
 35.Bröer S, Bröer A, Schneider HP, Stegen C, Halestrap AP, Deitmer JW. Characterization of the high‐affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem J 341: 529‐535, 1999.
 36.Bröer S, Rahman B, Pellegri G, Pellerin L, Martin JL, Verleysdonk S, Hamprecht B, Magistretti PJ. Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT 1) expressing Xenopus laevis oocytes ‐ expression of two different monocarboxylate transporters in astroglial cells and neurons. J Biol Chem 272: 30096‐30102, 1997.
 37.Bröer S, Schneider HP, Bröer A, Rahman B, Hamprecht B, Deitmer JW. Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 333: 167‐174, 1998.
 38.Brooks GA. Cell‐cell and intracellular lactate shuttles. J Physiol 587: 5591‐600, 2009.
 39.Brooks GA, Brown MA, Butz CE, Sicurello JP, Dubouchaud H. Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1. J Appl Physiol 87: 1713‐1718, 1999.
 40.Butz CE, McClelland GB, Brooks GA. MCT1 confirmed in rat striated muscle mitochondria. J Appl Physiol 97: 1059‐1066, 2004.
 41.Cairns SP. Lactic acid and exercise performance : Culprit or friend? Sports Med 36: 279‐91, 2006.
 42.Canis M, Maurer MH, Kuschinsky W, Duembgen L, Duelli R. Increased densities of monocarboxylate transporter MCT1 after chronic hyperglycemia in rat brain. Brain Res 1257: 32‐39, 2009.
 43.Carpenter L, Halestrap AP. The kinetics, substrate and inhibitor specificity of the lactate transporter of Ehrlich‐Lettre tumor cells studied with the intracellular pH indicator BCECF. Biochem J 304: 751‐760, 1994.
 44.Castorino JJ, Deborde S, Deora A, Schreiner R, Gallagher‐Colombo SM, Rodriguez‐Boulan E, Philp NJ. Basolateral sorting signals regulating tissue‐specific polarity of heteromeric monocarboxylate transporters in epithelia. Traffic 12: 483‐498, 2011.
 45.Chen X, Lin J, Kanekura T, Su J, Lin W, Xie H, Wu Y, Li J, Chen M, Chang J. A small interfering CD147‐targeting RNA inhibited the proliferation, invasiveness, metastatic activity of malignant melanoma. Cancer Res 66: 11323‐11330, 2006.
 46.Chenal J, Pellerin L. Noradrenaline enhances the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of PI3K/Akt and the mTOR/S6K pathway. J Neurochem 102: 389‐397, 2007.
 47.Chenal J, Pierre K, Pellerin L. Insulin and IGF‐1 enhance the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of the phosphoinositide 3‐kinase‐Akt‐mammalian target of rapamycin pathway. Eur J Neurosci 27: 53‐65, 2008.
 48.Cheng C, Edin NF, Lauritzen KH, Aspmodal I, Christoffersen S, Jian L, Rasmussen LJ, Pettersen EO, Xiaoqun G, Bergersen LH. Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumor cells. Cell Oncol (Dordr) 35: 217‐227, 2012.
 49.Chiche J, Lefur Y, Vilmen C, Frassineti F, Daniel L, Halestrap AP, Cozzone PJ, Pouyssegur J, Lutz NW. In vivo pH in metabolic‐defective Ras‐transformed fibroblast tumors. Key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH. Int J Cancer 130: 1511‐1520, 2011.
 50.Chiry O, Fishbein WN, Merezhinskaya N, Clarke S, Galuske R, Magistretti PJ, Pellerin L. Distribution of the monocarboxylate transporter MCT2 in human cerebral cortex: An immunohistochemical study. Brain Res 1226: 61‐69, 2008.
 51.Chiry O, Pellerin L, MonnetTschudi F, Fishbein WN, Merezhinskaya N, Magistretti PJ, Clarke S. Expression of the monocarboxylate transporter MCT1 in the adult human brain cortex. Brain Res 1070: 65‐70, 2006.
 52.Clarke SJ, Khaliulin I, Das M, Parker JE, Heesom KJ, Halestrap AP. Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation. Circ Res 102: 1082‐1090, 2008.
 53.Coady MJ, Chang MH, Charron FM, Plata C, Wallendorff B, Sah JF, Markowitz SD, Romero MF, Lapointe JY. The human tumor suppressor gene SLC5A8 expresses a Na+‐monocarboxylate cotransporter. J Physiol 557: 719‐731, 2004.
 54.Coleman ML, Ratcliffe PJ. Oxygen sensing and hypoxia‐induced responses. Essays Biochem 43: 1‐15, 2007.
 55.Coles L, Litt J, Hatta H, Bonen A. Exercise rapidly increases expression of the monocarboxylate transporters MCT1 and MCT4 in rat muscle. J Physiol 561: 253‐261, 2004.
 56.Coothankandaswamy V, Elangovan S, Singh N, Prasad PD, Thangaraju M, Ganapathy V. The plasma membrane transporter SLC5A8 suppresses tumor progression through depletion of survivin without involving its transport function. Biochem J 450: 169‐178, 2013.
 57.Crosnier C, Bustamante LY, Bartholdson SJ, Bei AK, Theron M, Uchikawa M, Mboup S, Ndir O, Kwiatkowski DP, Duraisingh MT, Rayner JC, Wright GJ. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature 480: 534‐537, 2011.
 58.Cross SH, Bird AP. CpG islands and genes. Curr Opin Genet Dev 5: 309‐314, 1995.
 59.Cuff M, Dyer J, Jones M, ShirazBeechey S. The human colonic monocarboxylate transporter isoform 1: Its potential importance to colonic tissue Homeostasis. Gastroenterology 128: 676‐686, 2005.
 60.Dang S, Sun L, Huang Y, Lu F, Liu Y, Gong H, Wang J, Yan N. Structure of a fucose transporter in an outward‐open conformation. Nature 467: 734‐738, 2010.
 61.Daniele LL, Sauer B, Gallagher SM, Pugh EN Jr, Philp NJ. Altered visual function in monocarboxylate transporter 3 (Slc16a8) knockout mice. Am J Physiol 295: C451‐7, 2008.
 62.De Bruijne AW, Vreeberg H, Van Steveninck J. Kinetic analysis of L‐lactate transport in human erythrocytes via the monocarboxylate‐specific carrier system. Biochim Biophys Acta 732: 562‐568, 1983.
 63.De Bruijne AW, Vreeberg H, Van Steveninck J. Alternative substrate inhibition of L‐lactate transport via the monocarboxylate‐specific carrier system in human erythrocytes. Biochim Biophys Acta 812: 841‐844, 1985.
 64.De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P. Lactate activates HIF‐1 in oxidative but not in Warburg‐phenotype human tumor cells. PLoS One 7: e46571, 2012.
 65.Denton RM, Halestrap AP. Regulation of pyruvate metabolism in mammalian tissues. Essays Biochem 15: 37‐47, 1979.
 66.Deora AA, Philp N, Hu J, Bok D, Rodriguez‐Boulan E. Mechanisms regulating tissue‐specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia. Proc Natl Acad Sci U S A 102(45): 16245‐16250, 2005.
 67.Deuticke B. Monocarboxylate transport in erythrocytes. J Membr Biol 70: 89‐103, 1982.
 68.Deuticke B, Beyer E, Forst B. Discrimination of three parallel pathways of L‐lactate transport in the human erythrocyte membrane by inhibitors and kinetic properties. Biochim Biophys Acta 684: 96‐110, 1982.
 69.Deuticke B, Rickert I, Beyer E. Stereoselective, SH‐dependent transfer of lactate in human erythrocytes. Biochim Biophys Acta 507: 137‐155, 1978.
 70.Dhup S, Dadhich RK, Porporato PE, Sonveaux P. Multiple biological activities of lactic acid in cancer: Influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des 18: 1319‐1330, 2012.
 71.Dimmer KS, Friedrich B, Lang F, Deitmer JW, Bröer S. The low‐affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 350: 219‐227, 2000.
 72.Divakaruni AS, Murphy AN. Cell biology. A mitochondrial mystery, solved. Science 337: 41‐43, 2012.
 73.Donovan JA, Jennings ML. Membrane polypeptide in rabbit erythrocytes associated with the inhibition of L‐lactate transport by a synthetic anhydride of lactic acid. Biochemistry 24: 561‐564, 1985.
 74.Donovan JA, Jennings ML. N‐Hydroxysulphosuccinimido active esters and the L‐(+)‐lactate transport protein in rabbit erythrocytes. Biochemistry 25: 1538‐1545, 1986.
 75.Dubinsky WP, Racker E. The mechanism of lactate transport in human erythrocytes. J Membr Biol 44: 25‐36, 1978.
 76.Edlund GL, Halestrap AP. The kinetics of transport of lactate and pyruvate into rat hepatocytes. Evidence for the presence of a specific carrier similar to that in erythrocytes. Biochem J 249: 117‐126, 1988.
 77.Ekberg H, Qi Z, Pahlman C, Veress B, Bundick RV, Craggs RI, Holness E, Edwards S, Murray CM, Ferguson D, Kerry PJ, Wilson E, Donald DK. The specific monocarboxylate transporter‐1 (MCT‐1) inhibitor, AR‐C117977, induces donor‐specific suppression, reducing acute and chronic allograft rejection in the rat. Transplantation 84: 1191‐1199, 2007.
 78.Enoki T, Yoshida Y, Hatta H, Bonen A. Exercise training alleviates MCT1 and 4 reductions in heart and skeletal muscles of STZ‐induced diabetic rats. J Appl Physiol 94: 2433‐2438, 2003.
 79.Evertsen F, Medbo JI, Bonen A. Effect of training intensity on muscle lactate transporters and lactate threshold of cross‐country skiers. Acta Physiol Scand 173: 195‐205, 2001.
 80.Fang J, Quinones QJ, Holman TL, Morowitz MJ, Wang Q, Zhao H, Sivo F, Maris JM, Wahl ML. The H+‐linked monocarboxylate transporter (MCT1/SLC16A1): A potential therapeutic target for high‐risk neuroblastoma. Mol Pharmacol 70: 2108‐2115, 2006.
 81.Fishbein WN. Lactate transporter defect: A new disease of muscle. Science 234: 1254‐1256, 1986.
 82.Fishbein WN, Merezhinskaya N, Foellmer JW. Relative distribution of three major lactate transporters in frozen human tissues and their localization in unfixed skeletal muscle. Muscle Nerve 26: 101‐112, 2002.
 83.Frank H, Groger N, Diener M, Becker C, Braun T, Boettger T. Lactaturia and loss of sodium‐dependent lactate uptake in the colon of SLC5A8‐deficient mice. J Biol Chem 283: 24729‐24737, 2008.
 84.Friesema ECH, Ganguly S, Abdalla A, Fox JEM, Halestrap AP, Visser TJ. Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 278: 40128‐40135, 2003.
 85.Furugen A, Kobayashi M, Narumi K, Watanabe M, Otake S, Itagaki S, Iseki K. AMP‐activated protein kinase regulates the expression of monocarboxylate transporter 4 in skeletal muscle. Life Sci 88: 163‐168, 2011.
 86.Galardo MN, Riera MF, Pellizzari EH, Cigorraga SB, Meroni SB. The AMP‐activated protein kinase activator, 5‐aminoimidazole‐4‐carboxamide‐1‐b‐D‐ribonucleoside, regulates lactate production in rat Sertoli cells. J Mol Endocrinol 39: 279‐288, 2007.
 87.Galic S, Schneider HP, Bröer A, Deitmer JW, Bröer S. The loop between helix 4 and helix 5 in the monocarboxylate transporter MCT1 is important for substrate selection and protein stability. Biochem J 376: 413‐422, 2003.
 88.Gallagher‐Colombo S, Maminishkis A, Tate S, Grunwald GB, Philp NJ. Modulation of MCT3 expression during wound healing of the retinal pigment epithelium. Invest Ophthalmol Vis Sci 51: 5343‐5350, 2010.
 89.Gallagher SM, Castorino JJ, Wang D, Philp NJ. Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA‐MB‐231. Cancer Res 67: 4182‐9, 2007.
 90.Ganapathy V, Thangaraju M, Gopal E, Martin P, Itagaki S, Miyauchi S, Prasad P. Sodium‐coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 10: 193‐199, 2008.
 91.Garcia CK, Brown MS, Pathak RK, Goldstein JL. cDNA cloning of MCT2, a second monocarboxylate transporter expressed in different cells than MCT1. J Biol Chem 270: 1843‐1849, 1995.
 92.Gerhart DZ, Enerson BE, Zhdankina OY, Leino RL, Drewes LR. Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am J Physiol 273: E207‐E213, 1997.
 93.Gerhart DZ, Leino RL, Drewes LR. Distribution of monocarboxylate transporters MCT1 and MCT2 in rat retina. Neuroscience 92: 367‐375, 1999.
 94.Gill RK, Saksena S, Alrefai WA, Sarwar Z, Goldstein JL, Carroll RE, Ramaswamy K, Dudeja PK. Expression and membrane localization of MCT isoforms along the length of the human intestine. Am J Physiol 289: C846‐C852, 2005.
 95.Gingras A‐C, Raught B, Sonenberg N. eIF4 initiation factors: Effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68: 913‐963, 1999.
 96.Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin P, Smith SB, Prasad PD, Ganapathy V. Expression of slc5a8 in kidney and its role in Na(+)‐coupled transport of lactate. J Biol Chem 279: 44522‐44532, 2004.
 97.Gopal E, Miyauchi S, Martin PM, Ananth S, Roon P, Smith SB, Ganapathy V. Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract. Pharm Res 24: 575‐584, 2007.
 98.Gopal E, Umapathy NS, Martin PM, Ananth S, Gnana‐Prakasam JP, Becker H, Wagner CA, Ganapathy V, Prasad PD. Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney. Biochim Biophys Acta 1768: 2690‐2697, 2007.
 99.Green H, Halestrap A, Mockett C, OToole D, Grant S, Ouyang J. Increases in muscle MCT are associated with reductions in muscle lactate after a single exercise session in humans. Am J Physiol 282: E154‐E160, 2002.
 100.Greiner EF, Guppy M, Brand K. Glucose is essential for proliferation and the glycolytic enzyme induction that provokes a transition to glycolytic energy production. J Biol Chem 269: 31484‐31490, 1994.
 101.Grollman EF, Philp NJ, McPhie P, Ward RD, Sauer B. Determination of transport kinetics of chick MCT3 monocarboxylate transporter from retinal pigment epithelium by expression in genetically modified yeast. Biochemistry 39: 9351‐9357, 2000.
 102.Guan L, Mirza O, Verner G, Iwata S, Kaback HR. Structural determination of wild‐type lactose permease. Proc Natl Acad Sci U S A 104: 15294‐15298, 2007.
 103.Guenette RS, Sridhar S, Herley M, Mooibroek M, Wong P, Tenniswood M. Embigin, a developmentally expressed member of the immunoglobulin super family is also expressed during regression of prostate and mammary gland. Dev Genet 21: 268‐278, 1997.
 104.Guile SD, Banticka JR, Cheshire DR, Cooper ME, Davis AM, Donald DK, Evans R, Eyssade C, Ferguson DD, Hill S, Hutchinson R, Ingall AH, Kingston LP, Martin I, Martin BP, Mohammed RT, Murray C, Perry MWD, Reynolds RH, Thorne PV, Wilkinson DJ, Withnall J. Potent blockers of the monocarboxylate transporter MCT1: Novel immunomodulatory compounds. Bioorg Medl Chem Lett 16: 2260‐2265, 2006.
 105.Guppy M, Greiner E, Brand K. The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes. Eur J Biochem 212: 95‐99, 1993.
 106.Gupta N, Martin PM, Prasad PD, Ganapathy V. SLC5A8 (SMCT1)‐mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci 78: 2419‐2425, 2006.
 107.Hajduch E, Heyes RR, Watt PW, Hundal HS. Lactate transport in rat adipocytes: Identification of monocarboxylate transporter 1 (MCT1) and its modulation during streptozotocin‐induced diabetes. FEBS Lett 479: 89‐92, 2000.
 108.Halestrap AP. The mitochondrial pyruvate carrier ‐ kinetics and specificity for substrates and inhibitors. Biochem J 148: 85‐96, 1975.
 109.Halestrap AP. The mechanism of the inhibition of the mitochondrial pyruvate transporter by α‐cyanocinnamate derivatives. Biochem J 156: 181‐183, 1976.
 110.Halestrap AP. Pyruvate and lactate transport into human erythrocytes. Evidence for the involvement of the chloride carrier and a chloride independent carrier. Biochem J 156: 193‐207, 1976.
 111.Halestrap AP. Pyruvate and ketone‐body transport across the mitochondrial membrane: Exchange properties, pH‐dependence and mechanism of the carrier. Biochem J 172: 377‐387, 1978.
 112.Halestrap AP. The monocarboxylate transporter family‐structure and functional characterization. IUBMB Life 64: 1‐9, 2012.
 113.Halestrap AP. The mitochondrial pyruvate carrier: Has it been unearthed at last? Cell Metab 16: 141‐143, 2012.
 114.Halestrap AP. The SLC16 gene family structure, role and regulation in health and disease. Mol Aspects Med 34: 337‐349, 2013.
 115.Halestrap AP, Brand MD, Denton RM. Inhibition of mitochondrial pyruvate transport by phenylpyruvate and α‐keto‐isocaproate. Biochim Biophys Acta 367: 102‐108, 1974.
 116.Halestrap AP, Denton RM. Specific inhibition of pyruvate transport in rat liver mitochondria and human erythrocytes by α‐cyano‐4‐hydroxycinnamate. Biochem J 138: 313‐316, 1974.
 117.Halestrap AP, Denton RM. The specificity and metabolic implications of the inhibition of pyruvate transport in isolated mitochondria and intact preparations by α‐cyano‐4‐hydroxycinnamate and related compounds. Biochem J 148: 97‐106, 1975.
 118.Halestrap AP, Meredith D. The SLC16 gene family ‐ from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447: 619‐628, 2004.
 119.Halestrap AP, Price NT. The proton‐linked monocarboxylate transporter (MCT) family: Structure, function and regulation. Biochem J 343: 281‐299, 1999.
 120.Halestrap AP, Scott RD, Thomas AP. Mitochondrial pyruvate transport and its hormonal regulation. Int J Biochem 11: 97‐105, 1980.
 121.Halestrap AP, Wang XM, Poole RC, Jackson VN, Price NT. Lactate transport in heart in relation to myocardial ischemia. Am J Cardiol 80: A17‐A25, 1997.
 122.Halestrap AP, Wilson MC. The monocarboxylate transporter family‐role and regulation. IUBMB Life 64: 109‐119, 2012.
 123.Hamann S, Kiilgaard JF, laCour M, Prause JU, Zeuthen T. Cotransport of H+, lactate, H2O in porcine retinal pigment epithelial cells. Exp Eye Res 76: 493‐504, 2003.
 124.Hanna SM, Kirk P, Holt OJ, Puklavec MJ, Brown MH, Barclay AN. A novel form of the membrane protein CD147 that contains an extra Ig‐like domain and interacts homophilically. BMC Biochem 4: 17, 2003.
 125.Harris T, Eliyahu G, Frydman L, Degani H. Kinetics of hyperpolarized 13C1‐pyruvate transport and metabolism in living human breast cancer cells. Proc Natl Acad Sci USA 106: 18131‐18136, 2009.
 126.Hashimoto T, Hussien R, Brooks GA. Colocalization of MCT1, CD147, LDH in mitochondrial inner membrane of L6 muscle cells: Evidence of a mitochondrial lactate oxidation complex. Am J Physiol 290: E1237‐E1244, 2006.
 127.Hashimoto T, Hussien R, Cho HS, Kaufer D, Brooks GA. Evidence for the mitochondrial lactate oxidation complex in rat neurons: Demonstration of an essential component of brain lactate shuttles. PLoS ONE 3: e2915, 2008.
 128.Hatta H, Tonouchi M, Miskovic D, Wang YX, Heikkila JJ, Bonen A. Tissue‐specific and isoform‐specific changes in MCT1 and MCT4 in heart and soleus muscle during a 1‐yr period. Am J Physiol 281: E749‐E756, 2001.
 129.Heesom KJ, Gampel A, Mellor H, Denton RM. Cell cycle‐dependent phosphorylation of the translational repressor eIF‐4E binding protein‐1 (4E‐BP1). Curr Biol 11: 1374‐1379, 2001.
 130.Helm J, Coppola D, Ganapathy V, Lloyd M, Centeno BA, Chen DT, Malafa MP, Park JY. SLC5A8 nuclear translocation and loss of expression are associated with poor outcome in pancreatic ductal adenocarcinoma. Pancreas 41: 904‐909, 2012.
 131.Herzig S, Raemy E, Montessuit S, Veuthey JL, Zamboni N, Westermann B, Kunji ER, Martinou JC. Identification and functional expression of the mitochondrial pyruvate carrier. Science 337: 93‐96, 2012.
 132.Hildmann B, Storelli C, Haase W, Barac‐Nieto M, Murer H. Sodium ion/L‐lactate co‐transport in rabbit small intestine brush border membrane vesicles. Biochem J 186: 169‐176, 1980.
 133.Hildyard JCW, Ammala C, Dukes ID, Thomson SA, Halestrap AP. Identification and characterisation of a new class of highly specific and potent inhibitors of the mitochondrial pyruvate carrier. Biochim Biophys Acta 1707: 221‐230, 2005.
 134.Hildyard JCW, Halestrap AP. Identification of the mitochondrial pyruvate carrier in Saccharomyces cerevisiae. Biochem J 374: 607‐611, 2003.
 135.Hollingsworth KG, Newton JL, Robinson L, Taylor R, Blamire AM, Jones DE. Loss of capacity to recover from acidosis in repeat exercise is strongly associated with fatigue in primary biliary cirrhosis. J Hepatol 53: 155‐161, 2010.
 136.Huang YF, Lemieux MJ, Song JM, Auer M, Wang DN. Structure and mechanism of the glycerol‐3‐phosphate transporter from Escherichia coli. Science 301: 616‐620, 2003.
 137.Hugo SE, Cruz‐Garcia L, Karanth S, erson RM, Stainier DY, Schlegel A. A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting. Genes Dev 26: 282‐293, 2012.
 138.Hutson SM, Hall TR. Identification of the mitochondrial branched chain aminotransferase as a branched chain alpha‐keto acid transport protein. J Biol Chem 268: 3084‐3091, 1993.
 139.Hutson SM, Rannels SL. Characterisation of a mitochondrial transport system for branched chain α‐keto acids. J Biol Chem 260: 14189‐14193, 1985.
 140.Hutson SM, Roten S, Kaplan RS. solubilization and functional reconstitution of the branched‐chain alpha‐keto acid transporter from rat heart mitochondria. Proc Natl Acad Sci U S A 87: 1028‐1031, 1990.
 141.Iacono KT, Brown AL, Greene MI, Saouaf SJ. CD147 immunoglobulin superfamily receptor function and role in pathology. Exp Mol Pathol 83: 283‐295, 2007.
 142.Igakura T, Kadomatsu K, Kaname T, Muramatsu H, Fan Q‐WF, Miyauchi T, Toyama Y, Kuno N, Yuasa S, Takahashi M, Takao S, Taguchi O, Yamamura K, Arimura K, Muramatsu T. A Null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri‐implantation development and spermatogenesis. Dev Biol 194: 152‐165, 1998.
 143.Iwanaga T, Takebe K, Kato I, Karaki S, Kuwahara A. Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, humans, with special reference to slc5a8. Biomed Res 27: 243‐254, 2006.
 144.Jackson VN, Halestrap AP. The kinetics, substrate, inhibitor specificity of the monocarboxylate (lactate) transporter of rat liver cells determined using the fluorescent intracellular pH indicator, 2′,7′‐bis(carboxyethyl)‐5(6)‐carboxyfluorescein. J Biol Chem 271: 861‐868, 1996.
 145.Jackson VN, Price NT, Carpenter L, Halestrap AP. Cloning of the monocarboxylate transporter isoform MCT2 from rat testis provides evidence that expression in tissues is species‐specific and may involve post‐transcriptional regulation. Biochem J 324: 447‐453, 1997.
 146.Jang C, Lee G, Chung J. LKB1 induces apical trafficking of Silnoon, a monocarboxylate transporter, in Drosophila melanogaster. J Cell Biol 183: 11‐17, 2008.
 147.Jansen S, Esmaeilpour T, Pantaleon M, Kaye PL. Glucose affects monocarboxylate cotransporter (MCT) 1 expression during mouse preimplantation development. Reproduction 131: 469‐479, 2006.
 148.Johannsson E, Lunde PK, Heddle C, Sjaastad I, Thomas MJ, Bergersen L, Halestrap AP, Blackstad TW, Ottersen OP, Sejersted OM. Upregulation of the cardiac monocarboxylate transporter MCT1 in a rat model of congestive heart failure. Circulation 104: 729‐734, 2001.
 149.Johnson JH, Belt JA, Dubinsky WP, Zimniak A, Racker E. Inhibition of lactate transport in Ehrlich ascites tumor cells and human erythrocytes by a synthetic anhydride of lactic acid. Biochemistry 19: 3836‐3840, 1980.
 150.Jorgensen KE, Sheikh MI. Renal transport of monocarboxylic acids: Heterogeneity of lactate transport systems along the proximal tubule. Biochem 223: 803‐807, 1984.
 151.Jorgensen KE, Sheikh MI. Transport of pyruvate by luminal membrane vesicles from pars convoluta and pars recta of rabbit proximal tubule. Biochim Biophys Acta 938: 345‐352, 1988.
 152.Juel C. Current aspects of lactate exchange: Lactate/H+ transport in human skeletal muscle. Eur J App Physiol 86: 12‐16, 2001.
 153.Juel C. Training‐induced changes in membrane transport proteins of human skeletal muscle. Eur J App Physiol 96: 627‐635, 2006.
 154.Juel C, Halestrap AP. Lactate transport in skeletal muscle ‐ role and regulation of the monocarboxylate transporter. J Physiol 517: 633‐642, 1999.
 155.Juel C, Klarskov C, Nielsen JJ, Krustrup P, Mohr M, Bangsbo J. Effect of high‐intensity intermittent training on lactate and H+ release from human skeletal muscle. Am J Physiol 286: E245‐E251, 2004.
 156.Kaelin WG Jr, Thompson CB. Q&A: Cancer: Clues from cell metabolism. Nature 465: 562‐564, 2010.
 157.Kim CM, Goldstein JL, Brown MS. cDNA cloning of MEV, a mutant protein that facilitates cellular uptake of mevalonate, identification of a point mutation responsible for its gain in function. J Biol Chem 267: 23113‐23121, 1992.
 158.Kim DK, Kanai Y, Matsuo H, Kim JY, Chairoungdua A, Kobayashi Y, Enomoto A, Cha SH, Goya T, Endou H. The human T‐type amino acid transporter‐1: Characterization, gene organization, chromosomal location. Genomics 79: 95‐103, 2002.
 159.Kim‐Garcia C, Goldstein JL, Pathak RK, erson RGW, Brown MS. Molecular characterization of a membrane transporter for lactate, pyruvate, other monocarboxylates ‐ implications for the Cori cycle. Cell 76: 865‐873, 1994.
 160.Kirk P, Wilson MC, Heddle C, Brown MH, Barclay AN, Halestrap AP. CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J 19: 3896‐3904, 2000.
 161.Klier M, Schuler C, Halestrap AP, Sly WS, Deitmer JW, Becker HM. Transport activity of the high‐affinity monocarboxylate transporter MCT2 is enhanced by extracellular carbonic anhydrase IV but not by intracellular carbonic anhydrase II. J Biol Chem 286: 27781‐27791, 2011.
 162.Krishnan MN, Ng A, Sukumaran B, Gilfoy FD, Uchil PD, Sultana H, Brass AL, Adametz R, Tsui M, Qian F, Montgomery RR, Lev S, Mason PW, Koski RA, Elledge SJ, Xavier RJ, Agaisse H, Fikrig E. RNA interference screen for human genes associated with West Nile virus infection. Nature 455: 242‐245, 2008.
 163.Kroemer G, Pouyssegur J. Tumor cell metabolism: Cancer's achilles' heel. Cancer Cell 13: 472‐482, 2008.
 164.Land JM, Clark JB. Inhibition of pyruvate and beta‐hydroxybutyrate oxidation in rat brain mitochondria by phenylpyruvate and alpha‐ketoisocaproate. FEBS Lett 44, 348‐351, 1974.
 165.Le Floch R, Chiche J, Marchiq I, Naiken T, Ilk K, Murray CM, Critchlow SE, Roux D, Simon MP, Pouyssegur J. CD147 subunit of lactate/H+ symporters MCT1 and hypoxia‐inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc Natl Acad Sci U S A 108: 16663‐16668, 2011.
 166.Lee WJ, Kim M, Park HS, Kim HS, Jeon MJ, Oh KS, Koh EH, Won JC, Kim MS, Oh GT, Yoon M, Lee KU, Park JY. AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC‐1. Biochem Biophys Res Commun 340: 291‐295, 2006.
 167.Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang PW, Pellerin L, Magistretti PJ, Rothstein JD. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487: 443‐448, 2012.
 168.Leeks DR, Halestrap AP. Chloride‐independent transport of pyruvate and lactate across the erythrocyte membrane. Biochem Soc Trans 6: 1363‐1366, 1978.
 169.Leino RL, Gerhart DZ, Drewes LR. Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: A quantitative electron microscopic immunogold study. Developmental Brain Research 113: 47‐54, 1999.
 170.Leino RL, Gerhart DZ, Duelli R, Enerson BE, Drewes LR. Diet‐induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain. Neurochem Int 38: 519‐527, 2001.
 171.Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, Rerko RM, Casey G, Issa JP, Willis J, Willson JK, Plass C, Markowitz SD. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A 100: 8412‐8417, 2003.
 172.Lin HY, Park HY, Radlein S, Mahajan NP, Sellers TA, Zachariah B, Pow‐Sang J, Coppola D, Ganapathy V, Park JY. Protein expressions and genetic variations of SLC5A8 in prostate cancer risk and aggressiveness. Urology 78: 971.e1‐9, 2011.
 173.Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel‐Duby R, Spiegelman BM. Transcriptional co‐activator PGC‐1 alpha drives the formation of slow‐twitch muscle fibres. Nature 418: 797‐801, 2002.
 174.Lin RY, Vera JC, Chaganti RSK, Golde DW. Human monocarboxylate transporter 2 (MCT2) is a high affinity pyruvate transporter. J Biol Chem 273: 28959‐28965, 1998.
 175.MacDonald PM. Translational control: A cup half full. Curr Biol 14: R282‐R283, 2004.
 176.Manning Fox JE, Meredith D, Halestrap AP. Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J Physiol 529: 285‐293, 2000.
 177.Mannowetz N, Wandernoth P, Wennemuth G. Basigin interacts with both MCT1 and MCT2 in murine spermatozoa. J Cell Physiol 227: 2154‐2162, 2012.
 178.Manoharan C, Wilson MC, Sessions RB, Halestrap AP. The role of charged residues in the transmembrane helices of monocarboxylate transporter 1 and its ancillary protein basigin in determining plasma membrane expression and catalytic activity. Mol Membr Biol 23: 486‐498, 2006.
 179.Martin PM, Dun Y, Mysona B, Ananth S, Roon P, Smith SB, Ganapathy V. Expression of the sodium‐coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina. Invest Ophthalmol Vis Sci 48: 3356‐3363, 2007.
 180.Martin PM, Gopal E, Ananth S, Zhuang L, Itagaki S, Prasad BM, Smith SB, Prasad PD, Ganapathy V. Identity of SMCT1 (SLC5A8) as a neuron‐specific Na+‐coupled transporter for active uptake of L‐lactate and ketone bodies in the brain. J Neurochem 98: 279‐288, 2006.
 181.Mason MJ, Thomas RC. A microelectrode study of the mechanisms of L‐lactate entry into and release from frog sartorius muscle. J Physiol 400: 459‐479, 1988.
 182.Matsuyama S, Ohkura S, Iwata K, Uenoyama Y, Tsukamura H, Maeda K, Kimura K. Food deprivation induces monocarboxylate transporter 2 expression in the brainstem of female rat. J Reprod Dev 55: 256‐261, 2009.
 183.Mccullagh KJA, Bonen A. Reduced lactate transport in denervated rat skeletal muscle. Am J Physiol 268: R884‐R888, 1995.
 184.McCullagh KJA, Poole RC, Halestrap AP, Tipton KF, OBrien M, Bonen A. Chronic electrical stimulation increases MCT1 and lactate uptake in red and white skeletal muscle. Am J Physiol 273: E239‐E246, 1997.
 185.Mendes‐Mourao J, Halestrap AP, Crisp DM, Pogson CI. The involvement of mitochondrial pyruvate transport in the pathways of gluconeogenesis from serine and alanine in isolated rat and mouse liver cells. FEBS Lett 53: 29‐32, 1975.
 186.Mendez R, Richter JD. Translational control by CPEB: A means to the end. Nat Rev Mol Cell Biol 2: 521‐529, 2001.
 187.Mengual R, Claudeschlageter MH, Poiree JC, Yagello M, Sudaka P. Characterization of sodium and pyruvate interactions of the 2 carrier systems specific of monocarboxylic and dicarboxylic or tricarboxylic acids by renal brush‐border membrane vesicles. J Membr Biol 108: 197‐205, 1989.
 188.Mengual R, Leblanc G, Sudaka P. The mechanism of Na‐L‐lactate cotransport by brush border membrane vesicles from horse kidney: Analysis by isotopic exchange kinetics of a sequential model and stoichiometry. J Biol Chem 258: 15071‐15078, 1983.
 189.Mengual R, Schlageter MH, Sudaka P. Kinetic asymmetry of renal Na+‐L‐lactate cotransport ‐ characteristic parameters and evidence for a ping pong mechanism of the trans‐stimulating exchange by pyruvate. J Biol Chem 265: 292‐299, 1990.
 190.Mengual R, Sudaka P. The mechanism of Na‐lactate co‐transport by brush border membrane vesicles from horse kidney; analysis of rapid equilibrium kinetics in absence of membrane potential. J Membr Biol 71: 163‐171, 1983.
 191.Meredith D, Bell P, McClure B, Wilkins R. Functional and molecular characterisation of lactic acid transport in bovine articular chondrocytes. Cell Physiol Biochem 12: 227‐234, 2002.
 192.Meredith D, Christian HC. The SLC16 monocaboxylate transporter family. Xenobiotica 38: 1072‐1106, 2008.
 193.Merezhinskaya N, Fishbein WN, Davis JI, Foellmer JW. Mutations in MCT1 cDNA in patients with symptomatic deficiency in lactate transport. Muscle & Nerve 23: 90‐97, 2000.
 194.Miyauchi S, Gopal E, Fei YJ, Ganapathy V. Functional identification of SLC5A8, a tumor suppressor down‐regulated in colon cancer, as a Na(+)‐coupled transporter for short‐chain fatty acids. J Biol Chem 279: 13293‐6, 2004.
 195.Moreira TJ, Pierre K, Maekawa F, Repond C, Cebere A, Liljequist S, Pellerin L. Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells. J Cereb Blood Flow Metab 29: 1273‐1283, 2009.
 196.Moschen I, Bröer A, Galic S, Lang F, Bröer S. Significance of short chain fatty acid transport by members of the Monocarboxylate Transporter Family (MCT). Neurochem Res 37: 2562‐2568, 2012.
 197.Murakami Y, Kohyama N, Kobayashi Y, Ohbayashi M, Ohtani H, Sawada Y, Yamamoto T. Functional characterization of human monocarboxylate transporter 6 (SLC16A5). Drug Metab Dispos 33: 1845‐1851, 2005.
 198.Muramatsu T, Miyauchi T. Basigin (CD147): A multifunctional transmembrane protein involved in reproduction, neural function, inflammation and tumor invasion. Histol Histopathol 18: 981‐987, 2003.
 199.Murer H, Berckhardt G. Membrane transport of anions across epithelia of mammalian intestine and kidney proximal tubules. Rev Physiol Biochem Pharmacol 96: 1‐51, 1983.
 200.Murray CM, Hutchinson R, Bantick JR, Belfield GP, Benjamin AD, Brazma D, Bundick RV, Cook ID, Craggs RI, Edwards S, Evans LR, Harrison R, Holness E, Jackson AP, Jackson CG, Kingston LP, Perry MWD, Ross ARJ, Rugman PA, Sidhu SS, Sullivan M, TaylorFishwick DA, Walker PC, Whitehead YM, Wilkinson DJ, Wright A, Donald DK. Monocarboxylate transporter MCT1 is a target for immunosuppression. Nat Chem Biol 1: 371‐376, 2005.
 201.Nabeshima K, Iwasaki H, Koga K, Hojo H, Suzumiya J, Kikuchi M. Emmprin (Basigin/CD147): Matrix metalloproteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression. Pathol Int 56: 359‐367, 2006.
 202.Nalecz KA, Bolli R, Wojtczak L, Azzi A. The monocarboxylate carrier from bovine heart mitochondria: Partial purification and its substrate‐transporting properties in a reconstituted system. Biochim Biophys Acta 851: 29‐37, 1986.
 203.Newstead S, Drew D, Cameron AD, Postis VL, Xia X, Fowler PW, Ingram JC, Carpenter EP, Sansom MS, McPherson MJ, Baldwin SA, Iwata S. Crystal structure of a prokaryotic homologue of the mammalian oligopeptide‐proton symporters, PepT1 and PepT2. EMBO J 30: 417‐426, 2011.
 204.Nord E, Wright SH, Kippen I, Wright EM. Pathways for monocarboxylic acid transport by rabbit renal brush border membrane vesicles. Am J Physiol 243: F456‐F462, 1982.
 205.Nord EP, Wright SH, Kippen I, Wright EM. Specificity of the Na‐dependent momcarboxylic acid transport pathway in rabbit renal brush border membranes. J Membr Biol 72: 213‐221, 1983.
 206.Ochrietor JD, Linser PJ. 5A11/Basigin gene products are necessary for proper maturation and function of the retina. Dev Neurosci 26: 380‐387, 2004.
 207.Ojuka EO. Role of calcium and AMP kinase in the regulation of mitochondrial biogenesis and GLUT4 levels in muscle. Proc Nutr Soc 63: 275‐278, 2004.
 208.Okamura H, Spicer SS, Schulte BA. Developmental expression of monocarboxylate transporter in the gerbil inner ear. Neuroscience 107: 499‐505, 2001.
 209.Olson EN, Williams RS. Calcineurin signaling and muscle remodeling. Cell 101: 689‐692, 2000.
 210.Orsenigo MN, Tosco M, Bazzini C, Laforenza U, Faelli A. A monocarboxylate transporter MCT1 is located at the basolateral pole of rat jejunum. Exp Physiol 84: 1033‐1042, 1999.
 211.Otonkoski T, Jiao H, Kaminen‐Ahola N, Tapia‐Paez I, Ullah MS, Parton LE, Schuit F, Quintens R, Sipila I, Mayatepek E, Meissner T, Halestrap AP, Rutter GA, Kere J. Physical exercise‐induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet 81: 467‐474, 2007.
 212.Ovens MJ, Davies AJ, Wilson MC, Murray CM, Halestrap AP. AR‐C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7‐10. Biochem J 425: 523‐530, 2010.
 213.Ovens MJ, Manoharan C, Wilson MC, Murray CM, Halestrap AP. The inhibition of monocarboxylate transporter 2 (MCT2) by AR‐C155858 is modulated by the associated ancillary protein. Biochem J 431: 217‐225, 2010.
 214.Pahlman C, Qi Z, Murray CM, Ferguson D, Bundick RV, Donald DK, Ekberg H. Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT‐1. Transpl Int 26: 22‐29, 2013.
 215.Palmieri F. The mitochondrial transporter family (SLC25): Physiological and pathological implications. Pflugers Arch 447: 689‐709, 2004.
 216.Papa S, Paradies G. On the mechanism of translocation of pyruvate and other monocarboxylic acids in rat‐liver mitochondria. Eur J Biochem 49: 265‐274, 1974.
 217.Paradies G. Interaction of alpha‐cyano‐[14C]cinnamate with the mitochondrial pyruvate translocator. Biochim Biophys Acta 766: 446‐450, 1984.
 218.Paradies G, Papa S. The transport of monocarboxylic oxoacids in rat liver mitochondria. FEBS Lett 52: 149‐152, 1975.
 219.Paradies G, Papa S. On the kinetics and substrate specificity of the pyruvate translocator in rat liver mitochondria. Biochim Biophys Acta 462: 333‐346, 1977.
 220.Paradies G, Ruggiero FM. Characterization of the alpha‐cyanocinnamate binding site in rat heart mitochondria and in submitochondrial particles. Biochim Biophys Acta 850: 249‐255, 1986.
 221.Park JY, Helm JF, Zheng W, Ly QP, Hodul PJ, Centeno BA, Malafa MP. Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer. Pancreas 36: e32‐39, 2008.
 222.Park JY, Zheng W, Kim D, Cheng JQ, Kumar N, Ahmad N, Pow‐Sang J. Candidate tumor suppressor gene SLC5A8 is frequently down‐regulated by promoter hypermethylation in prostate tumor. Cancer Detect Prev 31: 359‐365, 2007.
 223.Parks SK, Chiche J, Pouyssegur J. pH control mechanisms of tumor survival and growth. J Cell Physiol 226: 299‐308, 2011.
 224.Paroder V, Spencer SR, Paroder M, Arango D, Schwartz S, Mariadason JM, Augenlicht LH, Eskandari S, Carrasco N. Na+/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: Molecular characterization of SMCT. Proc Natl Acad Sci USA 103: 7270‐7275, 2006.
 225.PebayPeyroula E, DahoutGonzalez C, Kahn R, Trezeguet V, Lauquin GJM, Brandolin R. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature 426: 39‐44, 2003.
 226.Pellerin L, Bergersen LH, Halestrap AP, Pierre K. Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain. J Neurosci Res 79: 55‐64, 2005.
 227.Perez de Heredia F, Wood IS, Trayhurn P. Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, MCT4) expression in human adipocytes. Pflugers Arch 459: 509‐518, 2010.
 228.Philp A, Macdonald AL, Watt PW. Lactate ‐ a signal coordinating cell and systemic function. J Exp Biol 208: 4561‐4575, 2005.
 229.Philp N, Chu P, Pan TC, Zhang RZ, Chu ML, Stark K, Boettiger D, Yoon H, Emmons T. Developmental expression and molecular cloning of REMP, a novel retinal epithelial membrane protein. Exp Cell Res 219: 64‐73, 1995.
 230.Philp NJ, Ochrietor JD, Rudoy C, Muramatsu T, Linser PJ. Loss of MCT1, MCT3, MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin‐null mouse. Invest Ophth Vis Sci 44: 1305‐1311, 2003.
 231.Philp NJ, Yoon H, Grollman EF. Monocarboxylate transporter MCT1 is located in the apical membrane and MCT3 in the basal membrane of rat RPE ‐ Rapid Communication. Am J Physiol 274: R1824‐R1828, 1998.
 232.Philp NJ, Yoon HY, Lombardi L. Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia. Am J Physiol 280: C1319‐C1326, 2001.
 233.Pierre K, Parent A, Jayet PY, Halestrap AP, Scherrer U, Pellerin L. Enhanced expression of three monocarboxylate transporter isoforms in the brain of obese mice. J Physiol 583: 469‐486, 2007.
 234.Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system: Distribution, regulation and function. J Neurochem 94: 1‐14, 2005.
 235.Pilegaard H, Domino K, Noland T, Juel C, Hellsten Y, Halestrap AP, Bangsbo J. Effect of high‐intensity exercise training on lactate/H+ transport capacity in human skeletal muscle. Am J Physiol 276: E255‐E261, 1999.
 236.Pilegaard H, Juel C. Lactate transport studied in sarcolemmal giant vesicles from rat skeletal muscles: Effect of denervation. Am J Physiol 269: E679‐E682, 1995.
 237.Pilegaard H, Mohr T, Kjaer M, Juel C. Lactate/H+ transport in skeletal muscle from spinal‐cord‐injured patients. Scand J Med Sci Sports 8: 98‐101, 1998.
 238.Pinheiro C, Longatto‐Filho A, Azevedo‐Silva J, Casal M, Schmitt FC, Baltazar F. Role of monocarboxylate transporters in human cancers: State of the art. J Bioenerg Biomembr 44: 127‐139, 2012.
 239.Pinheiro C, Reis RM, Ricardo S, Longatto‐Filho A, Schmitt F, Baltazar F. Expression of monocarboxylate transporters 1, 2, 4 in human tumors and their association with CD147 and CD44. J Biomed Biotechnol 2010:427694. doi: 10.1155/2010/427694, 2010.
 240.Poole RC, Bowden NJ, Halestrap AP. Derivatives of cinnamic acid interact with the nucleotide binding site of mitochondrial aldehyde dehydrogenase ‐ effects on the dehydrogenase reaction and stimulation of esterase activity by nucleotides. Biochem Pharmacol 45: 1621‐1630, 1993.
 241.Poole RC, Cranmer SL, Halestrap AP, Levi AJ. substrate and inhibitor specificity of monocarboxylate transport into heart cells and erythrocytes ‐ further evidence for the existence of 2 distinct carriers. Biochem J 269: 827‐829, 1990.
 242.Poole RC, Cranmer SL, Holdup DW, Halestrap AP. Inhibition of L‐lactate transport and band‐3‐mediated anion transport in erythrocytes by the novel stilbenedisulphonate N,N,N′,N′‐tetrabenzyl‐4,4′‐diaminostilbene‐2,2′‐disulphonate (TBenzDS). Biochim Biophys Acta 1070: 69‐76, 1991.
 243.Poole RC, Halestrap AP. Reversible and irreversible inhibition, by stilbenedisulphonates, of lactate transport into rat erythrocytes ‐ identification of some new high‐affinity inhibitors. Biochem J 275: 307‐312, 1991.
 244.Poole RC, Halestrap AP. Identification and partial purification of the erythrocyte lactate transporter. Biochem J 283: 855‐862, 1992.
 245.Poole RC, Halestrap AP. Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am J Physiol 264: C761‐C782, 1993.
 246.Poole RC, Halestrap AP. N‐Terminal protein sequence analysis of the rabbit erythrocyte lactate transporter suggests identity with the cloned monocarboxylate transport protein MCT1. Biochem J 303: 755‐759, 1994.
 247.Poole RC, Halestrap AP. Interaction of the erythrocyte lactate transporter (monocarboxylate transporter 1) with an integral 70‐kDa membrane glycoprotein of the immunoglobulin superfamily. J Biol Chem 272: 14624‐14628, 1997.
 248.Poole RC, Halestrap AP, Price SJ, Levi AJ. The kinetics of transport of lactate and pyruvate into isolated cardiac myocytes from guinea pig ‐ kinetic evidence for the presence of a carrier distinct from that in erythrocytes and hepatocytes. Biochem J 264: 409‐418, 1989.
 249.Poole RC, Sansom CE, Halestrap AP. Studies of the membrane topology of the rat erythrocyte H+/lactate cotransporter (MCT1). Biochem J 320: 817‐824, 1996.
 250.Price NT, Jackson VN, Halestrap AP. Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past. Biochem J 329: 321‐328, 1998.
 251.Proud CG. Regulation of mRNA translation. Essays Biochem 37: 97‐108, 2001.
 252.Pullen TJ, da Silva Xavier G, Kelsey G, Rutter GA. miR‐29a and miR‐29b contribute to pancreatic beta‐cell‐specific silencing of monocarboxylate transporter 1 (Mct1). Mol Cell Biol 31: 3182‐3194, 2011.
 253.Pullen TJ, Sylow L, Sun G, Halestrap AP, Richter EA, Rutter GA. Overexpression of monocarboxylate transporter‐1 (SLC16A1) in mouse pancreatic beta‐cells leads to relative hyperinsulinism during exercise. Diabetes 61: 1719‐1725, 2012.
 254.Pushkarsky T, Zybarth G, Dubrovsky L, Yurchenko V, Tang H, Guo HM, Toole B, Sherry B, Bukrinsky M. CD147 facilitates HIV‐1 infection by interacting with virus‐associated cyclophilin A. Proc Natl Acad Sci U S A 98: 6360‐6365, 2001.
 255.Py G, Lambert K, Milhavet O, Eydoux N, Prefaut C, Mercier J. Effects of streptozotocin‐induced diabetes on markers of skeletal muscle metabolism and monocarboxylate transporter 1 to monocarboxylate transporter 4 transporters. Metabolism 51: 807‐813, 2002.
 256.Py G, Lambert K, PerezMartin A, Raynaud E, Prefaut C, Mercier J. Impaired sarcolemmal vesicle lactate uptake and skeletal muscle MCT1 and MCT4 expression in obese Zucker rats. Am J Physiol 281: E1308‐E1315, 2001.
 257.Rafiki A, Boulland JL, Halestrap AP, Ottersen OP, Bergersen L. Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain. Neuroscience 122: 677‐688, 2003.
 258.Rahman B, Schneider HP, Bröer A, Deitmer JW, Bröer S. Helix 8 and helix 10 are involved in substrate recognition in the rat monocarboxylate transporter MCT1. Biochemistry 38: 11577‐11584, 1999.
 259.Riazi R, Khairallah M, Cameron JM, Pencharz PB, Des Rosiers C, Robinson BH. Probing pyruvate metabolism in normal and mutant fibroblast cell lines using 13C‐labeled mass isotopomer analysis and mass spectrometry. Mol Genet Metab 98: 349‐355, 2009.
 260.Ritzhaupt A, Wood IS, Ellis A, Hosie KB, ShiraziBeechey SP. Identification and characterization of a monocarboxylate transporter (MCT1) in pig and human colon: Its potential to transport L‐lactate as well as butyrate. J Physiol 513: 719‐732, 1998.
 261.Robinet C, Pellerin L. Brain‐derived neurotrophic factor enhances the expression of the monocarboxylate transporter 2 through translational activation in mouse cultured cortical neurons. J Cereb Blood Flow Metab 30: 286‐298, 2010.
 262.Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 60: 143‐180, 1980.
 263.Robinson AJ, Overy C, Kunji ERS. The mechanism of transport by mitochondrial carriers based on analysis of symmetry. Proc Natl Acad Sci U S A 105: 17766‐17771, 2008.
 264.Sahlin K, Fernstrom M, Svensson M, Tonkonogi M. No evidence of an intracellular lactate shuttle in rat skeletal muscle. J Physiol 541: 569‐574, 2002.
 265.Schneider U, Poole RC, Halestrap AP, Grafe P. Lactate‐proton co‐transport and its contribution to interstitial acidification during hypoxia in isolated rat spinal roots. Neuroscience 53: 1153‐1162, 1993.
 266.Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 491: 364‐373, 2012.
 267.Sepponen K, Ruusunen M, Pakkanen JA, Poso AR. Expression of CD147 and monocarboxylate transporters MCT1, MCT2 and MCT4 in porcine small intestine and colon. Vet J 174: 122‐128, 2007.
 268.Shearman MS, Halestrap AP. The concentration of the mitochondrial pyruvate carrier in rat liver and heart mitochondria determined with α‐cyano‐β‐(1‐phenylindol‐3‐yl)acrylate. Biochem J 223: 673‐676, 1984.
 269.Shewan AM, Marsh BJ, Melvin DR, Martin S, Gould GW, James DE. The cytosolic C‐terminus of the glucose transporter GLUT4 contains an acidic cluster endosomal targeting motif distal to the dileucine signal. Biochem J 350: 99‐107, 2000.
 270.Siebens AW, Boron WF. Effect of electroneutral luminal and basolateral lactate transport om intracellular pH in salamander proximal tubules. J Gen Physiol 90: 799‐831, 1987.
 271.Singh B, Halestrap AP, Paraskeva C. Butyrate can act as a stimulator of growth or inducer of apoptosis in human colonic epithelial cell lines depending on the presence of alternative energy sources. Carcinogenesis 18: 1265‐1270, 1997.
 272.Smirnova I, Kasho V, Kaback HR. Lactose permease and the alternating access mechanism. Biochemistry 50: 9684‐9693, 2011.
 273.Smirnova I, Kasho V, Choe J‐Y, Altenbach C, Hubbell WL, Kaback HR. Sugar binding induces an outward facing conformation of LacY. Proc Natl Acad Sci U S A 104: 16504‐16509, 2007.
 274.Smith JP, Drewes LR. Modulation of monocarboxylic acid transporter‐1 kinetic function by the cAMP signaling pathway in rat brain endothelial cells. J Biol Chem 281: 2053‐2060, 2006.
 275.Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW. Targeting lactate‐fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118: 3930‐3942, 2008.
 276.Spencer TL, Lehninger AL. L‐lactate transport in Ehrlich ascites tumor cells. Biochem J 154: 405‐414, 1976.
 277.Srinivas SR, Gopal E, Zhuang L, Itagaki S, Martin PM, Fei YJ, Ganapathy V, Prasad PD. Cloning and functional identification of slc5a12 as a sodium‐coupled low‐affinity transporter for monocarboxylates (SMCT2). Biochem J 392: 655‐664, 2005.
 278.Storelli C, Corcelli A, Cassano G, Hildmann B, Murer H, Lippe C. Polar distribution of sodium‐dependent and sodium‐independent transport systems for L‐lactate in rat enterocytes. Pflugers Arch 388: 11‐16, 1980.
 279.Stridh MH, Alt MD, Wittmann S, Heidtmann H, Aggarwal M, Riederer B, Seidler U, Wennemuth G, McKenna R, Deitmer JW, Becker HM. Lactate flux in astrocytes is enhanced by a non‐catalytic action of carbonic anhydrase II. J Physiol 590: 2333‐2351, 2012.
 280.Su J, Chen X, Kanekura T. A CD147‐targeting siRNA inhibits the proliferation, invasiveness, VEGF production of human malignant melanoma cells by down‐regulating glycolysis. Cancer Lett 273: 140‐147, 2009.
 281.Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wagele B, Altmaier E, Deloukas P, Erdmann J, Grundberg E, Hammond CJ, de Angelis MH, Kastenmuller G, Kottgen A, Kronenberg F, Mangino M, Meisinger C, Meitinger T, Mewes HW, Milburn MV, Prehn C, Raffler J, Ried JS, Romisch‐Margl W, Samani NJ, Small KS, Wichmann HE, Zhai G, Illig T, Spector TD, Adamski J, Soranzo N, Gieger C. Human metabolic individuality in biomedical and pharmaceutical research. Nature 477: 54‐60, 2011.
 282.Sun L, Zeng X, Yan C, Sun X, Gong X, Rao Y, Yan N. Crystal structure of a bacterial homologue of glucose transporters GLUT1‐4. Nature 490: 361‐366, 2012.
 283.Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM. Astrocyte‐neuron lactate transport is required for long‐term memory formation. Cell 144: 810‐23, 2011.
 284.Tamai I, Takanaga H, Ogihara T, Higashida H, Maeda H, Sai Y, Tsuji A. Participation of a proton‐cotransporter, MCT1, in the intestinal transport of monocarboxylic acids. Biochem Biophys Res Commun 214: 482‐489, 1995.
 285.Teramae H, Yoshikawa T, Inoue R, Ushida K, Takebe K, Nio‐Kobayashi J, Iwanaga T. The cellular expression of SMCT2 and its comparison with other transporters for monocarboxylates in the mouse digestive tract. Biomed Res 31: 239‐249, 2010.
 286.Thangaraju M, Ananth S, Martin PM, Roon P, Smith SB, Sterneck E, Prasad PD, Ganapathy V. c/ebpdelta Null mouse as a model for the double knock‐out of slc5a8 and slc5a12 in kidney. J Biol Chem 281: 26769‐26773, 2006.
 287.Thangaraju M, Carswell KN, Prasad PD, Ganapathy V. Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. Biochem J 417: 379‐389, 2009.
 288.Thangaraju M, Karunakaran SK, Itagaki S, Gopal E, Elangovan S, Prasad PD, Ganapathy V. Transport by SLC5A8 with subsequent inhibition of histone deacetylase 1 (HDAC1) and HDAC3 underlies the antitumor activity of 3‐bromopyruvate. Cancer 115: 4655‐4666, 2009.
 289.Thomas AP, Halestrap AP. Identification of the protein responsible for pyruvate transport into rat liver and heart mitochondria by specific labelling with N‐phenylmaleimide. Biochem J 196: 471‐479, 1981.
 290.Thomas C, Bishop D, Moore‐Morris T, Mercier J. Effects of high‐intensity training on MCT1, MCT4, NBC expressions in rat skeletal muscles: Influence of chronic metabolic alkalosis. Am J Physiol 293: E916‐22, 2007.
 291.Thomas C, Perrey S, Lambert K, Hugon G, Mornet D, Mercier J. Monocarboxylate transporters, blood lactate removal after supramaximal exercise, fatigue indexes in humans. J Appl Physiol 98: 804‐809, 2005.
 292.Thomas JA, Buchsbaum RN, Zimniak A, Racker E. Intracellular pH measurements in Ehrlich ascites tumor cells utilising spectroscopic probes generated in situ. Biochemistry 18: 2210‐2218, 1979.
 293.Todisco S, Agrimi G, Castegna A, Palmieri F. Identification of the mitochondrial NAD+ transporter in Saccharomyces cerevisiae. J Biol Chem 281: 1524‐1531, 2006.
 294.Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up‐regulated by hypoxia through a HIF‐1 alpha‐dependent mechanism. J Biol Chem 281: 9030‐9037, 2006.
 295.Ullrich KJ, Rumrich G, Kloss S. Reabsorption of monocarboxylic acids in the proximal tubule of the rat kidney I. Transport kinetics of D‐lactate, Na‐dependence, pH dependence and effect of inhibitors. Pflugers Arch 395: 212‐219, 1982.
 296.Ullrich KJ, Rumrich G, Loss S, Fasold H. Reabsorption of monocarboxylic acids in the proximal tubule of the rat kidney III. Specificity for aromatic compounds. Pflugers Arch 395: 227‐231, 1982.
 297.Vandenberg JI, Metcalfe JC, Grace AA. Mechanisms of intracellular pH recovery following global ischaemia in the perfused heart. Circulation Res 72: 993‐1003, 1993.
 298.Vander Heiden MG. Targeting cancer metabolism: A therapeutic window opens. Nat Rev Drug Discov 10: 671‐684, 2011.
 299.VanItallie TB, Nufert TH. Ketones: Metabolism's ugly duckling. Nutr Rev 61: 327‐341, 2003.
 300.Varma MV, Ambler CM, Ullah M, Rotter CJ, Sun H, Litchfield J, Fenner KS, El‐Kattan AF. Targeting intestinal transporters for optimizing oral drug absorption. Curr Drug Metab 11: 730‐742, 2010.
 301.Vaughan‐Jones RD, Spitzer KW, Swietach P. Intracellular pH regulation in heart. J Mol Cell Cardiol 46: 318‐31, 2009.
 302.Visser WE, Friesema EC, Visser TJ. Minireview: Thyroid hormone transporters: The knowns and the unknowns. Mol Endocrinol 25: 1‐14, 2011.
 303.Vivekananda J, Oliver DJ. Detection of the monocarboxylate transporter from pea mitochondria by means of a specific monoclonal antibody. FEBS Lett 260: 217‐219, 1990.
 304.Von Grumbckow L, Elsner P, Hellsten Y, Quistorff B, Juel C. Kinetics of lactate and pyruvate transport in cultured rat myotubes. Biochim Biophys Acta 1417: 267‐275, 1999.
 305.Walter A, Gutknecht J. Monocarboxylic acid permeation through lipid bilayer membranes. J Membr Biol 77: 255‐264, 1984.
 306.Wang XM, Levi AJ, Halestrap AP. Kinetics of the sarcolemmal lactate carrier in single heart cells using BCECF to measure pH(i). Am J Physiol 267: H1759‐H1769, 1994.
 307.Wang XM, Poole RC, Halestrap AP, Levi AJ. Characterization of the inhibition by stilbene disulphonates and phloretin of lactate and pyruvate transport into rat and guinea‐pig cardiac myocytes suggests the presence of 2 kinetically distinct carriers in heart cells. Biochem J 290: 249‐258, 1993.
 308.Wang YX, Tonouchi M, Miskovic D, Hatta H, Bonen A. T‐3 increases lactate transport and the expression of MCT4, but not MCT1, in rat skeletal muscle. Am J Physiol 285: E622‐E628, 2003.
 309.Welter H, Claus R. Expression of the monocarboxylate transporter 1 (MCT1) in cells of the porcine intestine. Cell Biol Int 32: 638‐645, 2008.
 310.Wiederkehr A, Wollheim CB. Impact of mitochondrial calcium on the coupling of metabolism to insulin secretion in the pancreatic beta‐cell. Cell Calcium 44: 64‐76, 2008.
 311.Wilson MC, Jackson VN, Heddle C, Price NT, Pilegaard H, Juel C, Bonen A, Montgomery I, Hutter OF, Halestrap AP. Lactic acid efflux from white skeletal muscle is catalyzed by the monocarboxylate transporter isoform MCT3. J Biol Chem 273: 15920‐15926, 1998.
 312.Wilson MC, Meredith D, Fox JEM, Manoharan C, Davies AJ, Halestrap AP. Basigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4 ‐ the ancillary protein for the insensitive MCT2 is embigin (Gp70). J Biol Chem 280: 27213‐27221, 2005.
 313.Wilson MC, Meredith D, Halestrap AP. Fluorescence resonance energy transfer studies on the interaction between the lactate transporter MCT1 and CD147 provide information on the topology and stoichiometry of the complex in situ. J Biol Chem 277: 3666‐3672, 2002.
 314.Wilson MC, Meredith D, Bunnun C, Sessions RB, Halestrap AP. Studies on the DIDS binding site of monocarboxylate transporter 1 suggest a homology model of the open conformation and a plausible translocation cycle. J. Biol Chem 284: 20011‐20021, 2009.
 315.Wright EM. Transport of carboxylic acids by renal membrane vesicles. Ann Rev Physiol 47: 127‐141, 1985.
 316.Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflugers Arch 447: 510‐518, 2004.
 317.Yanase H, Takebe K, Nio‐Kobayashi J, Takahashi‐Iwanaga H, Iwanaga T. Cellular expression of a sodium‐dependent monocarboxylate transporter (Slc5a8) and the MCT family in the mouse kidney. Histochem Cell Biol 130: 957‐966, 2008.
 318.Yin Y, He X, Szewczyk P, Nguyen T, Chang G. Structure of the multidrug transporter EmrD from Escherichia coli. Science 312: 741‐744, 2006.
 319.Yoon H, Donoso LA, Philp NJ. Cloning of the human monocarboxylate transporter MCT3 gene: Localization to chromosome 22q12.3‐q13.2. Genomics 60: 366‐370, 1999.
 320.Yoon HY, Fanelli A, Grollman EF, Philp NJ. Identification of a unique monocarboxylate transporter (MCT3) in retinal pigment epithelium. Biochem Biophys Res Commun 234: 90‐94, 1997.
 321.Yoshida Y, Hatta H, Kato M, Enoki T, Kato H, Bonen A. Relationship between skeletal muscle MCT1 and accumulated exercise during voluntary wheel running. J Appl Physiol 97: 527‐534, 2004.
 322.Yoshida Y, Holloway GP, Ljubicic V, Hatta H, Spriet LL, Hood DA, Bonen A. Negligible direct lactate oxidation in subsarcolemmal and intermyofibrillar mitochondria obtained from red and white rat skeletal muscle. J Physiol 582: 1317‐1335, 2007.
 323.Yurchenko V, Constant S, Eisenmesser E, Bukrinsky M. Cyclophilin‐CD147 interactions: A new target for anti‐inflammatory therapeutics. Clin Exp Immunol 160: 305‐317, 2010.
 324.Zeuthen T, Hamann S, laCour M. Cotransport of H+, lactate and H2O by membrane proteins in retinal pigment epithelium of bullfrog. J Physiol 497: 3‐17, 1996.
 325.Zhao C, Wilson MC, Schuit F, Halestrap AP, Rutter GA. Expression and distribution of lactate/monocarboxylate transporter isoforms in pancreatic islets and the exocrine pancreas. Diabetes 50: 361‐366, 2001.
 326.Zhou Y, Guan L, Freites JA, Kaback HR. Opening and closing of the periplasmic gate in lactose permease. Proc Natl Acad Sci U S A 105: 3774‐3778, 2008.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Andrew P. Halestrap. Monocarboxylic Acid Transport. Compr Physiol 2013, 3: 1611-1643. doi: 10.1002/cphy.c130008