Monocarboxylate transporters in the brain and in cancer

Biochimica et Biophysica Acta - Molecular Cell Research

Volumn 1863, Issue 10, 2016, Pages 2481-2497

  Pérez Escuredo, Jhudit ^a   Van Hée, Vincent F ^a   Sboarina, Martina ^a   Falces, Jorge ^a   Payen, Valéry L ^a   Pellerin, Luc ^b   Sonveaux, Pierre ^a  

^a UNIVERSITÉ CATHOLIQUE DE LOUVAIN   (Belgium)

^b UNIVERSITY OF LAUSANNE   (Switzerland)

Author keywords

Astrocytes; Lactate shuttle; Metabolic cooperation; Neurons; Tumor cells; Tumor microenvironment

Indexed keywords

LACTIC ACID; MONOCARBOXYLATE TRANSPORTER; REGULATOR PROTEIN; KETONE BODY; LACTIC ACID DERIVATIVE; PYRUVIC ACID; TUMOR PROTEIN;

ANGIOGENESIS; ARTICLE; ASTROCYTE; BRAIN; BRAIN ISCHEMIA; BRAIN NERVE CELL; CANCER CELL; CELLULAR DISTRIBUTION; CENTRAL NERVOUS SYSTEM; COGNITIVE DEFECT; DEGENERATIVE DISEASE; ENDOTHELIUM CELL; EPIGENETICS; EPILEPSY; GLYCOLYSIS; HUMAN; IMMUNOCOMPETENT CELL; LEARNING; MEMORY; METABOLIC DISORDER; NEOPLASM; NONHUMAN; OXIDATIVE STRESS; PHASE 1 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; STROMA CELL; TRANSCRIPTION REGULATION; ACTIVE TRANSPORT; ANIMAL; ANTAGONISTS AND INHIBITORS; ANTIBODY SPECIFICITY; BRAIN DISEASE; COGNITION; GENE EXPRESSION REGULATION; GENETICS; LYMPHOCYTE; METABOLISM; MOUSE; NERVE CELL; OXIDATIVE PHOSPHORYLATION; PH; PHYSIOLOGY; RAT;

ANIMALS; ASTROCYTES; BIOLOGICAL TRANSPORT, ACTIVE; BRAIN; BRAIN DISEASES; COGNITION; GENE EXPRESSION REGULATION; GLYCOLYSIS; HUMANS; HYDROGEN-ION CONCENTRATION; KETONE BODIES; LACTATES; LYMPHOCYTES; MICE; MONOCARBOXYLIC ACID TRANSPORTERS; NEOPLASM PROTEINS; NEOPLASMS; NEURONS; ORGAN SPECIFICITY; OXIDATIVE PHOSPHORYLATION; PYRUVIC ACID; RATS;

EID: 84962315394     PISSN: 01674889     EISSN: 18792596     Source Type: Journal    
DOI: 10.1016/j.bbamcr.2016.03.013     Document Type: Article

References (248)

1. Halestrap, A.P., Price, N.T., The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem. J. 343:Pt 2 (1999), 281–299.
2. Halestrap, A.P., Meredith, D., The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 447 (2004), 619–628.
3. Visser, W.E., Friesema, E.C., Visser, T.J., Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol. Endocrinol. 25 (2011), 1–14.
4. 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 (2005), 1845–1851.
5. Hugo, S.E., Cruz-Garcia, L., Karanth, S., Anderson, R.M., Stainier, D.Y., Schlegel, A., A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting. Genes Dev. 26 (2012), 282–293.
6. Suhre, K., Shin, S.Y., Petersen, A.K., Mohney, R.P., Meredith, D., Wagele, B., Altmaier, E., Deloukas, P., Erdmann, J., Grundberg, E., Hammond, C.J., de Angelis, M.H., Kastenmuller, G., Kottgen, A., Kronenberg, F., Mangino, M., Meisinger, C., Meitinger, T., Mewes, H.W., Milburn, M.V., Prehn, C., Raffler, J., Ried, J.S., Romisch-Margl, W., Samani, N.J., Small, K.S., Wichmann, H.E., Zhai, G., Illig, T., Spector, T.D., Adamski, J., Soranzo, N., Gieger, C., Human metabolic individuality in biomedical and pharmaceutical research. Nature 477 (2011), 54–60.
7. Halestrap, A.P., The monocarboxylate transporter family—structure and functional characterization. IUBMB. Life 64 (2012), 1–9.
8. Manoharan, C., Wilson, M.C., Sessions, R.B., Halestrap, A.P., 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 (2006), 486–498.
9. Wilson, M.C., Meredith, D., Bunnun, C., Sessions, R.B., Halestrap, A.P., 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 (2009), 20011–20021.
10. Halestrap, A.P., The SLC16 gene family—structure, role and regulation in health and disease. Mol. Asp. Med. 34 (2013), 337–349.
11. Galic, S., Schneider, H.P., Broer, A., Deitmer, J.W., Broer, 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 (2003), 413–422.
12. Dimmer, K.S., Friedrich, B., Lang, F., Deitmer, J.W., Broer, S., The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem. J. 350:Pt 1 (2000), 219–227.
13. Chiche, J., Fur, Y.L., Vilmen, C., Frassineti, F., Daniel, L., Halestrap, A.P., Cozzone, P.J., Pouyssegur, J., Lutz, N.W., 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 (2012), 1511–1520.
14. Manning Fox, J.E., Meredith, D., Halestrap, A.P., Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J. Physiol. 529:Pt 2 (2000), 285–293.
15. Dhup, S., Dadhich, R.K., Porporato, P.E., Sonveaux, P., Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr. Pharm. Des. 18 (2012), 1319–1330.
16. Garcia, C.K., Brown, M.S., Pathak, R.K., Goldstein, J.L., cDNA cloning of MCT2, a second monocarboxylate transporter expressed in different cells than MCT1. J. Biol. Chem. 270 (1995), 1843–1849.
17. Philp, N.J., Yoon, H., Lombardi, L., Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia. Am. J. Physiol. Cell Physiol. 280 (2001), C1319–C1326.
18. Pérez de Heredia, F., Wood, I.S., Trayhurn, P., Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes. Pflugers Arch. 459 (2010), 509–518.
19. Broer, S., Broer, A., Schneider, H.P., Stegen, C., Halestrap, A.P., Deitmer, J.W., Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem. J. 341:Pt 3 (1999), 529–535.
20. Broer, S., Schneider, H.P., Broer, A., Rahman, B., Hamprecht, B., Deitmer, J.W., Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem. J. 333:Pt 1 (1998), 167–174.
21. Birsoy, K., Wang, T., Possemato, R., Yilmaz, O.H., Koch, C.E., Chen, W.W., Hutchins, A.W., Gultekin, Y., Peterson, T.R., Carette, J.E., Brummelkamp, T.R., Clish, C.B., Sabatini, D.M., MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nat. Genet. 45 (2013), 104–108.
22. Jackson, V.N., Halestrap, A.P., The kinetics, substrate, and 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 (1996), 861–868.
23. Halestrap, A.P., Wilson, M.C., The monocarboxylate transporter family—role and regulation. IUBMB Life 64 (2012), 109–119.
24. Ullah, M.S., Davies, A.J., Halestrap, A.P., The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J. Biol. Chem. 281 (2006), 9030–9037.
25. Sonveaux, P., Végran, F., Schroeder, T., Wergin, M.C., Verrax, J., Rabbani, Z.N., De Saedeleer, C.J., Kennedy, K.M., Diepart, C., Jordan, B.F., Kelley, M.J., Gallez, B., Wahl, M.L., Feron, O., Dewhirst, M.W., Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 118 (2008), 3930–3942.
26. Baltazar, F., Pinheiro, C., Morais-Santos, F., Azevedo-Silva, J., Queiros, O., Preto, A., Casal, M., Monocarboxylate transporters as targets and mediators in cancer therapy response. Histol. Histopathol. 29 (2014), 1511–1524.
27. Bonen, A., The expression of lactate transporters (MCT1 and MCT4) in heart and muscle. Eur. J. Appl. Physiol. 86 (2001), 6–11.
28. Kennedy, K.M., Scarbrough, P.M., Ribeiro, A., Richardson, R., Yuan, H., Sonveaux, P., Landon, C.D., Chi, J.T., Pizzo, S., Schroeder, T., Dewhirst, M.W., Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer. PLoS One, 8, 2013, e75154.
29. Van Hée, V.F., Pérez-Escuredo, J., Cacace, A., Copetti, T., Sonveaux, P., Lactate does not activate NF-kB in oxidative tumor cells. Front. Pharmacol., 6, 2015, 228.
30. Juel, C., Halestrap, A.P., Lactate transport in skeletal muscle—role and regulation of the monocarboxylate transporter. J. Physiol. 517:Pt 3 (1999), 633–642.
31. Brooks, G.A., Cell-cell and intracellular lactate shuttles. J. Physiol. 587 (2009), 5591–5600.
32. Pellerin, L., Magistretti, P.J., Sweet sixteen for ANLS. J. Cereb. Blood Flow Metab. 32 (2012), 1152–1166.
33. Funfschilling, U., Supplie, L.M., Mahad, D., Boretius, S., Saab, A.S., Edgar, J., Brinkmann, B.G., Kassmann, C.M., Tzvetanova, I.D., Mobius, W., Diaz, F., Meijer, D., Suter, U., Hamprecht, B., Sereda, M.W., Moraes, C.T., Frahm, J., Goebbels, S., Nave, K.A., Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485 (2012), 517–521.
34. Saab, A.S., Tzvetanova, I.D., Nave, K.A., The role of myelin and oligodendrocytes in axonal energy metabolism. Curr. Opin. Neurobiol. 23 (2013), 1065–1072.
35. Halestrap, A.P., Monocarboxylic acid transport. Compr. Physiol. 3 (2013), 1611–1643.
36. Ovens, M.J., Manoharan, C., Wilson, M.C., Murray, C.M., Halestrap, A.P., The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein. Biochem. J. 431 (2010), 217–225.
37. Draoui, N., Schicke, O., Fernandes, A., Drozak, X., Nahra, F., Dumont, A., Douxfils, J., Hermans, E., Dogne, J.M., Corbau, R., Marchand, A., Chaltin, P., Sonveaux, P., Feron, O., Riant, O., Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells. Bioorg. Med. Chem. 21 (2013), 7107–7117.
38. Draoui, N., Schicke, O., Seront, E., Bouzin, C., Sonveaux, P., Riant, O., Feron, O., Antitumor activity of 7-aminocarboxycoumarin derivatives, a new class of potent inhibitors of lactate influx but not efflux. Mol. Cancer Ther. 13 (2014), 1410–1418.
39. Carpenter, L., Halestrap, A.P., The kinetics, substrate and inhibitor specificity of the lactate transporter of Ehrlich-Lettre tumour cells studied with the intracellular pH indicator BCECF. Biochem. J. 304:Pt 3 (1994), 751–760.
40. Fenton, R.A., Chou, C.L., Stewart, G.S., Smith, C.P., Knepper, M.A., Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct. Proc. Natl. Acad. Sci. U. S. A. 101 (2004), 7469–7474.
41. Nelson, J.A., Falk, R.E., Phloridzin and phloretin inhibition of 2-deoxy-D-glucose uptake by tumor cells in vitro and in vivo. Anticancer Res. 13 (1993), 2293–2299.
42. Moskaug, J.O., Carlsen, H., Myhrstad, M., Blomhoff, R., Molecular imaging of the biological effects of quercetin and quercetin-rich foods. Mech. Ageing Dev. 125 (2004), 315–324.
43. Endeward, V., Cartron, J.P., Ripoche, P., Gros, G., Red cell membrane CO2 permeability in normal human blood and in blood deficient in various blood groups, and effect of DIDS. Transfus. Clin. Biol. 13 (2006), 123–127.
44. Reinertsen, K.V., Tonnessen, T.I., Jacobsen, J., Sandvig, K., Olsnes, S., Role of chloride/bicarbonate antiport in the control of cytosolic pH. Cell-line differences in activity and regulation of antiport. J. Biol. Chem. 263 (1988), 11117–11125.
45. Guile, S.D., Bantick, J.R., Cooper, M.E., Donald, D.K., Eyssade, C., Ingall, A.H., Lewis, R.J., Martin, B.P., Mohammed, R.T., Potter, T.J., Reynolds, R.H., St-Gallay, S.A., Wright, A.D., Optimization of monocarboxylate transporter 1 blockers through analysis and modulation of atropisomer interconversion properties. J. Med. Chem. 50 (2007), 254–263.
46. Ovens, M.J., Davies, A.J., Wilson, M.C., Murray, C.M., Halestrap, A.P., 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 (2010), 523–530.
47. Critchlow, S.E., Hopcroft, L., Curtis, L.N., Whalley, N., Zhong, H., Logie, A., Revill, M., Xie, L., Zhang, J., Yu, D.H., Murray, C., Smith, P.D., Abstract 3224: pre-clinical targeting of the metabolic phenotype of lymphoma by AZD3965, a selective inhibitor of monocarboxylate transporter 1 (MCT1). Cancer Res., 72, 2012, 3224.
48. McCullagh, K.J., Poole, R.C., Halestrap, A.P., O'Brien, M., Bonen, A., Role of the lactate transporter (MCT1) in skeletal muscles. Am. J. Phys. 271 (1996), E143–E150.
49. Pilegaard, H., Terzis, G., Halestrap, A., Juel, C., Distribution of the lactate/H + transporter isoforms MCT1 and MCT4 in human skeletal muscle. Am. J. Phys. 276 (1999), E843–E848.
50. Fishbein, W.N., Merezhinskaya, N., Foellmer, J.W., Relative distribution of three major lactate transporters in frozen human tissues and their localization in unfixed skeletal muscle. Muscle Nerve 26 (2002), 101–112.
51. Kobayashi, M., Fiber type-specific localization of monocarboxylate transporters MCT1 and MCT4 in rat skeletal muscle. Kurume Med. J. 51 (2004), 253–261.
52. Hashimoto, T., Masuda, S., Taguchi, S., Brooks, G.A., Immunohistochemical analysis of MCT1, MCT2 and MCT4 expression in rat plantaris muscle. J. Physiol. 567 (2005), 121–129.
53. Garcia, C.K., Goldstein, J.L., Pathak, R.K., Anderson, R.G., Brown, M.S., Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell 76 (1994), 865–873.
54. Johannsson, E., Nagelhus, E.A., McCullagh, K.J., Sejersted, O.M., Blackstad, T.W., Bonen, A., Ottersen, O.P., Cellular and subcellular expression of the monocarboxylate transporter MCT1 in rat heart. A high-resolution immunogold analysis. Circ. Res. 80 (1997), 400–407.
55. Kirat, D., Inoue, H., Iwano, H., Yokota, H., Taniyama, H., Kato, S., Monocarboxylate transporter 1 (MCT1) in the liver of pre-ruminant and adult bovines. Vet. J. 173 (2007), 124–130.
56. Tamai, I., Takanaga, H., Maeda, H., Sai, Y., Ogihara, T., Higashida, H., Tsuji, A., Participation of a proton-cotransporter, MCT1, in the intestinal transport of monocarboxylic acids. Biochem. Biophys. Res. Commun. 214 (1995), 482–489.
57. Ritzhaupt, A., Wood, I.S., Ellis, A., Hosie, K.B., Shirazi-Beechey, S.P., 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:Pt 3 (1998), 719–732.
58. Orsenigo, M.N., Tosco, M., Bazzini, C., Laforenza, U., Faelli, A., A monocarboxylate transporter MCT1 is located at the basolateral pole of rat jejunum. Exp. Physiol. 84 (1999), 1033–1042.
59. Kirat, D., Inoue, H., Iwano, H., Hirayama, K., Yokota, H., Taniyama, H., Kato, S., Monocarboxylate transporter 1 gene expression in the ovine gastrointestinal tract. Vet. J. 171 (2006), 462–467.
60. Iwanaga, T., Takebe, K., Kato, I., Karaki, S., Kuwahara, A., Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, and humans, with special reference to slc5a8. Biomed. Res. 27 (2006), 243–254.
61. Shimoyama, Y., Kirat, D., Akihara, Y., Kawasako, K., Komine, M., Hirayama, K., Matsuda, K., Okamoto, M., Iwano, H., Kato, S., Taniyama, H., Expression of monocarboxylate transporter 1 (MCT1) in the dog intestine. J. Vet. Med. Sci. 69 (2007), 599–604.
62. Welter, H., Claus, R., Expression of the monocarboxylate transporter 1 (MCT1) in cells of the porcine intestine. Cell Biol. Int. 32 (2008), 638–645.
63. Poole, R.C., Halestrap, A.P., N-terminal protein sequence analysis of the rabbit erythrocyte lactate transporter suggests identity with the cloned monocarboxylate transport protein MCT1. Biochem. J. 303:Pt 3 (1994), 755–759.
64. Koho, N.M., Vaihkonen, L.K., Poso, A.R., Lactate transport in red blood cells by monocarboxylate transporters. Equine Vet. J. Suppl. 34 (2002), 555–559.
65. Koho, N.M., Raekallio, M., Kuusela, E., Vuolle, J., Poso, A.R., Lactate transport in canine red blood cells. Am. J. Vet. Res. 69 (2008), 1091–1096.
66. Merezhinskaya, N., Ogunwuyi, S.A., Mullick, F.G., Fishbein, W.N., Presence and localization of three lactic acid transporters (MCT1, − 2, and − 4) in separated human granulocytes, lymphocytes, and monocytes. J. Histochem. Cytochem. 52 (2004), 1483–1493.
67. Hajduch, E., Heyes, R.R., Watt, P.W., Hundal, H.S., Lactate transport in rat adipocytes: identification of monocarboxylate transporter 1 (MCT1) and its modulation during streptozotocin-induced diabetes. FEBS Lett. 479 (2000), 89–92.
68. Settle, P., Mynett, K., Speake, P., Champion, E., Doughty, I.M., Sibley, C.P., D'Souza, S.W., Glazier, J., Polarized lactate transporter activity and expression in the syncytiotrophoblast of the term human placenta. Placenta 25 (2004), 496–504.
69. Nagai, A., Takebe, K., Nio-Kobayashi, J., Takahashi-Iwanaga, H., Iwanaga, T., Cellular expression of the monocarboxylate transporter (MCT) family in the placenta of mice. Placenta 31 (2010), 126–133.
70. Takebe, K., Nio-Kobayashi, J., Takahashi-Iwanaga, H., Yajima, T., Iwanaga, T., Cellular expression of a monocarboxylate transporter (MCT1) in the mammary gland and sebaceous gland of mice. Histochem. Cell Biol. 131 (2009), 401–409.
71. Gerhart, D.Z., Enerson, B.E., Zhdankina, O.Y., Leino, R.L., Drewes, L.R., Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am. J. Phys. 273 (1997), E207–E213.
72. Pellerin, L., Pellegri, G., Martin, J.L., Magistretti, P.J., Expression of monocarboxylate transporter mRNAs in mouse brain: support for a distinct role of lactate as an energy substrate for the neonatal vs. adult brain. Proc. Natl. Acad. Sci. U. S. A. 95 (1998), 3990–3995.
73. Mac, M., Nalecz, K.A., Expression of monocarboxylic acid transporters (MCT) in brain cells. Implication for branched chain alpha-ketoacids transport in neurons. Neurochem. Int. 43 (2003), 305–309.
74. Broer, S., Rahman, B., Pellegri, G., Pellerin, L., Martin, J.L., Verleysdonk, S., Hamprecht, B., Magistretti, P.J., 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 (1997), 30096–30102.
75. Leino, R.L., Gerhart, D.Z., Drewes, L.R., Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Brain Res. Dev. Brain Res. 113 (1999), 47–54.
76. Hanu, R., McKenna, M., O'Neill, A., Resneck, W.G., Bloch, R.J., Monocarboxylic acid transporters, MCT1 and MCT2, in cortical astrocytes in vitro and in vivo. Am. J. Physiol. Cell Physiol. 278 (2000), C921–C930.
77. Pierre, K., Pellerin, L., Debernardi, R., Riederer, B.M., Magistretti, P.J., Cell-specific localization of monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain revealed by double immunohistochemical labeling and confocal microscopy. Neuroscience 100 (2000), 617–627.
78. Rinholm, J.E., Hamilton, N.B., Kessaris, N., Richardson, W.D., Bergersen, L.H., Attwell, D., Regulation of oligodendrocyte development and myelination by glucose and lactate. J. Neurosci. 31 (2011), 538–548.
79. Lee, Y., Morrison, B.M., Li, Y., Lengacher, S., Farah, M.H., Hoffman, P.N., Liu, Y., Tsingalia, A., Jin, L., Zhang, P.W., Pellerin, L., Magistretti, P.J., Rothstein, J.D., Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487 (2012), 443–448.
80. Moreira, T.J., 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 (2009), 1273–1283.
81. Nijland, P.G., Michailidou, I., Witte, M.E., Mizee, M.R., van der Pol, S.M., van Het, H.B., Reijerkerk, A., Pellerin, L., van V, d., de Vries, H.E., van, H.J., Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions. Glia 62 (2014), 1125–1141.
82. Debernardi, R., Pierre, K., Lengacher, S., Magistretti, P.J., Pellerin, L., Cell-specific expression pattern of monocarboxylate transporters in astrocytes and neurons observed in different mouse brain cortical cell cultures. J. Neurosci. Res. 73 (2003), 141–155.
83. Pellerin, L., Bergersen, L.H., Halestrap, A.P., Pierre, K., Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain. J. Neurosci. Res. 79 (2005), 55–64.
84. Ainscow, E.K., Mirshamsi, S., Tang, T., Ashford, M.L., Rutter, G.A., Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K(+) channels. J. Physiol. 544 (2002), 429–445.
85. Carneiro, L., Geller, S., Fioramonti, X., Hébert, A., Repond, C., Leloup, C., Pellerin, L., Evidence for hypothalamic ketone bodies sensing: impact on food intake and peripheral metabolic responses in mice. Am. J. Phys. 310 (2016), E103–E115.
86. Cortes-Campos, C., Elizondo, R., Llanos, P., Uranga, R.M., Nualart, F., Garcia, M.A., MCT expression and lactate influx/efflux in tanycytes involved in glia-neuron metabolic interaction. PLoS One, 6, 2011, e16411.
87. Domenech-Estevez, E., Baloui, H., Repond, C., Rosafio, K., Medard, J.J., Tricaud, N., Pellerin, L., Chrast, R., Distribution of monocarboxylate transporters in the peripheral nervous system suggests putative roles in lactate shuttling and myelination. J. Neurosci. 35 (2015), 4151–4156.
88. Morrison, B.M., Tsingalia, A., Vidensky, S., Lee, Y., Jin, L., Farah, M.H., Lengacher, S., Magistretti, P.J., Pellerin, L., Rothstein, J.D., Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush. Exp. Neurol. 263 (2015), 325–338.
89. Takebe, K., Nio-Kobayashi, J., Takahashi-Iwanaga, H., Iwanaga, T., Histochemical demonstration of a monocarboxylate transporter in the mouse perineurium with special reference to GLUT1. Biomed. Res. 29 (2008), 297–306.
90. Boussouar, F., Mauduit, C., Tabone, E., Pellerin, L., Magistretti, P.J., Benahmed, M., Developmental and hormonal regulation of the monocarboxylate transporter 2 (MCT2) expression in the mouse germ cells. Biol. Reprod. 69 (2003), 1069–1078.
91. Pierre, K., Magistretti, P.J., Pellerin, L., MCT2 is a major neuronal monocarboxylate transporter in the adult mouse brain. J. Cereb. Blood Flow Metab. 22 (2002), 586–595.
92. Balmaceda-Aguilera, C., Cortes-Campos, C., Cifuentes, M., Peruzzo, B., Mack, L., Tapia, J.C., Oyarce, K., Garcia, M.A., Nualart, F., Glucose transporter 1 and monocarboxylate transporters 1, 2, and 4 localization within the glial cells of shark blood-brain-barriers. PLoS One, 7, 2012, e32409.
93. Gerhart, D.Z., Enerson, B.E., Zhdankina, O.Y., Leino, R.L., Drewes, L.R., Expression of the monocarboxylate transporter MCT2 by rat brain glia. Glia 22 (1998), 272–281.
94. Yoon, H., Fanelli, A., Grollman, E.F., Philp, N.J., Identification of a unique monocarboxylate transporter (MCT3) in retinal pigment epithelium. Biochem. Biophys. Res. Commun. 234 (1997), 90–94.
95. Philp, N.J., Yoon, H., Grollman, E.F., Monocarboxylate transporter MCT1 is located in the apical membrane and MCT3 in the basal membrane of rat RPE. Am. J. Phys. 274 (1998), R1824–R1828.
96. Bonen, A., Miskovic, D., Tonouchi, M., Lemieux, K., Wilson, M.C., Marette, A., Halestrap, A.P., Abundance and subcellular distribution of MCT1 and MCT4 in heart and fast-twitch skeletal muscles. Am. J. Physiol. Endocrinol. Metab. 278 (2000), E1067–E1077.
97. Merezhinskaya, N., Ogunwuyi, S.A., Fishbein, W.N., Expression of monocarboxylate transporter 4 in human platelets, leukocytes, and tissues assessed by antibodies raised against terminal versus pre-terminal peptides. Mol. Genet. Metab. 87 (2006), 152–161.
98. Tan, Z., Xie, N., Banerjee, S., Cui, H., Fu, M., Thannickal, V.J., Liu, G., The monocarboxylate transporter 4 is required for glycolytic reprogramming and inflammatory response in macrophages. J. Biol. Chem. 290 (2015), 46–55.
99. Rafiki, A., Boulland, J.L., Halestrap, A.P., Ottersen, O.P., Bergersen, L., Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain. Neuroscience 122 (2003), 677–688.
100. Bergersen, L., Waerhaug, O., Helm, J., Thomas, M., Laake, P., Davies, A.J., Wilson, M.C., Halestrap, A.P., Ottersen, O.P., 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 (2001), 523–534.
101. Bergersen, L.H., Magistretti, P.J., Pellerin, L., Selective postsynaptic co-localization of MCT2 with AMPA receptor GluR2/3 subunits at excitatory synapses exhibiting AMPA receptor trafficking. Cereb. Cortex 15 (2005), 361–370.
102. Pierre, K., Chatton, J.Y., Parent, A., Repond, C., Gardoni, F., Di, L.M., Pellerin, L., Linking supply to demand: the neuronal monocarboxylate transporter MCT2 and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptor GluR2/3 subunit are associated in a common trafficking process. Eur. J. Neurosci. 29 (2009), 1951–1963.
103. Pinheiro, C., Reis, R.M., Ricardo, S., Longatto-Filho, A., Schmitt, F., Baltazar, F., Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J. Biomed. Biotechnol., 2010, 2010, 427694.
104. Eilertsen, M., Andersen, S., Al-Saad, S., Kiselev, Y., Donnem, T., Stenvold, H., Pettersen, I., Al-Shibli, K., Richardsen, E., Busund, L.T., Bremnes, R.M., Monocarboxylate transporters 1–4 in NSCLC: MCT1 is an independent prognostic marker for survival. PLoS One, 9, 2014, e105038.
105. Hashimoto, T., Hussien, R., Cho, H.S., Kaufer, D., Brooks, G.A., Evidence for the mitochondrial lactate oxidation complex in rat neurons: demonstration of an essential component of brain lactate shuttles. PLoS One, 3, 2008, e2915.
106. Tescarollo, F., Covolan, L., Pellerin, L., Glutamate reduces glucose utilization while concomitantly enhancing AQP9 and MCT2 expression in cultured rat hippocampal neurons. Front. Neurosci., 8, 2014, 246.
107. Hashimoto, T., Brooks, G.A., Mitochondrial lactate oxidation complex and an adaptive role for lactate production. Med. Sci. Sports Exerc. 40 (2008), 486–494.
108. Brooks, G.A., Brown, M.A., Butz, C.E., Sicurello, J.P., Dubouchaud, H., Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1. J. Appl. Physiol. 87 (1999), 1713–1718.
109. Butz, C.E., McClelland, G.B., Brooks, G.A., MCT1 confirmed in rat striated muscle mitochondria. J. Appl. Physiol. 97 (2004), 1059–1066.
110. Lee, W.J., Kim, M., Park, H.S., Kim, H.S., Jeon, M.J., Oh, K.S., Koh, E.H., Won, J.C., Kim, M.S., Oh, G.T., Yoon, M., Lee, K.U., Park, J.Y., AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1. Biochem. Biophys. Res. Commun. 340 (2006), 291–295.
111. Halestrap, A.P., Monocarboxylate transporter 1. UCSD Nature Molecule Pages, 2009, 10.1038/mp.a001490.01.
112. Olson, E.N., Williams, R.S., Calcineurin signaling and muscle remodeling. Cell 101 (2000), 689–692.
113. Benton, C.R., Yoshida, Y., Lally, J., Han, X.X., 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 (2008), 45–54.
114. Takimoto, M., Takeyama, M., Hamada, T., Possible involvement of AMPK in acute exercise-induced expression of monocarboxylate transporters MCT1 and MCT4 mRNA in fast-twitch skeletal muscle. Metabolism 62 (2013), 1633–1640.
115. Kitaoka, Y., Takahashi, Y., Machida, M., Takeda, K., Takemasa, T., Hatta, H., Effect of AMPK activation on monocarboxylate transporter (MCT)1 and MCT4 in denervated muscle. J. Physiol. Sci. 64 (2014), 59–64.
116. Galardo, M.N., Riera, M.F., Pellizzari, E.H., Cigorraga, S.B., Meroni, S.B., 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 (2007), 279–288.
117. Wang, Y., Tonouchi, M., Miskovic, D., Hatta, H., Bonen, A., T3 increases lactate transport and the expression of MCT4, but not MCT1, in rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 285 (2003), E622–E628.
118. Asada, K., Miyamoto, K., Fukutomi, T., Tsuda, H., Yagi, Y., Wakazono, K., Oishi, S., Fukui, H., Sugimura, T., Ushijima, T., Reduced expression of GNA11 and silencing of MCT1 in human breast cancers. Oncology 64 (2003), 380–388.
119. Boidot, R., Végran, F., Meulle, A., Le Breton, A., Dessy, C., Sonveaux, P., Lizard-Nacol, S., Feron, O., Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors. Cancer Res. 72 (2012), 939–948.
120. 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 (2009), 256–261.
121. 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 (2007), 389–397.
122. 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 (2008), 53–65.
123. 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 (2010), 286–298.
124. Pertega-Gomes, N., Vizcaino, J.R., Felisbino, S., Warren, A.Y., Shaw, G., Kay, J., Whitaker, H., Lynch, A.G., Fryer, L., Neal, D.E., Massie, C.E., Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer. Oncotarget 6 (2015), 21675–21684.
125. Fisel, P., Kruck, S., Winter, S., Bedke, J., Hennenlotter, J., Nies, A.T., Scharpf, M., Fend, F., Stenzl, A., Schwab, M., Schaeffeler, E., DNA methylation of the SLC16A3 promoter regulates expression of the human lactate transporter MCT4 in renal cancer with consequences for clinical outcome. Clin. Cancer Res. 19 (2013), 5170–5181.
126. Johannsson, E., Lunde, P.K., Heddle, C., Sjaastad, I., Thomas, M.J., Bergersen, L., Halestrap, A.P., Blackstad, T.W., Ottersen, O.P., Sejersted, O.M., Upregulation of the cardiac monocarboxylate transporter MCT1 in a rat model of congestive heart failure. Circulation 104 (2001), 729–734.
127. Poole, R.C., Halestrap, A.P., Interaction of the erythrocyte lactate transporter (monocarboxylate transporter 1) with an integral 70-kDa membrane glycoprotein of the immunoglobulin superfamily. J. Biol. Chem. 272 (1997), 14624–14628.
128. Wilson, M.C., Meredith, D., Fox, J.E., Manoharan, C., Davies, A.J., Halestrap, A.P., 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 (2005), 27213–27221.
129. Iacono, K.T., Brown, A.L., Greene, M.I., Saouaf, S.J., CD147 immunoglobulin superfamily receptor function and role in pathology. Exp. Mol. Pathol. 83 (2007), 283–295.
130. Yurchenko, V., Constant, S., Bukrinsky, M., Dealing with the family: CD147 interactions with cyclophilins. Immunology 117 (2006), 301–309.
131. Philp, N.J., Ochrietor, J.D., Rudoy, C., Muramatsu, T., Linser, P.J., Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5 A11/basigin-null mouse. Invest. Ophthalmol. Vis. Sci. 44 (2003), 1305–1311.
132. Kirk, P., Wilson, M.C., Heddle, C., Brown, M.H., Barclay, A.N., Halestrap, A.P., CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J. 19 (2000), 3896–3904.
133. Wilson, M.C., Meredith, D., Halestrap, A.P., 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 (2002), 3666–3672.
134. Visser, W.E., Philp, N.J., van Dijk, T.B., Klootwijk, W., Friesema, E.C., Jansen, J., Beesley, P.W., Ianculescu, A.G., Visser, T.J., Evidence for a homodimeric structure of human monocarboxylate transporter 8. Endocrinology 150 (2009), 5163–5170.
135. Klier, M., Schuler, C., Halestrap, A.P., Sly, W.S., Deitmer, J.W., Becker, H.M., 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 (2011), 27781–27791.
136. Klier, M., Andes, F.T., Deitmer, J.W., Becker, H.M., Intracellular and extracellular carbonic anhydrases cooperate non-enzymatically to enhance activity of monocarboxylate transporters. J. Biol. Chem. 289 (2014), 2765–2775.
137. Hashimoto, T., Hussien, R., Brooks, G.A., Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. Am. J. Physiol. Endocrinol. Metab. 290 (2006), E1237–E1244.
138. Maekawa, F., Tsuboi, T., Fukuda, M., Pellerin, L., Regulation of the intracellular distribution, cell surface expression, and protein levels of AMPA receptor GluR2 subunits by the monocarboxylate transporter MCT2 in neuronal cells. J. Neurochem. 109 (2009), 1767–1778.
139. Wilson, M.C., Kraus, M., Marzban, H., Sarna, J.R., Wang, Y., Hawkes, R., Halestrap, A.P., Beesley, P.W., The neuroplastin adhesion molecules are accessory proteins that chaperone the monocarboxylate transporter MCT2 to the neuronal cell surface. PLoS One, 8, 2013, e78654.
140. Bittar, P.G., Charnay, Y., Pellerin, L., Bouras, C., Magistretti, P.J., Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain. J. Cereb. Blood Flow Metab. 16 (1996), 1079–1089.
141. Pellerin, L., Pellegri, G., Bittar, P.G., Charnay, Y., Bouras, C., Martin, J.L., Stella, N., Magistretti, P.J., Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev. Neurosci. 20 (1998), 291–299.
142. Pellerin, L., Bouzier-Sore, A.K., Aubert, A., Serres, S., Merle, M., Costalat, R., Magistretti, P.J., Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55 (2007), 1251–1262.
143. Pellerin, L., Brain energetics (thought needs food). Curr. Opin. Clin. Nutr. Metab. Care 11 (2008), 701–705.
144. Pellerin, L., Magistretti, P.J., Glutamate uptake stimulates Na +,K + -ATPase activity in astrocytes via activation of a distinct subunit highly sensitive to ouabain. J. Neurochem. 69 (1997), 2132–2137.
145. Abe, K., Saito, H., Involvement of Na + -K + pump in L-glutamate clearance by cultured rat cortical astrocytes. Biol. Pharm. Bull. 23 (2000), 1051–1054.
146. Chatton, J.Y., Marquet, P., Magistretti, P.J., A quantitative analysis of L-glutamate-regulated Na + dynamics in mouse cortical astrocytes: implications for cellular bioenergetics. Eur. J. Neurosci. 12 (2000), 3843–3853.
147. Magistretti, P.J., Chatton, J.Y., Relationship between L-glutamate-regulated intracellular Na + dynamics and ATP hydrolysis in astrocytes. J. Neural Transm. 112 (2005), 77–85.
148. Pellerin, L., Magistretti, P.J., Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl. Acad. Sci. U. S. A. 91 (1994), 10625–10629.
149. Pellerin, L., Magistretti, P.J., Excitatory amino acids stimulate aerobic glycolysis in astrocytes via an activation of the Na +/K + ATPase. Dev. Neurosci. 18 (1996), 336–342.
150. Maekawa, F., Minehira, K., Kadomatsu, K., Pellerin, L., Basal and stimulated lactate fluxes in primary cultures of astrocytes are differentially controlled by distinct proteins. J. Neurochem. 107 (2008), 789–798.
151. Rosafio, K., Pellerin, L., Oxygen tension controls the expression of the monocarboxylate transporter MCT4 in cultured mouse cortical astrocytes via a hypoxia-inducible factor-1alpha-mediated transcriptional regulation. Glia 62 (2014), 477–490.
152. Bittner, C.X., Loaiza, A., Ruminot, I., Larenas, V., Sotelo-Hitschfeld, T., Gutierrez, R., Cordova, A., Valdebenito, R., Frommer, W.B., Barros, L.F., High resolution measurement of the glycolytic rate. Front. Neuroenerg., 2, 2010, 26.
153. Bittner, C.X., Valdebenito, R., Ruminot, I., Loaiza, A., Larenas, V., Sotelo-Hitschfeld, T., Moldenhauer, H., San, M.A., Gutierrez, R., Zambrano, M., Barros, L.F., Fast and reversible stimulation of astrocytic glycolysis by K + and a delayed and persistent effect of glutamate. J. Neurosci. 31 (2011), 4709–4713.
154. Ruminot, I., Gutierrez, R., Pena-Munzenmayer, G., Anazco, C., Sotelo-Hitschfeld, T., Lerchundi, R., Niemeyer, M.I., Shull, G.E., Barros, L.F., NBCe1 mediates the acute stimulation of astrocytic glycolysis by extracellular K +. J. Neurosci. 31 (2011), 14264–14271.
155. Lerchundi, R., Fernandez-Moncada, I., Contreras-Baeza, Y., Sotelo-Hitschfeld, T., Machler, P., Wyss, M.T., Stobart, J., Baeza-Lehnert, F., Alegria, K., Weber, B., Barros, L.F., NH4 + triggers the release of astrocytic lactate via mitochondrial pyruvate shunting. Proc. Natl. Acad. Sci. U. S. A. 112 (2015), 11090–11095.
156. Bouzier-Sore, A.K., Voisin, P., Canioni, P., Magistretti, P.J., Pellerin, L., Lactate is a preferential oxidative energy substrate over glucose for neurons in culture. J. Cereb. Blood Flow Metab. 23 (2003), 1298–1306.
157. Bouzier-Sore, A.K., Voisin, P., Bouchaud, V., Bezancon, E., Franconi, J.M., Pellerin, L., Competition between glucose and lactate as oxidative energy substrates in both neurons and astrocytes: a comparative NMR study. Eur. J. Neurosci. 24 (2006), 1687–1694.
158. Serres, S., Bouyer, J.J., Bezancon, E., Canioni, P., Merle, M., Involvement of brain lactate in neuronal metabolism. NMR Biomed. 16 (2003), 430–439.
159. Serres, S., Bezancon, E., Franconi, J.M., Merle, M., Ex vivo analysis of lactate and glucose metabolism in the rat brain under different states of depressed activity. J. Biol. Chem. 279 (2004), 47881–47889.
160. Serres, S., Bezancon, E., Franconi, J.M., Merle, M., Ex vivo NMR study of lactate metabolism in rat brain under various depressed states. J. Neurosci. Res. 79 (2005), 19–25.
161. Wyss, M.T., Jolivet, R., Buck, A., Magistretti, P.J., Weber, B., In vivo evidence for lactate as a neuronal energy source. J. Neurosci. 31 (2011), 7477–7485.
162. Pierre, K., Debernardi, R., Magistretti, P.J., Pellerin, L., Noradrenaline enhances monocarboxylate transporter 2 expression in cultured mouse cortical neurons via a translational regulation. J. Neurochem. 86 (2003), 1468–1476.
163. Robinet, C., Pellerin, L., Brain-derived neurotrophic factor enhances the hippocampal expression of key postsynaptic proteins in vivo including the monocarboxylate transporter MCT2. Neuroscience 192 (2011), 155–163.
164. Suzuki, A., Stern, S.A., Bozdagi, O., Huntley, G.W., Walker, R.H., Magistretti, P.J., Alberini, C.M., Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144 (2011), 810–823.
165. Newman, L.A., Korol, D.L., Gold, P.E., Lactate produced by glycogenolysis in astrocytes regulates memory processing. PLoS One, 6, 2011, e28427.
166. Yang, J., Ruchti, E., Petit, J.M., Jourdain, P., Grenningloh, G., Allaman, I., Magistretti, P.J., Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc. Natl. Acad. Sci. U. S. A. 111 (2014), 12228–12233.
167. Morrison, B.M., Lee, Y., Rothstein, J.D., Oligodendroglia: metabolic supporters of axons. Trends Cell Biol. 23 (2013), 644–651.
168. Lu, W., Huang, J., Sun, S., Huang, S., Gan, S., Xu, J., Yang, M., Xu, S., Jiang, X., Changes in lactate content and monocarboxylate transporter 2 expression in Abeta(2)(5)(−)(3)(5)-treated rat model of Alzheimer's disease. Neurol. Sci. 36 (2015), 871–876.
169. Puchades, M., Sogn, C.J., Maehlen, J., Bergersen, L.H., Gundersen, V., Unaltered lactate and glucose transporter levels in the MPTP mouse model of Parkinson's disease. J. Parkinsons Dis. 3 (2013), 371–385.
170. Lauritzen, F., de Lanerolle, N.C., Lee, T.S., Spencer, D.D., Kim, J.H., Bergersen, L.H., Eid, T., Monocarboxylate transporter 1 is deficient on microvessels in the human epileptogenic hippocampus. Neurobiol. Dis. 41 (2011), 577–584.
171. Lauritzen, F., Heuser, K., de Lanerolle, N.C., Lee, T.S., Spencer, D.D., Kim, J.H., Gjedde, A., Eid, T., Bergersen, L.H., Redistribution of monocarboxylate transporter 2 on the surface of astrocytes in the human epileptogenic hippocampus. Glia 60 (2012), 1172–1181.
172. Leroy, C., Pierre, K., Simpson, I.A., Pellerin, L., Vannucci, S.J., Nehlig, A., Temporal changes in mRNA expression of the brain nutrient transporters in the lithium-pilocarpine model of epilepsy in the immature and adult rat. Neurobiol. Dis. 43 (2011), 588–597.
173. Lauritzen, F., Perez, E.L., Melillo, E.R., Roh, J.M., Zaveri, H.P., Lee, T.S., Wang, Y., Bergersen, L.H., Eid, T., Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy. Neurobiol. Dis. 45 (2012), 165–176.
174. Liu, B., Niu, L., Shen, M.Z., Gao, L., Wang, C., Li, J., Song, L.J., Tao, Y., Meng, Q., Yang, Q.L., Gao, G.D., Zhang, H., Decreased astroglial monocarboxylate transporter 4 expression in temporal lobe epilepsy. Mol. Neurobiol. 50 (2014), 327–338.
175. Tseng, M.T., Chan, S.A., Schurr, A., Ischemia-induced changes in monocarboxylate transporter 1 reactive cells in rat hippocampus. Neurol. Res. 25 (2003), 83–86.
176. Gao, C., Zhou, L., Zhu, W., Wang, H., Wang, R., He, Y., Li, Z., Monocarboxylate transporter-dependent mechanism confers resistance to oxygen- and glucose-deprivation injury in astrocyte-neuron co-cultures. Neurosci. Lett. 594 (2015), 99–104.
177. Gao, C., Wang, C., Liu, B., Wu, H., Yang, Q., Jin, J., Li, H., Dong, S., Gao, G., Zhang, H., Intermittent hypoxia preconditioning-induced epileptic tolerance by upregulation of monocarboxylate transporter 4 expression in rat hippocampal astrocytes. Neurochem. Res. 39 (2014), 2160–2169.
178. Vavaiya, K.V., Paranjape, S.A., Patil, G.D., Briski, K.P., Vagal complex monocarboxylate transporter-2 expression during hypoglycemia. Neuroreport 17 (2006), 1023–1026.
179. Vavaiya, K.V., Paranjape, S.A., Briski, K.P., Testicular regulation of neuronal glucose and monocarboxylate transporter gene expression profiles in CNS metabolic sensing sites during acute and recurrent insulin-induced hypoglycemia. J. Mol. Neurosci. 31 (2007), 37–46.
180. Briski, K.P., Cherian, A.K., Genabai, N.K., Vavaiya, K.V., In situ coexpression of glucose and monocarboxylate transporter mRNAs in metabolic-sensitive caudal dorsal vagal complex catecholaminergic neurons: transcriptional reactivity to insulin-induced hypoglycemia and caudal hindbrain glucose or lactate repletion during insulin-induced hypoglycemia. Neuroscience 164 (2009), 1152–1160.
181. Canis, M., Maurer, M.H., Kuschinsky, W., Duembgen, L., Duelli, R., Increased densities of monocarboxylate transporter MCT1 after chronic hyperglycemia in rat brain. Brain Res. 1257 (2009), 32–39.
182. Allard, C., Carneiro, L., Collins, S.C., Chretien, C., Grall, S., Penicaud, L., Leloup, C., Alteration of hypothalamic glucose and lactate sensing in 48 h hyperglycemic rats. Neurosci. Lett. 534 (2013), 75–79.
183. Pierre, K., Parent, A., Jayet, P.Y., Halestrap, A.P., Scherrer, U., Pellerin, L., Enhanced expression of three monocarboxylate transporter isoforms in the brain of obese mice. J. Physiol. 583 (2007), 469–486.
184. Lengacher, S., Nehiri-Sitayeb, T., Steiner, N., Carneiro, L., Favrod, C., Preitner, F., Thorens, B., Stehle, J.C., Dix, L., Pralong, F., Magistretti, P.J., Pellerin, L., Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice. PLoS One, 8, 2013, e82505.
185. Kennedy, K.M., Dewhirst, M.W., Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol. 6 (2010), 127–148.
186. Pinheiro, C., Longatto-Filho, A., Azevedo-Silva, J., Casal, M., Schmitt, F.C., Baltazar, F., Role of monocarboxylate transporters in human cancers: state of the art. J. Bioenerg. Biomembr. 44 (2012), 127–139.
187. Miranda-Goncalves, V., Honavar, M., Pinheiro, C., Martinho, O., Pires, M.M., Pinheiro, C., Cordeiro, M., Bebiano, G., Costa, P., Palmeirim, I., Reis, R.M., Baltazar, F., Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro-Oncol. 15 (2013), 172–188.
188. Afonso, J., Santos, L.L., Miranda-Goncalves, V., Morais, A., Amaro, T., Longatto-Filho, A., Baltazar, F., CD147 and MCT1-potential partners in bladder cancer aggressiveness and cisplatin resistance. Mol. Carcinog. 54 (2015), 1451–1466.
189. Pertega-Gomes, N., Baltazar, F., Lactate transporters in the context of prostate cancer metabolism: what do we know?. Int. J. Mol. Sci. 15 (2014), 18333–18348.
190. DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G., Thompson, C.B., The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7 (2008), 11–20.
191. Vander Heiden, M.G., Cantley, L.C., Thompson, C.B., Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324 (2009), 1029–1033.
192. Hanahan, D., Weinberg, R.A., Hallmarks of cancer: the next generation. Cell 144 (2011), 646–674.
193. Porporato, P.E., Dhup, S., Dadhich, R.K., Copetti, T., Sonveaux, P., Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front. Pharmacol., 2, 2011, 49.
194. Payen, V.L., Brisson, L., Dewhirst, M.W., Sonveaux, P., Common responses of tumors and wounds to hypoxia. Cancer J. 21 (2015), 75–87.
195. Spugnini, E.P., Sonveaux, P., Stock, C., Perez-Sayans, M., De, M.A., Avnet, S., Garcia, A.G., Harguindey, S., Fais, S., Proton channels and exchangers in cancer. Biochim. Biophys. Acta 1848 (2015), 2715–2726.
196. Brizel, D.M., Schroeder, T., Scher, R.L., Walenta, S., Clough, R.W., Dewhirst, M.W., Mueller-Klieser, W., Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 51 (2001), 349–353.
197. Schwickert, G., Walenta, S., Sundfor, K., Rofstad, E.K., Mueller-Klieser, W., Correlation of high lactate levels in human cervical cancer with incidence of metastasis. Cancer Res. 55 (1995), 4757–4759.
198. Walenta, S., Salameh, A., Lyng, H., Evensen, J.F., Mitze, M., Rofstad, E.K., Mueller-Klieser, W., Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am. J. Pathol. 150 (1997), 409–415.
199. Walenta, S., Snyder, S., Haroon, Z.A., Braun, R.D., Amin, K., Brizel, D., Mueller-Klieser, W., Chance, B., Dewhirst, M.W., Tissue gradients of energy metabolites mirror oxygen tension gradients in a rat mammary carcinoma model. Int. J. Radiat. Oncol. Biol. Phys. 51 (2001), 840–848.
200. Walenta, S., Chau, T.V., Schroeder, T., Lehr, H.A., Kunz-Schughart, L.A., Fuerst, A., Mueller-Klieser, W., Metabolic classification of human rectal adenocarcinomas: a novel guideline for clinical oncologists?. J. Cancer Res. Clin. Oncol. 129 (2003), 321–326.
201. Walenta, S., Schroeder, T., Mueller-Klieser, W., Lactate in solid malignant tumors: potential basis of a metabolic classification in clinical oncology. Curr. Med. Chem. 11 (2004), 2195–2204.
202. Walenta, S., Mueller-Klieser, W.F., Lactate: mirror and motor of tumor malignancy. Semin. Radiat. Oncol. 14 (2004), 267–274.
203. Corbet, C., Draoui, N., Polet, F., Pinto, A., Drozak, X., Riant, O., Feron, O., The SIRT1/HIF2alpha axis drives reductive glutamine metabolism under chronic acidosis and alters tumor response to therapy. Cancer Res. 74 (2014), 5507–5519.
204. Semenza, G.L., Tumor metabolism: cancer cells give and take lactate. J. Clin. Invest. 118 (2008), 3835–3837.
205. Feron, O., Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother. Oncol. 92 (2009), 329–333.
206. Galeffi, F., Turner, D.A., Exploiting metabolic differences in glioma therapy. Curr. Drug Discov. Technol. 9 (2012), 280–293.
207. De Saedeleer, C.J., Copetti, T., Porporato, P.E., Verrax, J., Feron, O., Sonveaux, P., Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One, 7, 2012, e46571.
208. De Saedeleer, C.J., Porporato, P.E., Copetti, T., Perez-Escuredo, J., Payen, V.L., Brisson, L., Feron, O., Sonveaux, P., Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration. Oncogene 33 (2014), 4060–4068.
209. Lu, H., Forbes, R.A., Verma, A., Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem. 277 (2002), 23111–23115.
210. Lu, H., Dalgard, C.L., Mohyeldin, A., McFate, T., Tait, A.S., Verma, A., Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J. Biol. Chem. 280 (2005), 41928–41939.
211. Semenza, G.L., Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29 (2010), 625–634.
212. Izumi, H., Takahashi, M., Uramoto, H., Nakayama, Y., Oyama, T., Wang, K.Y., Sasaguri, Y., Nishizawa, S., Kohno, K., Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells. Cancer Sci. 102 (2011), 1007–1013.
213. Sonveaux, P., Copetti, T., De Saedeleer, C.J., Végran, F., Verrax, J., Kennedy, K.M., Moon, E.J., Dhup, S., Danhier, P., Frérart, F., Gallez, B., Ribeiro, A., Michiels, C., Dewhirst, M.W., Feron, O., Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One, 7, 2012, e33418.
214. Végran, F., Boidot, R., Michiels, C., Sonveaux, P., Feron, O., Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 71 (2011), 2550–2560.
215. Végran, F., Seront, E., Sonveaux, P., Feron, O., Lactate-induced IL-8 pathway in endothelial cells—response. Cancer Res. 72 (2012), 1903–1904.
216. Porporato, P.E., Payen, V.L., De Saedeleer, C.J., Préat, V., Thissen, J.P., Feron, O., Sonveaux, P., Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis 15 (2012), 581–592.
217. Pavlides, S., Whitaker-Menezes, D., Castello-Cros, R., Flomenberg, N., Witkiewicz, A.K., Frank, P.G., Casimiro, M.C., Wang, C., Fortina, P., Addya, S., Pestell, R.G., Martinez-Outschoorn, U.E., Sotgia, F., Lisanti, M.P., The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8 (2009), 3984–4001.
218. Whitaker-Menezes, D., Martinez-Outschoorn, U.E., Lin, Z., Ertel, A., Flomenberg, N., Witkiewicz, A.K., Birbe, R.C., Howell, A., Pavlides, S., Gandara, R., Pestell, R.G., Sotgia, F., Philp, N.J., Lisanti, M.P., Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 10 (2011), 1772–1783.
219. Martinez-Outschoorn, U.E., Curry, J.M., Ko, Y.H., Lin, Z., Tuluc, M., Cognetti, D., Birbe, R.C., Pribitkin, E., Bombonati, A., Pestell, R.G., Howell, A., Sotgia, F., Lisanti, M.P., Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFkappaB target stromal MCT4. Cell Cycle 12 (2013), 2580–2597.
220. Sotgia, F., Whitaker-Menezes, D., Martinez-Outschoorn, U.E., Flomenberg, N., Birbe, R.C., Witkiewicz, A.K., Howell, A., Philp, N.J., Pestell, R.G., Lisanti, M.P., Mitochondrial metabolism in cancer metastasis: visualizing tumor cell mitochondria and the “reverse Warburg effect” in positive lymph node tissue. Cell Cycle 11 (2012), 1445–1454.
221. Whitaker-Menezes, D., Martinez-Outschoorn, U.E., Flomenberg, N., Birbe, R.C., Witkiewicz, A.K., Howell, A., Pavlides, S., Tsirigos, A., Ertel, A., Pestell, R.G., Broda, P., Minetti, C., Lisanti, M.P., Sotgia, F., Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle 10 (2011), 4047–4064.
222. Witkiewicz, A.K., Dasgupta, A., Sotgia, F., Mercier, I., Pestell, R.G., Sabel, M., Kleer, C.G., Brody, J.R., Lisanti, M.P., An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am. J. Pathol. 174 (2009), 2023–2034.
223. Witkiewicz, A.K., Whitaker-Menezes, D., Dasgupta, A., Philp, N.J., Lin, Z., Gandara, R., Sneddon, S., Martinez-Outschoorn, U.E., Sotgia, F., Lisanti, M.P., Using the “reverse Warburg effect” to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle 11 (2012), 1108–1117.
224. Curry, J.M., Tuluc, M., Whitaker-Menezes, D., Ames, J.A., Anantharaman, A., Butera, A., Leiby, B., Cognetti, D.M., Sotgia, F., Lisanti, M.P., Martinez-Outschoorn, U.E., Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle 12 (2013), 1371–1384.
225. Giatromanolaki, A., Koukourakis, M.I., Koutsopoulos, A., Mendrinos, S., Sivridis, E., The metabolic interactions between tumor cells and tumor-associated stroma (TAS) in prostatic cancer. Cancer Biol. Ther. 13 (2012), 1284–1289.
226. Koukourakis, M.I., Giatromanolaki, A., Bougioukas, G., Sivridis, E., Lung cancer: a comparative study of metabolism related protein expression in cancer cells and tumor associated stroma. Cancer Biol. Ther. 6 (2007), 1476–1479.
227. Hirt, C., Papadimitropoulos, A., Mele, V., Muraro, M.G., Mengus, C., Iezzi, G., Terracciano, L., Martin, I., Spagnoli, G.C., “In vitro” 3D models of tumor-immune system interaction. Adv. Drug Deliv. Rev. 79-80 (2014), 145–154.
228. Singer, K., Gottfried, E., Kreutz, M., Mackensen, A., Suppression of T-cell responses by tumor metabolites. Cancer Immunol. Immunother. 60 (2011), 425–431.
229. Puig-Kroger, A., Pello, O.M., Selgas, R., Criado, G., Bajo, M.A., Sanchez-Tomero, J.A., Alvarez, V., del Peso, G., Sanchez-Mateos, P., Holmes, C., Faict, D., Lopez-Cabrera, M., Madrenas, J., Corbi, A.L., Peritoneal dialysis solutions inhibit the differentiation and maturation of human monocyte-derived dendritic cells: effect of lactate and glucose-degradation products. J. Leukoc. Biol. 73 (2003), 482–492.
230. Nasi, A., Fekete, T., Krishnamurthy, A., Snowden, S., Rajnavolgyi, E., Catrina, A.I., Wheelock, C.E., Vivar, N., Rethi, B., Dendritic cell reprogramming by endogenously produced lactic acid. J. Immunol. 191 (2013), 3090–3099.
231. Murray, C.M., Hutchinson, R., Bantick, J.R., Belfield, G.P., Benjamin, A.D., Brazma, D., Bundick, R.V., Cook, I.D., Craggs, R.I., Edwards, S., Evans, L.R., Harrison, R., Holness, E., Jackson, A.P., Jackson, C.G., Kingston, L.P., Perry, M.W., Ross, A.R., Rugman, P.A., Sidhu, S.S., Sullivan, M., Taylor-Fishwick, D.A., Walker, P.C., Whitehead, Y.M., Wilkinson, D.J., Wright, A., Donald, D.K., Monocarboxylate transporter MCT1 is a target for immunosuppression. Nat. Chem. Biol. 1 (2005), 371–376.
232. Bueno, V., Binet, I., Steger, U., Bundick, R., Ferguson, D., Murray, C., Donald, D., Wood, K., The specific monocarboxylate transporter (MCT1) inhibitor, AR-C117977, a novel immunosuppressant, prolongs allograft survival in the mouse. Transplantation 84 (2007), 1204–1207.
233. Ekberg, H., Qi, Z., Pahlman, C., Veress, B., Bundick, R.V., Craggs, R.I., Holness, E., Edwards, S., Murray, C.M., Ferguson, D., Kerry, P.J., Wilson, E., Donald, D.K., 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 (2007), 1191–1199.
234. Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., Renner, K., Timischl, B., Mackensen, A., Kunz-Schughart, L., Andreesen, R., Krause, S.W., Kreutz, M., Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109 (2007), 3812–3819.
235. Mendler, A.N., Hu, B., Prinz, P.U., Kreutz, M., Gottfried, E., Noessner, E., Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int. J. Cancer 131 (2012), 633–640.
236. Husain, Z., Huang, Y., Seth, P., Sukhatme, V.P., Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J. Immunol. 191 (2013), 1486–1495.
237. Colegio, O.R., Chu, N.Q., Szabo, A.L., Chu, T., Rhebergen, A.M., Jairam, V., Cyrus, N., Brokowski, C.E., Eisenbarth, S.C., Phillips, G.M., Cline, G.W., Phillips, A.J., Medzhitov, R., Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513 (2014), 559–563.
238. Brooks, G.A., Lactate shuttles in nature. Biochem. Soc. Trans. 30 (2002), 258–264.
239. Gladden, L.B., Lactate metabolism: a new paradigm for the third millennium. J. Physiol. 558 (2004), 5–30.
240. Brooks, G.A., The lactate shuttle during exercise and recovery. Med. Sci. Sports Exerc. 18 (1986), 360–368.
241. Mita, M., Hall, P.F., Metabolism of round spermatids from rats: lactate as the preferred substrate. Biol. Reprod. 26 (1982), 445–455.
242. Mosconi, L., Glucose metabolism in normal aging and Alzheimer's disease: methodological and physiological considerations for PET studies. Clin. Transl. Imaging, 1, 2013, 10.1007/s40336-013-0026-y.
243. Sapolsky, R.M., Neuroprotective gene therapy against acute neurological insults. Nat. Rev. Neurosci. 4 (2003), 61–69.
244. Demetrius, L.A., Magistretti, P.J., Pellerin, L., Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect. Front. Physiol., 5, 2014, 522.
245. Mathupala, S.P., Parajuli, P., Sloan, A.E., Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery 55 (2004), 1410–1419.
246. Gallagher, S.M., Castorino, J.J., Wang, D., Philp, N.J., 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 (2007), 4182–4189.
247. Doherty, J.R., Yang, C., Scott, K.E., Cameron, M.D., Fallahi, M., Li, W., Hall, M.A., Amelio, A.L., Mishra, J.K., Li, F., Tortosa, M., Genau, H.M., Rounbehler, R.J., Lu, Y., Dang, C.V., Kumar, K.G., Butler, A.A., Bannister, T.D., Hooper, A.T., Unsal-Kacmaz, K., Roush, W.R., Cleveland, J.L., Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis. Cancer Res. 74 (2014), 908–920.
248. Le Floch, R., Chiche, J., Marchiq, I., Naiken, T., Ilk, K., Murray, C.M., Critchlow, S.E., Roux, D., Simon, M.P., 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 (2011), 16663–16668.