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Including the mitochondrial metabolism of l-lactate in cancer metabolic reprogramming

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Abstract

Glucose avidity, high glycolysis and l-lactate production, regardless of oxygen availability, are the main traits of cancer metabolic reprogramming. The idea that mitochondria are dysfunctional in cancer, thus causing a glycolysis increase for ATP production and l-lactate accumulation as a dead-end product of glucose catabolism, has oriented cancer research for many years. However, it was shown that mitochondrial metabolism is essential for cancer cell proliferation and tumorigenesis and that l-lactate is a fundamental energy substrate with tumor growth-promoting and signaling capabilities. Nevertheless, the known ability of mitochondria to take up and oxidize l-lactate has remained ignored by cancer research. Beginning with a brief overview of the metabolic changes occurring in cancer, we review the present knowledge of l-lactate formation, transport, and intracellular oxidation and underline the possible role of l-lactate metabolism as energetic, signaling and anabolic support for cancer cell proliferation. These unexplored aspects of cancer biochemistry might be exploited for therapeutic benefit.

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Abbreviations

F2,6BP:

Fructose-2,6-bisphosphate

GLN:

Glutamine

GLU:

Glucose

GLUT:

Glucose transporter

G6P:

Glucose-6-phosphate

HK:

Hexokinase

l-LAC:

l-Lactate

l-LDHA:

l-Lactate dehydrogenase A

cl-LDH:

Cytosolic l-lactate dehydrogenase

ml-LDH:

Mitochondrial l-lactate dehydrogenase

MCT:

Monocarboxylate carrier

MIM:

Mitochondrial inner membrane

MOM:

Mitochondrial outer membrane

MPC:

Mitochondrial pyruvate carrier

mRC:

Mitochondrial respiratory chain

OXPHOS:

Oxidative phosphorylation

PDH:

Pyruvate dehydrogenase

PDK:

Pyruvate dehydrogenase kinase

PFK:

6-Phosphofructo-1-kinase

PFKFB:

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase

PK:

Pyruvate kinase

PKM2:

Pyruvate kinase isoform M2

PP pathway:

Pentose phosphate pathway

PYR:

Pyruvate

RLM:

Rat liver mitochondria

ROS:

Reactive oxygen species

VDAC:

Voltage-dependent anion channel

References

  1. Griguer CE, Oliva CR (2011) Bioenergetics pathways and therapeutic resistance in gliomas: emerging role of mitochondria. Curr Pharm Des 17:2421–2427

    Article  PubMed  CAS  Google Scholar 

  2. Ippolito L, Marini A, Cavallini L et al (2016) Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells. Oncotarget 7:61890–61904

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gogvadze V, Zhivotovsky B, Orrenius S (2010) The Warburg effect and mitochondrial stability in cancer cells. Mol Asp Med 31:60–74

    Article  CAS  Google Scholar 

  4. Obre E, Rossignol R (2015) Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodelling, signaling and bioenergetic therapy. Int J Biochem Cell Biol 59:167–181

    Article  PubMed  CAS  Google Scholar 

  5. Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP (2017) Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14:11–31

    Article  PubMed  CAS  Google Scholar 

  6. Brooks GA (2016) Energy flux, lactate shuttling, mitochondrial dynamics, and hypoxia. Adv Exp Med Biol 903:439–455

    Article  PubMed  CAS  Google Scholar 

  7. Passarella S, de Bari L, Valenti D et al (2008) Mitochondria and l-lactate metabolism. FEBS Lett 582:3569–3576

    Article  PubMed  CAS  Google Scholar 

  8. San-Millán I, Brooks GA (2017) Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg effect. Carcinogenesis 38:119–133

    PubMed  Google Scholar 

  9. Brand A, Singer K, Koehl GE et al (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24:657–671

    Article  PubMed  CAS  Google Scholar 

  10. de Bari L, Valenti D, Atlante A, Passarella S (2010) l-Lactate generates hydrogen peroxide in purified rat liver mitochondria due to the putative l-lactate oxidase localized in the intermembrane space. FEBS Lett 584:2285–2290

    Article  PubMed  CAS  Google Scholar 

  11. Guppy M, Leedman P, Zu X, Russell V (2002) Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J 364:309–315

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Moreno-Sánchez R, Marín-Hernández A, Saavedra E et al (2014) Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism. Int J Biochem Cell Biol 50:10–23

    Article  PubMed  CAS  Google Scholar 

  13. Viale A, Corti D, Draetta GF (2015) Tumors and mitochondrial respiration: a neglected connection. Cancer Res 75:3687–3691

    Article  CAS  Google Scholar 

  14. Galina A (2014) Mitochondria: 3-bromopyruvate vs. mitochondria? A small molecule that attacks tumors by targeting their bioenergetic diversity. Int J Biochem Cell Biol 54:266–271

    Article  PubMed  CAS  Google Scholar 

  15. Valenti D, Vacca RA, de Bari L (2015) 3-Bromopyruvate induces rapid human prostate cancer cell death by affecting cell energy metabolism, GSH pool and the glyoxalase system. J Bioenerg Biomembr 47:493–506

    Article  PubMed  CAS  Google Scholar 

  16. Kee HJ, Cheong JH (2014) Tumor bioenergetics: an emerging avenue for cancer metabolism targeted therapy. BMB Rep 47:158–166

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685–698

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Jose C, Melser S, Benard G, Rossignol R (2013) Mitoplasticity: adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis. Antioxid Redox Signal 18:808–849

    Article  PubMed  CAS  Google Scholar 

  19. Wood IS, Trayhurn P (2003) Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 89:3–9

    Article  PubMed  CAS  Google Scholar 

  20. Airley R, Loncaster J, Davidson S et al (2001) Glucose transporter Glut-1 expression correlates with tumor hypoxia and predicts metastasis—free survival in advanced carcinoma of the cervix. Cancer Res 7:928–934

    CAS  Google Scholar 

  21. Szablewski L (2013) Expression of glucose transporters in cancers. Biochim Biophys Acta 1835:164–169

    PubMed  CAS  Google Scholar 

  22. Zhao F, Ming J, Zhou Y, Fan L (2016) Inhibition of Glut1 by WZB117 sensitizes radioresistant breast cancer cells to irradiation. Cancer Chemother Pharmacol 77:963–972

    Article  PubMed  CAS  Google Scholar 

  23. Liu Y, Cao Y, Zhang W et al (2012) A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther 11:1672–1682

    Article  PubMed  CAS  Google Scholar 

  24. Liu TQ, Fan J, Zhou L, Zheng S-S (2011) Effects of suppressing glucose transporter-1 by the antisense oligodeoxynucleotide on the growth of human hepatocellular carcinoma cells. Hepatobiliary Pancreat Dis Int 10:72–77

    Article  PubMed  Google Scholar 

  25. Rastogi S, Banerjee S, Chellappan S, Simon GR (2007) Glut-1 antibodies induce growth arrest and apoptosis in human cancer cell lines. Cancer Lett 257:244–251

    Article  PubMed  CAS  Google Scholar 

  26. Martel F, Guedes M, Keating E (2016) Effect of polyphenols on glucose and lactate transport by breast cancer cells. Breast Cancer Res Treat 157:1–11

    Article  PubMed  CAS  Google Scholar 

  27. Gwak H, Haegeman G, Tsang BK, Song YS (2015) Cancer-specific interruption of glucose metabolism by resveratrol is mediated through inhibition of Akt/GLUT1 axis in ovarian cancer cells. Mol Carcinog 54:1529–1540

    Article  PubMed  CAS  Google Scholar 

  28. Mathupala SP, Ko YH, Pedersen PL (2006) Hexokinase II: cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25:4777–4786

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Mathupala SP, Ko YH, Pedersen PL (2009) Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol 19:17–24

    Article  PubMed  CAS  Google Scholar 

  30. Pedersen PL (2008) Voltage dependent anion channels (VDACs): a brief introduction with a focus on the outer mitochondrial compartment’s roles together with hexokinase-2 in the “Warburg effect” in cancer. J Bioenerg Biomembr 40:123–126

    Article  PubMed  CAS  Google Scholar 

  31. Marín-Hernández A, Rodríguez-Enríquez S, Vital-González PA et al (2006) Determining and understanding the control of glycolysis in fast-growth tumor cells: flux control by an over-expressed but strongly product-inhibited hexokinase. FEBS J 273:1975–1988

    Article  PubMed  CAS  Google Scholar 

  32. Liu VM, Vander Heiden MG (2015) The role of pyruvate kinase M2 in cancer metabolism. Brain Pathol 25:781–783

    Article  PubMed  CAS  Google Scholar 

  33. Dong G, Mao Q, Xia W et al (2016) PKM2 and cancer: the function of PKM2 beyond glycolysis. Oncol Lett 11:1980–1986

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Vander Heiden MG, Lunt SY, Dayton TL et al (2011) Metabolic pathway alterations that support cell proliferation. Cold Spring Harb Symp Quant Biol 76:325–334

    Article  PubMed  CAS  Google Scholar 

  35. DeBerardinis RJ, Cheng T (2010) Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:313–324

    Article  PubMed  CAS  Google Scholar 

  36. Locasale JW (2012) The consequences of enhanced cell-autonomous glucose metabolism. Trends Endocrinol Metab 23:545–551

    Article  PubMed  CAS  Google Scholar 

  37. Board M, Humm S, Newsholme EA (1990) Maximum activities of key enzymes of glycolysis, glutaminolysis, pentose phosphate pathway and tricarboxylic acid cycle in normal, neoplastic and suppressed cells. Biochem J 265:503–509

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Mc Dermott EW, Barron ET, Smyth PP, O’Higgins NJ (1990) Premorphological metabolic changes in human breast carcinogenesis. Br J Surg 77:1179–1182

    Article  CAS  Google Scholar 

  39. Zaccarin M, Bosello-Travain V, Di Paolo ML et al (2017) Redox status in a model of cancer stem cells. Arch Biochem Biophys 617:120–128

    Article  PubMed  CAS  Google Scholar 

  40. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Chandel NS (2014) Mitochondria as signaling organelles. BMC Biol 12:34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Arco AD, Satrùstegui J (2005) New mitochondrial carriers: an overview. Cell Mol Life Sci 62:2204–2227

    Article  PubMed  CAS  Google Scholar 

  43. Ozkaya AB, Ak H, Atay S, Aydin HH (2015) Targeting mitochondrial citrate transport in breast cancer cell lines. Anticancer Agents Med Chem 15:374–381

    Article  PubMed  CAS  Google Scholar 

  44. Senyilmaz D, Teleman AA (2015) Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep 7:41

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. DeBerardinis RJ, Mancuso A, Daikhin E et al (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104:19345–19350

    Article  PubMed  PubMed Central  Google Scholar 

  46. Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G (2015) Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab 21:805–821

    Article  PubMed  CAS  Google Scholar 

  47. Galluzzi L, Kepp O, Kroemer G (2012) Mitochondria: master regulators of danger signalling. Nat Rev 13:780–788

    Article  CAS  Google Scholar 

  48. Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947

    Article  PubMed  CAS  Google Scholar 

  49. Schumacker PT (2015) Reactive oxygen species in cancer: a dance with the devil. Cancer Cell 27:156–157

    Article  PubMed  CAS  Google Scholar 

  50. Sabharwal SS, Schumacker PT (2014) Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer 14:709–721

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Okon IS, Zou MH (2015) Mitochondrial ROS and cancer drug resistance: implications for therapy. Pharmacol Res 100:170–174

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Zu XL, Guppy M (2004) Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun 313:459–465

    Article  PubMed  CAS  Google Scholar 

  53. Weinberg SE, Chandel NS (2015) Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol 11:9–15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Adeva-Andany M, López-Ojén M, Funcasta-Calderón R et al (2014) Comprehensive review on lactate metabolism in human health. Mitochondrion 17:76–100

    Article  PubMed  CAS  Google Scholar 

  56. Proia P, Di Liegro CM, Schiera G, Fricano A, Di Liegro I (2016) Lactate as a metabolite and a regulator in the central nervous system. Int J Mol Sci 17:76–100

    Article  CAS  Google Scholar 

  57. Schurr A (2006) Lactate: the ultimate cerebral oxidative energy substrate? J Cereb Blood Flow Metab 26:142–152

    Article  PubMed  CAS  Google Scholar 

  58. Quistorff B, Grunnet N (2011) The isoenzyme pattern of LDH does not play a physiological role; except perhaps during fast transitions in energy metabolism. Aging (Albany NY) 3:457–460

    Article  CAS  Google Scholar 

  59. Compan V, Pierredon S, Vanderperre B et al (2015) Monitoring mitochondrial pyruvate carrier activity in real time using a BRET-based biosensor: investigation of the Warburg effect. Mol Cell 59:491–501

    Article  PubMed  CAS  Google Scholar 

  60. Hall MM, Rajasekaran S, Thomsen TW, Peterson AR (2016) Lactate: friend or foe. PM R 8:S8–S15

    Article  PubMed  Google Scholar 

  61. Kemppainen J, Fujimoto T, Kalliokoski KK et al (2002) Myocardial and skeletal muscle glucose uptake during exercise in humans. J Physiol 542:403–412

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Chatham JC (2002) Lactate: the forgotten fuel! J Physiol 542:333

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell 134:703–707

    Article  PubMed  CAS  Google Scholar 

  64. Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N et al (2011) Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle 10:4047–4064

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Sacktor B, Packerl L, Estabrookp R (1959) Respiratory activity in brain mitochondria. Arch Biochem Biophys 80:68–71

    Article  CAS  Google Scholar 

  66. Cruz RS, de Aguiar RA, Turnes T et al (2012) Intracellular shuttle: the lactate aerobic metabolism. Sci World J 2012:420984. https://doi.org/10.1100/2012/420984

    Article  CAS  Google Scholar 

  67. Blanco A, Zinkham WH (1963) Lactate dehydrogenases in human testes. Science 139:601–602

    Article  PubMed  CAS  Google Scholar 

  68. Goldberg E (1963) Lactic and malic dehydrogenases in human spermatozoa. Science 139:602–603

    Article  PubMed  CAS  Google Scholar 

  69. Swegen A, Curry BJ, Gibb Z et al (2015) Investigation of the stallion sperm proteome by mass spectrometry. Reproduction (Cambridge) 149:235–244

    Article  CAS  Google Scholar 

  70. Laughlin MR, Taylor J, Chesnick AS, DeGroot M, Balaban RS (1993) Pyruvate and lactate metabolism in the in vivo dog heart. Am J Physiol 264:H2068–H2079

    PubMed  CAS  Google Scholar 

  71. de Bari L, Atlante A, Valenti D, Passarella S (2004) Partial reconstruction of in vitro gluconeogenesis arising from mitochondrial l-lactate uptake/metabolism and oxaloacetate export via novel l-lactate translocators. Biochem J 380:231–242

    Article  PubMed  PubMed Central  Google Scholar 

  72. Pizzuto R, Paventi G, Porcile C et al (2012) l-Lactate metabolism in HEP G2 cell mitochondria due to the l-lactate dehydrogenase determines the occurrence of the lactate/pyruvate shuttle and the appearance of oxaloacetate, malate and citrate outside mitochondria. Biochim Biophys Acta 1817:1679–1690

    Article  PubMed  CAS  Google Scholar 

  73. Lemire J, Mailloux RJ, Appanna VD (2008) Mitochondrial lactate dehydrogenase is involved in oxidative-energy metabolism in human astrocytoma cells (CCF-STTG1). PLoS One 3:e1550. https://doi.org/10.1371/journal.pone.0001550

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Chatham JC, Des Rosiers C, Forder JR (2001) Evidence of separate pathways for lactate uptake and release by the perfused rat heart. Am J Physiol Endocrinol Metab 281:E794–E802

    Article  PubMed  CAS  Google Scholar 

  75. Passarella S, Paventi G, Pizzuto R (2014) The mitochondrial l-lactate dehydrogenase affair. Front Neurosci 8:407

    Article  PubMed  PubMed Central  Google Scholar 

  76. Kane DA (2014) Lactate oxidation at the mitochondria: a lactate–malate–aspartate shuttle at work. Front Neurosci 8:366

    Article  PubMed  PubMed Central  Google Scholar 

  77. Halestrap AP (1975) The mitochondrial pyruvate carrier. Kinetics and specificity for substrates and inhibitors. Biochem J 148:85–96

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Gallina FG, Gerez de Burgos NM, Burgos C, Coronel CE, Blanco A (1994) The lactate/pyruvate shuttle in spermatozoa: operation in vitro. Arch Biochem Biophys 308:515–519

    Article  PubMed  Google Scholar 

  79. Chiaretti B, Casciaro A, Minotti G, Eboli ML, Galeotti T (1979) Quantitative evaluation of the activity of the malate-aspartate shuttle in Ehrlich ascites tumor cells. Cancer Res 39:2195–2199

    PubMed  CAS  Google Scholar 

  80. Chiarugi A, Dölle C, Felici R, Ziegler M (2012) The NAD metabolome—a key determinant of cancer cell biology. Nat Rev Cancer 12:741–752

    Article  PubMed  CAS  Google Scholar 

  81. Nikiforov A, Kulikova V, Ziegler M (2015) The human NAD metabolome: functions, metabolism and compartmentalization. Crit Rev Biochem Mol Biol 50:284–297

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Zelenka J, Dvořák A, Alán L (2015) l-Lactate protects skin fibroblasts against aging-associated mitochondrial dysfunction via mitohormesis. Oxid Med Cell Longev 2015:351698

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Rooney K, Trayhurn P (2011) Lactate and the GPR81 receptor in metabolic regulation: implications for adipose tissue function and fatty acid utilisation by muscle during exercise. Br J Nutr 106:1310–1316

    Article  PubMed  CAS  Google Scholar 

  84. Morland C, Lauritzen KH, Puchades M et al (2015) The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: expression and action in brain. J Neurosci Res 93:1045–1055

    Article  PubMed  CAS  Google Scholar 

  85. Yang J, Ruchti E, Petit JM et al (2014) Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc Natl Acad Sci 111:12228–12233

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Thomas AP, Halestrap AP (1981) The role of mitochondrial pyruvate transport in the stimulation by glucagon and phenylephrine of gluconeogenesis from l-lactate in isolated rat hepatocytes. Biochem J 198:551–560

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Bonuccelli G, Tsirigos A, Whitaker-Menezes D et al (2010) Ketones and lactate “fuel” tumor growth and metastasis: evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 9:3506–3514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Sonveaux P, Végran F, Schroeder T et al (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Investig 118:3930–3942

    PubMed  PubMed Central  CAS  Google Scholar 

  89. de Bari L, Chieppa G, Marra E, Passarella S (2010) l-Lactate metabolism can occur in normal and cancer prostate cells via the novel mitochondrial l-lactate dehydrogenase. Int J Oncol 37:1607–1620

    PubMed  Google Scholar 

  90. Chen YJ, Mahieu NG, Huang X et al (2016) Lactate metabolism is associated with mammalian mitochondria. Nat Chem Biol 12:937–943

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23:27–47

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Sellers K, Fox MP, Bousamra M et al (2015) Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J Clin Investig 125:687–698

    Article  PubMed  PubMed Central  Google Scholar 

  93. Hensley CT, Faubert B, Yuan Q et al (2016) Metabolic heterogeneity in human lung tumors. Cell 164:681–694

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Faubert B, Li KY, Cai L et al (2017) Lactate metabolism in human lung tumors. Cell 171:358–371

    Article  PubMed  CAS  Google Scholar 

  95. Hui S, Ghergurovich JM, Morscher RJ et al (2017) Glucose feeds the TCA cycle via circulating lactate. Nature 551:115–118

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Lunt SY, Vander Heiden MG (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 27:441–464

    Article  PubMed  CAS  Google Scholar 

  97. Pérez-Escuredo J, Dadhich RK, Dhup S et al (2016) Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle 15:72–83

    Article  PubMed  CAS  Google Scholar 

  98. Girgis H, Masui O, White NM et al (2014) Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma. Mol Cancer 13:101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Lee M, Yoon JH (2015) Metabolic interplay between glycolysis and mitochondrial oxidation: the reverse Warburg effect and its therapeutic implication. World J Biol Chem 6:148–161

    Article  PubMed  PubMed Central  Google Scholar 

  100. Martinez-Outschoorn UE, Pavlides S, Howell A et al (2011) Stromal–epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol 43:1045–1051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    Article  PubMed  CAS  Google Scholar 

  102. Ho PC, Bihuniak JD, Macintyre AN et al (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:1217–1228

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Chang CH, Qiu J, O’Sullivan D et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Li F, Wang Y, Zeller KI, Potter JJ et al (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25:6225–6234

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Lezi E, Swerdlow RH (2016) Lactate’s effect on human neuroblastoma cell bioenergetic fluxes. Biochem Pharmacol 99:88–100

    Article  CAS  Google Scholar 

  106. Jose C, Bellance N, Rossignol R (2011) Choosing between glycolysis and oxidative phosphorylation: a tumor’s dilemma? Biochim Biophys Acta 1807:552–561

    Article  PubMed  CAS  Google Scholar 

  107. Chen X, Qian Y, Wu S (2015) The Warburg effect: evolving interpretations of an established concept. Free Radic Biol Med 79:253–263

    Article  PubMed  CAS  Google Scholar 

  108. Marín-Hernández A, Gallardo-Pérez JC, Ralph SJ, Rodríguez-Enríquez S, Moreno-Sánchez R (2009) HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem 9:1084–1101

    Article  PubMed  Google Scholar 

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  1. Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari (IBIOM)-CNR, Via G. Amendola 165/A, 70126, Bari, Italy

    Lidia de Bari & Anna Atlante

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  1. Lidia de Bari
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  2. Anna Atlante
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Correspondence to Lidia de Bari.

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de Bari, L., Atlante, A. Including the mitochondrial metabolism of l-lactate in cancer metabolic reprogramming. Cell. Mol. Life Sci. 75, 2763–2776 (2018). https://doi.org/10.1007/s00018-018-2831-y

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