title: Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited.
abstract: BACKGROUND
  Cancer cells simultaneously exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen, a phenomenon known as the Warburg effect. The maintenance of this mixed metabolic phenotype is seemingly counterintuitive given that aerobic glycolysis is far less efficient in terms of ATP yield per moles of glucose than mitochondrial respiration.
  
  
  RESULTS
  Here, we resolve this apparent contradiction by expanding the notion of metabolic efficiency. We study a reduced flux balance model of ATP production that is constrained by the glucose uptake capacity and by the solvent capacity of the cell's cytoplasm, the latter quantifying the maximum amount of macromolecules that can occupy the intracellular space. At low glucose uptake rates we find that mitochondrial respiration is indeed the most efficient pathway for ATP generation. Above a threshold glucose uptake rate, however, a gradual activation of aerobic glycolysis and slight decrease of mitochondrial respiration results in the highest rate of ATP production.
  
  
  CONCLUSIONS
  Our analyses indicate that the Warburg effect is a favorable catabolic state for all rapidly proliferating mammalian cells with high glucose uptake capacity. It arises because while aerobic glycolysis is less efficient than mitochondrial respiration in terms of ATP yield per glucose uptake, it is more efficient in terms of the required solvent capacity. These results may have direct relevance to chemotherapeutic strategies attempting to target cancer metabolism.
authors.affiliation: Department of Radiation Oncology, The Cancer Institute of New Jersey and UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08963, USA. vazqueal@umdnj.edu
authors.forename: Alexei
authors.initials: A
authors.lastname: Vazquez
authors.forename: Jiangxia
authors.initials: J
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zoltán N
authors.initials: ZN
authors.lastname: Oltvai
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D004734:Energy Metabolism; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007773:Lactates / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D010101:Oxygen Consumption; D010641:Phenotype; D049490:Systems Biology
chemical_list: D007773:Lactates; D000255:Adenosine Triphosphate; D005947:Glucose
references.citation: Mol Cancer. 2009 Jul 31;8:54
references.pmid: 19646236
references.citation: J Appl Physiol (1985). 1992 Nov;73(5):2004-10
references.pmid: 1474078
references.citation: Cancer Res. 1963 Aug;23:995-1002
references.pmid: 14050771
references.citation: J Cell Sci. 1971 May;8(3):701-8
references.pmid: 4253330
references.citation: Methods Mol Biol. 2002;197:107-17
references.pmid: 12013789
references.citation: Cell Metab. 2008 Jan;7(1):11-20
references.pmid: 18177721
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12663-8
references.pmid: 17652176
references.citation: J Cell Biol. 2006 Dec 18;175(6):913-23
references.pmid: 17158952
references.citation: Proc Natl Acad Sci U S A. 1989 Mar;86(5):1583-7
references.pmid: 2922400
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5992-7
references.pmid: 15840712
references.citation: Biosci Rep. 1985 May;5(5):393-400
references.pmid: 3896338
references.citation: Ann N Y Acad Sci. 2005 May;1042:109-22
references.pmid: 15965052
references.citation: J Biosci Bioeng. 2003;95(4):317-27
references.pmid: 16233414
references.citation: Proc Natl Acad Sci U S A. 1983 Jan;80(2):622-6
references.pmid: 6572909
references.citation: J Cell Biol. 1966 Jun;29(3):507-23
references.pmid: 5962940
references.citation: Science. 2006 Jun 16;312(5780):1650-3
references.pmid: 16728594
references.citation: Clin Physiol Funct Imaging. 2002 May;22(3):226-32
references.pmid: 12076351
references.citation: Nat Rev Cancer. 2004 Nov;4(11):891-9
references.pmid: 15516961
references.citation: Nature. 2008 Mar 13;452(7184):230-3
references.pmid: 18337823
references.citation: Cytotechnology. 1989 May;2(2):85-94
references.pmid: 22358620
references.citation: Leukemia. 2003 Aug;17(8):1437-47
references.pmid: 12886229
references.citation: Nature. 1999 Jul 29;400(6743):464-8
references.pmid: 10440377
references.citation: Microb Cell Fact. 2005 Nov 03;4:30
references.pmid: 16269086
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: BMC Syst Biol. 2008 Jan 23;2:7
references.pmid: 18215292
references.citation: Trends Biochem Sci. 2001 Oct;26(10):597-604
references.pmid: 11590012
references.citation: Biochim Biophys Acta. 2003 Jul 30;1649(2):127-39
references.pmid: 12878031
references.citation: Br J Cancer. 2008 Oct 7;99(7):989-94
references.pmid: 18766181
references.citation: Interact Cardiovasc Thorac Surg. 2008 Dec;7(6):954-8
references.pmid: 18685121
references.citation: In Vitro. 1974 Nov-Dec;10(5-6):295-305
references.pmid: 4616003
references.citation: Curr Opin Cell Biol. 2007 Apr;19(2):223-9
references.pmid: 17303407
references.citation: Cancer Invest. 2002;20(4):557-69
references.pmid: 12094550
references.citation: Cancer Cell. 2008 Jun;13(6):472-82
references.pmid: 18538731
references.citation: Biochem J. 1973 May;134(1):197-208
references.pmid: 4269207
references.citation: Mol Biol Cell. 2007 Apr;18(4):1437-46
references.pmid: 17301289
references.citation: Am J Physiol Endocrinol Metab. 2001 May;280(5):E761-9
references.pmid: 11287359
references.citation: Cell. 2006 Jul 14;126(1):107-20
references.pmid: 16839880
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683
references.citation: Biochem Biophys Res Commun. 2004 Jan 16;313(3):459-65
references.pmid: 14697210