Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited.
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.
Vazquez
Alexei
A
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
Liu
Jiangxia
J
Zhou
Yi
Y
Oltvai
Zoltán N
ZN
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
D007773:Lactates; D000255:Adenosine Triphosphate; D005947:Glucose
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