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.

Figure 1

Reduced model of cell metabolism. Schematic representation of ATP generation pathways via aerobic glycolysis (glycolysis + pyruvate reduction to lactate) and oxidative phosphorylation (glycolysis + mitochondrial respiration). The variable f_G, denotes the glucose uptake rate, f_L and f_M, the components of the glucose uptake routed towards lactate excretion and respiration, respectively, and f_ATP the ATP production rate. Intermediate substrates of glucose catabolism are also used in a third process accounting for the production of precursor metabolites needed in anabolic processes (f_P). The pathways considered in our model are shown in the gray-shaded area, while f_P is treated as constant.

Figure 2

Catabolic regimes within proliferating mammalian cells. a, b, c, d) Model-predicted (lines) and measured (symbols) fluxes as a function of the glucose uptake rate: a) and b) LS mouse cells, c) hybridoma cells and d) mixture of cancer and normal cells. The two different metabolic regimes are indicated by the white and gray backgrounds, respectively. All fluxes are reported in units of f₁, the glucose uptake rate threshold, reported in panel e).