Limits of aerobic metabolism in cancer cells

Abstract

Cancer cells exhibit high rates of glycolysis and glutaminolysis. Glycolysis can provide energy and glutaminolysis can provide carbon for anaplerosis and reductive carboxylation to citrate. However, all these metabolic requirements could be in principle satisfied from glucose. Here we investigate why cancer cells do not satisfy their metabolic demands using aerobic biosynthesis from glucose. Based on the typical composition of a mammalian cell we quantify the energy demand and the OxPhos burden of cell biosynthesis from glucose. Our calculation demonstrates that aerobic growth from glucose is feasible up to a minimum doubling time that is proportional to the OxPhos burden and inversely proportional to the mitochondria OxPhos capacity. To grow faster cancer cells must activate aerobic glycolysis for energy generation and uncouple NADH generation from biosynthesis. To uncouple biosynthesis from NADH generation cancer cells can synthesize lipids from carbon sources that do not produce NADH in their catabolism, including acetate and the amino acids glutamate, glutamine, phenylalanine and tyrosine. Finally, we show that cancer cell lines have an OxPhos capacity that is insufficient to support aerobic biosynthesis from glucose. We conclude that selection for high rate of biosynthesis implies a selection for aerobic glycolysis and uncoupling biosynthesis from NADH generation.

A physical model of cell metabolism

“…Provided that the motors persistence parameter p is of the order of 1, the energy demand of cell maintenance predicted from this model (∼ 0.5 mol/L/h, Fig. 3B, I) is in the range of what is observed experimentally (around 0.3 mol ATP/L/h [17]). This is a striking observation given that our estimate is based on microscopic parameters characterizing molecular motors (Methods).…”

“…It has been estimated from the extrapolation of the growth dependence of the energy demand to the zero growth limit. For mammalian cells it is particularly high, with values around 0.3 mol ATP/L/h [17]. When cells grow, move or perform other functions the energy requirements increase beyond the basal maintenance demand.…”

“…Cells utilize glycolysis and oxidative phosphorylation to satisfy these energetic demands. Glycolysis has a low yield of 2 mol ATP/mol glucose [47], but it is characterized by a high horsepower (energy produced per volume of enzymes) [17,44]. Oxidative phosphorylation has a higher yield of 32 mol ATP/mol glucose [47], but it is characterized by a lower horsepower [17,44].…”

“…Glycolysis has a low yield of 2 mol ATP/mol glucose [47], but it is characterized by a high horsepower (energy produced per volume of enzymes) [17,44]. Oxidative phosphorylation has a higher yield of 32 mol ATP/mol glucose [47], but it is characterized by a lower horsepower [17,44]. The differences in yield and horsepower imply a metabolic switch from pure oxidative phosphorylation at low energy demands to mixed oxidative phosphorylation plus obligatory fermentation (glycolysis + lactate release) at high energy demands [46,44].…”

Noninvasive quantification of oxygen saturation in the portal and hepatic veins in healthy mice and those with colorectal liver metastases using QSM MRI

“…The extent to which this increased metabolic burden is oxidative, however, remains unclear. It is known that cancer cells exhibit a high rate of glycolysis even in aerobic conditions (the Warburg effect), but conventional acceptance of this being the only metabolic pathway is now being challenged. Although it has been noted that tumor cell proliferation increases oxygen consumption by tumor tissues, accumulating evidence suggests that the Warburg effect is only one aspect of cancer metabolism, which otherwise includes aerobic glycolysis, increased pentose phosphate pathway, increased macromolecule biosynthesis through redox homeostasis, and autophagy …”