Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology

Alexei Vazquez

doi:10.1038/npre.2011.5784.1

Abstract

AbstractAerobic glycolysis is a seemingly wasteful mode of ATP production that is seen both in rapidly proliferating mammalian cells and highly active contracting muscles, but whether there is a common origin for its presence in these widely different systems is unknown. To study this issue, here we develop a model of human central metabolism that incorporates a solvent capacity constraint of metabolic enzymes and mitochondria, accounting for their occupied volume densities, while assuming glucose and/or fatty acid utilization. The model demonstrates that activation of aerobic glycolysis is favored above a threshold metabolic rate in both rapidly proliferating cells and heavily contracting muscles, because it provides higher ATP yield per volume density than mitochondrial oxidative phosphorylation. In the case of muscle physiology, the model also predicts that before the lactate switch, fatty acid oxidation increases, reaches a maximum, and then decreases to zero with concomitant increase in glucose utilization, in agreement with the empirical evidence. These results are further corroborated by a larger scale model, including biosynthesis of major cell biomass components. The larger scale model also predicts that in proliferating cells the lactate switch is accompanied by activation of glutaminolysis, another distinctive feature of the Warburg effect. In conclusion, intracellular molecular crowding is a fundamental constraint for cell metabolism in both rapidly proliferating- and non-proliferating cells with high metabolic demand. Addition of this constraint to metabolic flux balance models can explain several observations of mammalian cell metabolism under steady state conditions.

Highlights

The Warburg effect, i.e., glycolysis with lactic acid production even under normal oxygen saturation concomitant with mitochondrial oxidative phosphorylation (OxPhos), is a metabolic phenotype displayed by most cancer cells [1]
It has been argued that the Warburg effect represents a compromise between conflicting metabolic needs, in which beside the need for ATP the increased production of glycolytic intermediates is critical to satisfy the need of proliferating cells for biosynthetic precursor molecules [8], and that the high level of NADH produced during this enhanced glycolysis can be most efficiently converted back to NAD+ by the reduction of pyruvate to lactate [9]
Anaerobic glucose metabolism is decomposed into glycolysis, converting glucose into pyruvate, and pyruvate reduction by lactate dehydrogenase (LDH) in the cytosol, resulting in the end product lactate that is excreted to the extracellular milieu with a yield of YL = 2 moles of ATP per mole of glucose

Summary

Introduction

The Warburg effect, i.e., glycolysis with lactic acid production even under normal oxygen saturation (aerobic glycolysis) concomitant with mitochondrial oxidative phosphorylation (OxPhos), is a metabolic phenotype displayed by most cancer cells [1]. It has been argued that the Warburg effect represents a compromise between conflicting metabolic needs, in which beside the need for ATP the increased production of glycolytic intermediates is critical to satisfy the need of proliferating cells for biosynthetic precursor molecules [8], and that the high level of NADH produced during this enhanced glycolysis can be most efficiently converted back to NAD+ by the reduction of pyruvate to lactate [9]. Anabolic processes may not represent the main factors underlying the Warburg effect because non-proliferating cells can display similar metabolic phenotypes. In contrast to proliferating cells, anabolic processes are downregulated in heavily working muscles leading to decreased demand for biosynthetic precursors [15]

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Methods

Results