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

Vazquez, A and Oltvai, ZN (2011) Molecular crowding defines a common origin for the warburg effect in proliferating cells and the lactate threshold in muscle physiology. PLoS ONE, 6 (4).

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Aerobic 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. © 2011 Vazquez, Oltvai.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Vazquez, A
Oltvai, ZNoltvai@pitt.eduOLTVAI
ContributionContributors NameEmailPitt UsernameORCID
Date: 13 May 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0019538
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
MeSH Headings: Adenosine Triphosphate--chemistry; Animals; Cell Proliferation; Energy Metabolism--physiology; Glucose--chemistry; Glucose--metabolism; Glycolysis; Humans; Lactic Acid--chemistry; Metabolism; Models, Biological; Models, Statistical; Muscles--physiology; Oxidative Phosphorylation; Oxygen--chemistry; Solvents--chemistry; Time Factors
Other ID: NLM PMC3084886
PubMed Central ID: PMC3084886
PubMed ID: 21559344
Date Deposited: 29 Aug 2012 21:12
Last Modified: 02 Feb 2019 14:55


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