The Warburg Effect Reinterpreted 100 yr on: A First-Principles Stoichiometric Analysis and Interpretation from the Perspective of ATP Metabolism in Cancer Cells

• Published in: Function (Oxford, England) Vol. 5; no. 3; p. zqae008
• Main Authors: Nath, Sunil, Balling, Rudi
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 2024
• Subjects: Adenosine triphosphate; Adenosine Triphosphate - metabolism; Antineoplastic drugs; Cancer; Drug delivery; Drug development; Drug metabolism; Energy coupling; Energy Metabolism; Glycolysis; Humans; Metabolism; Metabolites; Models, Biological; Neoplasms - metabolism; Neoplasms - pathology; Original Research; Quantitative analysis; Stoichiometry; Symbiosis; Warburg Effect, Oncologic; oxidative phosphorylation (OXPHOS) and F; biomass yield coefficients based on ATP; F; cancer, malignancy, and heterogeneity; metabolic coupling and symbiosis; aerobic glycolysis and the Warburg Effect; lactate and lactic acid; ATP synthase; mathematical model; Nath’s two-ion theory of energy coupling and torsional mechanism of ATP synthesis; Warburg-Nath ratio; Nath-Warburg number, NaWa; metabolic regulation based on ATP demand and supply; stoichiometry and available electron balance; Nath’s unified theory of ATP synthesis/hydrolysis; oxidative phosphorylation (OXPHOS) and F0F1-ATP synthase
• ISSN: 2633-8823; 2633-8823
• DOI: 10.1093/function/zqae008

The Warburg Effect is a longstanding enigma in cancer biology. Despite the passage of 100 yr since its discovery, and the accumulation of a vast body of research on the subject, no convincing biochemical explanation has been given for the original observations of aerobic glycolysis in cancer cell metabolism. Here, we have worked out a first-principles quantitative analysis of the problem from the principles of stoichiometry and available electron balance. The results have been interpreted using Nath’s unified theory of energy coupling and adenosine triphosphate (ATP) synthesis, and the original data of Warburg and colleagues have been analyzed from this new perspective. Use of the biomass yield based on ATP per unit substrate consumed, ${{Y}_{X/S}}\ ATP$, or the Nath-Warburg number, NaWa has been shown to excellently model the original data on the Warburg Effect with very small standard deviation values, and without employing additional fitted or adjustable parameters. Based on the results of the quantitative analysis, a novel conservative mechanism of synthesis, utilization, and recycling of ATP and other key metabolites (eg, lactate) is proposed. The mechanism offers fresh insights into metabolic symbiosis and coupling within and/or among proliferating cells. The fundamental understanding gained using our approach should help in catalyzing the development of more efficient metabolism-targeting anticancer drugs. Graphical Abstract Graphical Abstract