A Flux Balance of Glucose Metabolism Clarifies the Requirements of the Warburg Effect.
The Warburg effect, or aerobic glycolysis, is marked by the increased metabolism of glucose to lactate in the presence of oxygen. Despite its widespread prevalence in physiology and cancer biology, the causes and consequences remain incompletely understood. Here, we show that a simple balance of interacting fluxes in glycolysis creates constraints that impose the necessary conditions for glycolytic flux to generate lactate as opposed to entering into the mitochondria. These conditions are determined by cellular redox and energy demands. By analyzing the constraints and sampling the feasible region of the model, we further study how cell proliferation rate and mitochondria-associated NADH oxidizing and ATP producing fluxes are interlinked. Together this analysis illustrates the simplicity of the origins of the Warburg effect by identifying the flux distributions that are necessary for its instantiation.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke Molecular Physiology Institute, Duke Cancer Institute, Durham, North Carolina; Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Ziwei
Z
Dai
Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Alexander A
AA
Shestov
Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Luhua
L
Lai
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke Molecular Physiology Institute, Duke Cancer Institute, Durham, North Carolina. Electronic address: jason.locasale@duke.edu.
Jason W
JW
Locasale
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000465:Algorithms; D001943:Breast Neoplasms / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005947:Glucose / Q000737:chemistry / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*
D009243:NAD; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D010100:Oxygen