Abstract
Aerobic glycolysis or the Warburg effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although the WE is ubiquitous, its biological role remains controversial, and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, here we evolved resistance to koningic acid (KA), a natural product that specifically inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme, during the WE. We found that KA-resistant cells lose the WE but continue to conduct glycolysis and surprisingly remain dependent on glucose as a carbon source and also on central carbon metabolism. Consequently, this altered state of glycolysis led to differential metabolic activity and requirements, including emergent activities in and dependences on fatty acid metabolism. These findings reveal that aerobic glycolysis is a process functionally distinct from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.
Highlights
Aerobic glycolysis or the Warburg effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibition leads to different phenotypic outcomes from targeting glucose uptake We first sought to determine whether disrupting GAPDH activity results in different outcomes from other perturbations to glycolysis
Our current study extends from this understanding to show that cells that evolve resistance to a specific GAPDH inhibitor, koningic acid (KA), lose the WE but remain dependent on glycolysis with different metabolic outputs from cells undergoing the WE or not
Summary
Whether it has any distinct biological function outside of glycolysis for cellular metabolism. We sought to address the question of whether the WE can be phenotypically defined apart from glycolysis and fully oxidative glucose metabolism. Using acquired resistance to GAPDH inhibition as a model and KA as a tool, we show that cells can simultaneously evolve loss of the WE but continue to remain dependent on glycolysis. These cells that have a selection pressure to lose the WE display widespread changes in metabolism downstream of glycolysis changes, including a marked rewiring of fatty acid metabolism. Our study provides evidence that the WE can be a biologically distinct form of glycolysis
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