Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters

Simple Summary The Warburg effect refers to the situation wherein cellular energetics (ATP formation) use aerobic glycolysis (i.e., glucose use with the release of lactate (2 ATP per glucose)) even if oxygen present would authorize full oxidation with a much higher yield (34 ATP per glucose). The present article reviews possible reasons to explain this metabolic bias. Cellular bioenergetics requires an intense ATP turnover that is increased further by hypermetabolic states caused by cancer growth or inflammation. Both are associated with metabolic alterations and, notably, enhancement of the Warburg effect (also known as aerobic glycolysis) of poor efficiency with regard to glucose consumption when compared to mitochondrial respiration. Therefore, beside this efficiency issue, other properties of these two pathways should be considered to explain this paradox: (1) biosynthesis, for this only indirect effect should be considered, since lactate release competes with biosynthetic pathways in the use of glucose; (2) ATP production, although inefficient, glycolysis shows other advantages when compared to mitochondrial respiration and lactate release may therefore reflect that the glycolytic flux is higher than required to feed mitochondria with pyruvate and glycolytic NADH; (3) Oxygen supply becomes critical under hypermetabolic conditions, and the ATP/O-2 ratio quantifies the efficiency of oxygen use to regenerate ATP, although aerobic metabolism remains intense the participation of anaerobic metabolisms (lactic fermentation or succinate generation) could greatly increase ATP/O-2 ratio; (4) time and space constraints would explain that anaerobic metabolism is required while the general metabolism appears oxidative; and (5) active repression of respiration by glycolytic intermediates, which could ensure optimization of glucose and oxygen use.

Automated summary

The Warburg effect refers to the phenomenon where cells choose to undergo glycolysis for energy production even in the presence of oxygen, instead of more efficient oxidation. This metabolic bias is likely influenced by hypermetabolic states caused by cancer growth or inflammation. In addition to efficiency issues, factors like biosynthesis, ATP production, oxygen supply, and time-space constraints may also play a role in the enhancement of the Warburg effect.