Warburg Effect

Normally, cells use oxidative phosphorylation when oxygen is available, but in the case of aerobic glycolysis (or aerobic fermentation), they continue producing ATP through glycolysis, followed by lactate production, despite oxygen being present.

Aerobic fermentation and aerobic glycolysis can be used interchangeably, particularly in the context of the Warburg effect. However, "fermentation" typically implies anaerobic conditions, which can create confusion.

Cancer cells exhibit metabolic flexibility or plasticity, switching between anaerobic glycolysis, aerobic glycolysis, and sometimes oxidative phosphorylation (OXPHOS) depending on oxygen availability. In low oxygen (hypoxic) conditions, cancer cells primarily rely on anaerobic glycolysis to produce energy. However, when sufficient oxygen is present, they often still engage in aerobic glycolysis (Warburg effect), producing lactate despite oxygen availability. If oxygen levels increase significantly, cancer cells may also shift toward oxidative phosphorylation for more efficient ATP production. This adaptability supports their growth in diverse environments.

Fermentation and aerobic glycolysis lead to the accumulation of lactate. The lactate is then converted back to glucose in the liver via the Cori cycle, helping to maintain glucose supply.

Excess glucose intake feeds into this cycle, allowing continuous glycolysis. When sugars are provided in excess, when metabolism is pushed to its limits, cells exhibit fermentation even if there's sufficient oxygen.{ref | ref}.

Under certain stress conditions, such as lactate buildup, cells can revert to metabolic programs that resemble fetal metabolism, where mitochondria are less developed and more reliant on glycolysis. In this state, mitochondria behave immaturely, with lower ATP output from oxidative phosphorylation, less efficient ADP/ATP exchange, and reduced mitochondrial enzyme activity.

Glycolysis provides several advantages to cancer cells that promote their growth and survival e.g.rapid ATP Production. Glycolysis is a relatively fast way to generate ATP compared to oxidative phosphorylation. Although glycolysis produces less ATP per glucose molecule (2 ATP vs. 36 ATP in oxidative phosphorylation), the speed of glycolysis can compensate for the apparent lower efficiency. However, oxidative phosphorylation isn't more efficient when glucose is abundant than glycolysis. This is very well explained in this book. As the author describes it, fermentation (glycolysis) is the Ferrari of energy metabolism. Although there's still debate about the cause of the Warburg effect, in my view it could simply be a result of an initial adaptation to low oxygen in sites that aren't readily subjected to anaerobiosis, after which cancer cells continue glycolysis aerobically. Once you've driven a Ferrari it's hard to go back.

Warburg effect in cancer cells

The diagram illustrates the distinct aspects of the Warburg effect in cancer cells, containing glycolysis, pentose pyruvate pathway, lactate fermentation, glutamine metabolism, reactive oxygen species (ROS) generation, Tri-Carboxylic Acid (TCA) cycle, intermediates from the TCA cycle to synthesize lipids, and use of mutations in the TCA cycle (highlighted red) to synthesize oncometabolites. Important metabolic pathways are highlighted in yellow and important enzyme-regulating steps in glycolysis are highlighted in purple. Red lines with blunt ends indicate an inhibitory mode of action.{ref}

Glucose enters the cell and undergoes glycolysis to form pyruvate. In cancer cells, most of the pyruvate is converted to lactate (via lactate dehydrogenase, LDH).

Some of the pyruvate can still enter the mitochondria to form acetyl-CoA, feeding into the tricarboxylic acid (TCA) cycle.

Fumarate hydratase (FH) and succinate dehydrogenase (SDH) mutations are depicted as key players in disrupting normal TCA function. These mutations can lead to the accumulation of fumarate and succinate, which inhibit prolyl hydroxylase (PHD), stabilizing HIF-1α (hypoxia-inducible factor 1-alpha), contributing to the hypoxia response and promoting glycolysis.

Hypoxia or low oxygen levels cause stabilization of HIF-1α, which promotes glycolysis and reduces oxidative phosphorylation, further driving the Warburg effect.

The accumulation of ROS (reactive oxygen species) further enhances this cycle, damaging cellular components and promoting tumor growth.

Glucose-6-phosphate (G6P) can be diverted into the Pentose Phosphate Pathway  PPP, producing NADPH and GSH (glutathione), which are important for managing oxidative stress (represented by H₂O₂ detoxification).

Glutamine enters cells and is converted to glutamate, which can be further converted into α-ketoglutarate (α-KG) to fuel the TCA cycle. The mutant IDH2 (isocitrate dehydrogenase) produces 2-hydroxyglutarate, an oncometabolite, contributing to tumor progression by inhibiting α-KG-dependent enzymes.