Otto Warburg originally proposed that cancer arose from a two-step process. The first
step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos),
while the second step involved a protracted compensatory energy synthesis through
lactic acid fermentation. His extensive findings showed that oxygen consumption was
lower while lactate production was higher in cancerous tissues than in non-cancerous
tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate
markers for ATP production through OxPhos and glycolysis, respectively. Warburg’s
hypothesis was challenged from findings showing that oxygen consumption remained high
in some cancer cells despite the elevated production of lactate suggesting that OxPhos
was largely unimpaired. New information indicates that neither oxygen consumption
nor lactate production are accurate surrogates for quantification of ATP production
in cancer cells. Warburg also did not know that a significant amount of ATP could
come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis
pathway with succinate produced as end product, thus confounding the linkage of oxygen
consumption to the origin of ATP production within mitochondria. Moreover, new information
shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation
are both biomarkers for OxPhos insufficiency. Warburg’s original hypothesis can now
be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated
cancer cell growth. These findings can also address several questionable assumptions
regarding the origin of cancer thus allowing the field to advance with more effective
therapeutic strategies for a less toxic metabolic management and prevention of cancer.
