Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells

Yahui Wang, Ethan Stancliffe, Ronald Fowle-Grider, Rencheng Wang, Cheng Wang, Michaela Schwaiger-Haber, Leah P. Shriver, Gary J. Patti

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


Proliferating cells exhibit a metabolic phenotype known as “aerobic glycolysis,” which is characterized by an elevated rate of glucose fermentation to lactate irrespective of oxygen availability. Although several theories have been proposed, a rationalization for why proliferating cells seemingly waste glucose carbon by excreting it as lactate remains elusive. Using the NCI-60 cell lines, we determined that lactate excretion is strongly correlated with the activity of mitochondrial NADH shuttles, but not proliferation. Quantifying the fluxes of the malate-aspartate shuttle (MAS), the glycerol 3-phosphate shuttle (G3PS), and lactate dehydrogenase under various conditions demonstrated that proliferating cells primarily transform glucose to lactate when glycolysis outpaces the mitochondrial NADH shuttles. Increasing mitochondrial NADH shuttle fluxes decreased glucose fermentation but did not reduce the proliferation rate. Our results reveal that glucose fermentation, a hallmark of cancer, is a secondary consequence of MAS and G3PS saturation rather than a unique metabolic driver of cellular proliferation.

Original languageEnglish
Pages (from-to)3270-3283.e9
JournalMolecular cell
Issue number17
StatePublished - Sep 1 2022


  • NADH shuttles
  • aerobic glycolysis
  • cancer metabolism
  • glycerol 3-phosphate shuttle
  • isotope-tracer analysis
  • malate-aspartate shuttle
  • metabolic flux
  • metabolomics
  • the Warburg effect


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