Molecular Cell
Volume 82, Issue 17, 1 September 2022, Pages 3270-3283.e9
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Article
Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells

https://doi.org/10.1016/j.molcel.2022.07.007Get rights and content
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Highlights

  • Fermentation correlates with NADH shuttle flux but not proliferation in cancer cells

  • The rate of glycolysis outpaces the flux of NADH shuttles in proliferating cells

  • Saturating NADH shuttle activity drives lactate production during aerobic glycolysis

  • The fraction of glucose-derived NADH oxidized in mitochondria is cell-type dependent

Summary

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.

Keywords

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

Data and code availability

  • Original Western Blot images have been deposited in Mendeley and are publicly available as of the date of publication. The DOI is listed in the key resources table.

  • All original code has been deposited in Github and is publicly available as of the date of publication. The link is listed in the key resources table.

  • Any additional information required to reanalyze data reported in this study is available from the lead contact upon reasonable request.

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