Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells
Open accessAbstract
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.
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One clear advantage of aerobic glycolysis is that it allows cells to robustly regenerate NAD+ in the cytosol.
“While the field continues to debate the underlying benefits of engaging in aerobic glycolysis, one clear advantage to the process is that it allows cells to robustly regenerate NAD+ in the cytosol (57).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [57]
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Regulation and function of the mammalian tricarboxylic acid cycle
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- Authors
- Wang, Y., Stancliffe, E., Fowle-Grider, R., Wang, R., Wang, C., Schwaiger-Haber, M., Shriver, L. P., & Patti, G. J.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Patti, Gary J.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 82
- Issue
- 17
- Pages
- 3270-3283.e9
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC10134440
- OpenAlex
- W4291787698
- Cited by
- 180
- References
- 55
- Citations by year
- 2026: 36 · 2025: 46 · 2024: 47 · 2023: 42 · 2022: 9
- FWCI
- 15.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 365 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Edward Mallinckrodt, Jr. Foundation
- National Institutes of Health (R24OD024624)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056341)
- National Institute of Environmental Health Sciences (R35ES028365)
- National Center for Advancing Translational Sciences (L30 TR000589)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- aerobic glycolysis, malate-aspartate shuttle, glycerol-3-phosphate shuttle, lactate dehydrogenase, lactate excretion, glucose fermentation, cell proliferation, cancer metabolism, NCI-60 cell lines
- MeSH terms
- Aspartic Acid, Glucose, Glycolysis, Malates, NAD, Lactic Acid
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