Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited
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Abstract
Production of oxidized biomass, which requires regeneration of the cofactor NAD+, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD+ deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD+ consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD+ is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD+ availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD+ consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia.
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Electron shuttles facilitate oxidation of cytosolic NADH, which is required to support continued glycolysis and de novo synthesis of serine and lipids.
“Beyond supporting net NADH “import” into the mitochondria, these shuttles also facilitate the oxidation of cytosolic NADH, which is required to support continued glycolysis and the de novo synthesis of serine and lipids (101, 102, 103).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [103]
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- Authors
- Li, Z., Ji, B. W., Dixit, P. D., Tchourine, K., Lien, E. C., Hosios, A. M., Abbott, K. L., Rutter, J. C., Westermark, A. M., Gorodetsky, E. F., Sullivan, L. B., Vander Heiden, M. G., & Vitkup, D.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- University of California San Diego (US)
- University of Florida (US)
- Columbia University (US)
- Harvard University (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Vitkup, Dennis
- ORCID
- Venue
- Nature Metabolism
- Published
- 2022-06-23
- Volume
- 4
- Issue
- 6
- Pages
- 711-723
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC10305743
- OpenAlex
- W4283331833
- Cited by
- 81
- References
- 91
- Citations by year
- 2026: 15 · 2025: 22 · 2024: 22 · 2023: 15 · 2022: 7
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Metabolism (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (T32GM007753)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- tumor cell proliferation, NAD+ regeneration, lipogenesis, fatty acid synthesis, hypoxia, acetate uptake, oxidative metabolism, cancer metabolism
- MeSH terms
- Hypoxia, Electrons, Humans, Lipids, NAD, Neoplasms, Cell Proliferation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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