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Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway
Open accessAbstract
One-carbon (1C) units for purine and thymidine synthesis can be generated from serine by cytosolic or mitochondrial folate metabolism. The mitochondrial 1C pathway is consistently overexpressed in cancer. Here, we show that most but not all proliferating mammalian cell lines use the mitochondrial pathway as the default for making 1C units. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This reversal in cytosolic flux is triggered by depletion of a single metabolite, 10-formyl-tetrahydrofolate (10-formyl-THF), and enables rapid cell growth in nutrient-replete conditions. Loss of the mitochondrial pathway, however, renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione. HCT-116 colon cancer xenografts lacking mitochondrial 1C pathway activity generate the 1C units required for growth by cytosolic serine catabolism. Loss of both pathways precludes xenograft formation. Thus, either mitochondrial or cytosolic 1C metabolism can support tumorigenesis, with the mitochondrial pathway required in nutrient-poor conditions.
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“For example, eliminating environmental serine, limiting aspartate synthesis via mitochondrial inhibition, and ablating the mitochondrial folate pathway impairs purine biosynthesis (Ducker et al., 2016; Labuschagne et al., 2014; Sullivan et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Ducker et al., 2016
In the citing paper
“In the absence of SHMT2, cytosolic SHMT1 reverses flux to compensate69”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [69]
In the citing paper
“Additionally, when the mitochondrial folate pathway is inhibited, the cytosolic pathway reverses flux to compensate; therefore, inhibition of both isoforms is essential for antitumor activity.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [158]
In the citing paper
“In addition to its involvement in nutrient regulation, MTHFD2 plays a role in redox homeostasis through the use of its cofactor NAD+, as well as involvement with expression of hypoxia-related proteins such as HIF-2α.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [158]
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Metadata
- Authors
- Ducker, G. S., Chen, L., Morscher, R. J., Ghergurovich, J. M., Esposito, M., Teng, X., Kang, Y., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Innsbruck Medical University (AT)
- Corresponding author
- Rabinowitz, Joshua D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 23
- Issue
- 6
- Pages
- 1140-1153
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4909566
- OpenAlex
- W2405069786
- Cited by
- 419
- References
- 41
- Citations by year
- 2026: 29 · 2025: 48 · 2024: 48 · 2023: 47 · 2022: 50 · 2021: 41 · 2020: 45 · 2019: 40 · 2018: 35 · 2017: 21 · 2016: 15
- FWCI
- 39.37
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-10-11)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- US National Institutes of Health (R01CA16359-01A1)
- Stand Up to Cancer (SU2C-AACR-DT0509)
- Brewster Foundation
- NIH (R01CA141062, F31CA192461)
- US Department of Defense (BC123187)
- American Cancer Society (PF-15-190-01- TBE)
- NJCCR postdoctoral fellowship (DFHS15PPC044)
- PMU-FFF fellowship (L-15/03/004-MOR)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- one-carbon metabolism, serine catabolism, glutathione synthesis, glycine, CRISPR knockout, tumor cell proliferation, colon cancer xenografts, tumor growth
- MeSH terms
- Aminoimidazole Carboxamide, Carbon, Cell Compartmentation, Leucovorin, Colonic Neoplasms, Cytosol, Folic Acid, Formates, Glycine, Humans, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, Mutation, NADP, Ribonucleotides, Serine, Glycine Hydroxymethyltransferase, Gene Library, Xenograft Model Antitumor Assays, HCT116 Cells, Cell Proliferation, Metabolic Networks and Pathways, Gene Knockout Techniques, HEK293 Cells, CRISPR-Cas Systems
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