Cited by 1,114Folate and B Vitamins ResearchCancer, Hypoxia, and MetabolismBiochemical and Molecular Research

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Quantitative flux analysis reveals folate-dependent NADPH production

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Fan, Jing, Ye, Jiangbin, Kamphorst, Jurre J., Shlomi, Tomer, Thompson, Craig B., Rabinowitz, Joshua D.·2014·Nature

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Abstract

ATP is the dominant energy source in animals for mechanical and electrical work (for example, muscle contraction or neuronal firing). For chemical work, there is an equally important role for NADPH, which powers redox defence and reductive biosynthesis. The most direct route to produce NADPH from glucose is the oxidative pentose phosphate pathway, with malic enzyme sometimes also important. Although the relative contribution of glycolysis and oxidative phosphorylation to ATP production has been extensively analysed, similar analysis of NADPH metabolism has been lacking. Here we demonstrate the ability to directly track, by liquid chromatography-mass spectrometry, the passage of deuterium from labelled substrates into NADPH, and combine this approach with carbon labelling and mathematical modelling to measure NADPH fluxes. In proliferating cells, the largest contributor to cytosolic NADPH is the oxidative pentose phosphate pathway. Surprisingly, a nearly comparable contribution comes from serine-driven one-carbon metabolism, in which oxidation of methylene tetrahydrofolate to 10-formyl-tetrahydrofolate is coupled to reduction of NADP(+) to NADPH. Moreover, tracing of mitochondrial one-carbon metabolism revealed complete oxidation of 10-formyl-tetrahydrofolate to make NADPH. As folate metabolism has not previously been considered an NADPH producer, confirmation of its functional significance was undertaken through knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD) genes. Depletion of either the cytosolic or mitochondrial MTHFD isozyme resulted in decreased cellular NADPH/NADP(+) and reduced/oxidized glutathione ratios (GSH/GSSG) and increased cell sensitivity to oxidative stress. Thus, although the importance of folate metabolism for proliferating cells has been long recognized and attributed to its function of producing one-carbon units for nucleic acid synthesis, another crucial function of this pathway is generating reducing power.

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Authors: Fan, J., Ye, J., Kamphorst, J. J., Shlomi, T., Thompson, C. B., & Rabinowitz, J. D.
Affiliations: Princeton University (US)
Memorial Sloan Kettering Cancer Center (US)
Technion – Israel Institute of Technology (IL)
Corresponding author: Rabinowitz, Joshua D.
ORCID: Fan, Jing
Ye, Jiangbin
Kamphorst, Jurre J.
Shlomi, Tomer
Thompson, Craig B.
Rabinowitz, Joshua D.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2014-05-04
Volume: 510
Issue: 7504
Pages: 298-302
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature13236
PMC: PMC4104482
OpenAlex: W2017035524
Cited by: 1,114
References: 41
Citations by year: 2026: 65 · 2025: 90 · 2024: 91 · 2023: 79 · 2022: 87 · 2021: 116 · 2020: 109 · 2019: 102 · 2018: 65 · 2017: 106 · 2016: 98 · 2015: 74 · 2014: 31
FWCI: 86.15
Type: journal article
Language: en
Update notices: erratum (2014-09-24)
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
Funders: Howard Hughes Medical Institute
Memorial Sloan-Kettering Cancer Center
National Institutes of Health
National Cancer Institute (P01CA104838, R01CA105463, P30CA072720, R01CA163591)
National Institute of General Medical Sciences (P50GM071508)
National Institute of Allergy and Infectious Diseases (R01AI097382)
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: NADPH production, folate metabolism, methylenetetrahydrofolate dehydrogenase, oxidative pentose phosphate pathway, one-carbon metabolism, serine metabolism, glycine metabolism, deuterium labeling, carbon labeling
MeSH terms: Animals, Carbon, Cell Line, Leucovorin, Cytosol, Folic Acid, Glutathione, Glycine, Humans, Isoenzymes, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, NADP, Oxidation-Reduction, Pentose Phosphate Pathway, Serine, Tetrahydrofolates, Oxidative Stress, Cell Line, Tumor, Mice, HEK293 Cells

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Quantitative flux analysis reveals folate-dependent NADPH production

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