Cited by 422Folate and B Vitamins ResearchCancer, Hypoxia, and MetabolismBiochemical and Molecular Research

The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Open access

Ducker, Gregory S., Chen, Li, Morscher, Raphael J., Ghergurovich, Jonathan M., Esposito, Mark, Teng, Xin, Kang, Yibin, Rabinowitz, Joshua D.·2016·Cell Metabolism

DOI 10.1016/j.cmet.2016.04.016PMC PMC4909566

Open this paper in CoChat — free account Open PDF

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2016.04.016

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Genome engineering using the CRISPR-Cas9 system
Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013) · Nature Protocols · doi:10.1038/nprot.2013.143 · Cited by 11,133
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587
5-Fluorouracil: mechanisms of action and clinical strategies
Longley, D. B., Harkin, D. P., & Johnston, P. G. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1074 · Cited by 5,332
Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity
Ran, F. A., Hsu, P. D., Lin, C.-Y., Gootenberg, J. S., Konermann, S., Trevino, A. E., Scott, D. A., Inoue, A., Matoba, S., Zhang, Y., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.021 · Cited by 3,299
Cellular energy utilization and molecular origin of standard metabolic rate in mammals
Rolfe, D. F., & Brown, G. C. (1997) · Physiological Reviews · doi:10.1152/physrev.1997.77.3.731 · Cited by 2,021
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683
Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation
Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A. L., Kafri, R., Kirschner, M. W., Clish, C. B., & Mootha, V. K. (2012) · Science · doi:10.1126/science.1218595 · Cited by 1,403
Oxidative stress inhibits distant metastasis by human melanoma cells
Piskounova, E., Agathocleous, M., Murphy, M. M., Hu, Z., Huddlestun, S. E., Zhao, Z., Leitch, A. M., Johnson, T. M., DeBerardinis, R. J., & Morrison, S. J. (2015) · Nature · doi:10.1038/nature15726 · Cited by 1,269
Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., et al. (2011) · Nature Genetics · doi:10.1038/ng.890 · Cited by 1,120
Quantitative flux analysis reveals folate-dependent NADPH production
Fan, J., Ye, J., Kamphorst, J. J., Shlomi, T., Thompson, C. B., & Rabinowitz, J. D. (2014) · Nature · doi:10.1038/nature13236 · Cited by 1,114
Self-citation

Flagged first, then by citations

Show all 41 references

Sorted by citations

Items 101–200 of 422

Methionine synthase supports tumour tetrahydrofolate pools
Ghergurovich, J. M., Xu, X., Wang, J. Z., Yang, L., Ryseck, R.-P., Wang, L., & Rabinowitz, J. D. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00465-w · Cited by 86
Self-citation
Glycine decarboxylase maintains mitochondrial protein lipoylation to support tumor growth
Mukha, D., Fokra, M., Feldman, A., Sarvin, B., Sarvin, N., Nevo-Dinur, K., Besser, E., Hallo, E., Aizenshtein, E., Schug, Z. T., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.04.006 · Cited by 69
Spatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells
Lee, W. D., Mukha, D., Aizenshtein, E., & Shlomi, T. (2019) · Nature Communications · doi:10.1038/s41467-019-09352-1 · Cited by 70
Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential
Zhao, L. N., Björklund, M., Caldez, M. J., Zheng, J., & Kaldis, P. (2021) · Oncogene · doi:10.1038/s41388-021-01695-8 · Cited by 70
Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy
Perea‐Gil, I., Seeger, T., Bruyneel, A. A. N., Termglinchan, V., Monte, E., Lim, E. W., Vadgama, N., Furihata, T., Gavidia, A. A., Ataam, J. A., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac305 · Cited by 71
Serine catabolism is essential to maintain mitochondrial respiration in mammalian cells
Lucas, S., Chen, G., Aras, S., & Wang, J. (2018) · Life Science Alliance · doi:10.26508/lsa.201800036 · Cited by 65
The emerging role for metabolism in fueling neutrophilic inflammation
Morrison, T., Watts, E., Sadiku, P., & Walmsley, S. R. (2022) · Immunological Reviews · doi:10.1111/imr.13157 · Cited by 67
ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia
Di Marcantonio, D., Martinez, E., Kanefsky, J. S., Huhn, J. M., Gabbasov, R., Gupta, A., Krais, J. J., Peri, S., Tan, Y., Skorski, T., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.05.008 · Cited by 67
Hypoxia drives the assembly of the multienzyme purinosome complex
Doigneaux, C., Pedley, A. M., Mistry, I. N., Papayova, M., Benkovic, S. J., & Tavassoli, A. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.012175 · Cited by 65
Tumor Reliance on Cytosolic versus Mitochondrial One-Carbon Flux Depends on Folate Availability
Lee, W. D., Pirona, A. C., Sarvin, B. A., Stern, A., Nevo‐Dinur, K., Besser, E., Sarvin, N., Lagziel, S., Mukha, D., Raz, S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.12.002 · Cited by 67
Glycine homeostasis requires reverse SHMT flux
McBride, M. J., Hunter, C. J., Zhang, Z., TeSlaa, T. A., Xu, X., Ducker, G. S., & Rabinowitz, J. D. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.001 · Cited by 71
Self-citation
Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression
Zheng, Y., Le, Z., Qin, Z., Guo, Y., Wang, S., Xue, M., Shen, K.-Y., Hu, B., Wang, X., Wang, C., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112666 · Cited by 67
Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
Shin, M., Momb, J., & Appling, D. R. (2017) · Cancer & Metabolism · doi:10.1186/s40170-017-0173-0 · Cited by 66
Sensitisation of cancer cells to radiotherapy by serine and glycine starvation
Falcone, M., Uribe, A. H., Papalazarou, V., Newman, A. C., Athineos, D., Stevenson, K. H., Sauvé, C.-E. G., Gao, Y., Kim, J. K., Latto, M. D., et al. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-01965-6 · Cited by 65
Metabolic interactions in cancer: cellular metabolism at the interface between the microenvironment, the cancer cell phenotype and the epigenetic landscape
Rinaldi, G., Rossi, M., & Fendt, S. (2017) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1397 · Cited by 65
Recent advances in cancer metabolism: a technological perspective
Kang, Y. P., Ward, N. P., & DeNicola, G. M. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0027-z · Cited by 65
Self-citation
ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer
Krupenko, S. A., & Krupenko, N. I. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-98788-0_10 · Cited by 63
Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy
Pikman, Y., Ocasio-Martinez, N., Alexe, G., Dimitrov, B., Kitara, S., Diehl, F. F., Robichaud, A. L., Conway, A. S., Ross, L. S., Su, A. H., et al. (2021) · Leukemia · doi:10.1038/s41375-021-01361-8 · Cited by 59
Cycling back to folate metabolism in cancer
Lee, Y., Vousden, K. H., & Hennequart, M. (2024) · Nature Cancer · doi:10.1038/s43018-024-00739-8 · Cited by 68
Formate Induces a Metabolic Switch in Nucleotide and Energy Metabolism
Oizel, K., Tait-Mulder, J., Fernández-de-Cossio-Díaz, J., Pietzke, M., Brunton, H., Lilla, S., Dhayade, S., Athineos, D., Blanco, G. R., Sumpton, D. P., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-020-2523-z · Cited by 57
Cytosolic and mitochondrial NADPH fluxes are independently regulated
Niu, X., Stancliffe, E., Gelman, S. J., Wang, L., Schwaiger-Haber, M., Rowles, J. L., Shriver, L. P., & Patti, G. J. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01283-9 · Cited by 59
Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade
Rowe, J. H., Elia, I., Shahid, O., Gaudiano, E. F., Sifnugel, N. E., Johnson, S., Reynolds, A. G., Fung, M. E., Joshi, S., LaFleur, M. W., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1301 · Cited by 59
Self-citation
Novel Pyrrolo[3,2- d ]pyrimidine Compounds Target Mitochondrial and Cytosolic One-carbon Metabolism with Broad-spectrum Antitumor Efficacy
Dekhne, A. S., Shah, K., Ducker, G. S., Katinas, J. M., Wong-Roushar, J., Nayeen, M. J., Doshi, A., Ning, C., Bao, X., Frühauf, J., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0037 · Cited by 59
Self-citation
A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight
Cuthbertson, C. R., Arabzada, Z., Bankhead, A., Kyani, A., & Neamati, N. (2021) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.0c00223 · Cited by 57
The moonlighting RNA-binding activity of cytosolic serine hydroxymethyltransferase contributes to control compartmentalization of serine metabolism
Guiducci, G., Paone, A., Tramonti, A., Giardina, G., Rinaldo, S., Bouzidi, A., Magnifico, M. C., Marani, M., Menéndez, J. A., Fatica, A., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz129 · Cited by 56
Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
Green, A. C., Marttila, P., Kiweler, N., Chalkiadaki, C., Wiita, E., Cookson, V. J., Lesur, A., Eiden, K., Bernardin, F., Vallin, K. S. A., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00771-5 · Cited by 56
Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal
Tani, H., Ohnishi, S., Shitara, H., Mito, T., Yamaguchi, M., Yonekawa, H., Hashizume, O., Ishikawa, K., Nakada, K., & Hayashi, J. (2018) · Scientific Reports · doi:10.1038/s41598-017-18828-3 · Cited by 54
Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function
Ward, N. P., Kang, Y. P., Falzone, A., Boyle, T. A., & DeNicola, G. M. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20191689 · Cited by 55
Self-citation
Refining Classification of Cholangiocarcinoma Subtypes via Proteogenomic Integration Reveals New Therapeutic Prospects
Cho, S. Y., Hwang, H., Kim, Y., Yoo, B. C., Han, N., Kong, S., Baek, M.-J., Kim, K., Lee, M. R., Park, J. G., et al. (2023) · Gastroenterology · doi:10.1053/j.gastro.2023.02.045 · Cited by 54
Loss of ALDH1L1 folate enzyme confers a selective metabolic advantage for tumor progression
Krupenko, S. A., & Krupenko, N. I. (2019) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2019.02.013 · Cited by 51
Ursodeoxycholic acid protects against cisplatin-induced acute kidney injury and mitochondrial dysfunction through acting on ALDH1L2
Yang, Y., Liu, S., Gao, H., Wang, P., Zhang, Y., Zhang, A., Jia, Z., & Huang, S. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.01.182 · Cited by 53
Mitochondrial and Metabolic Pathways Regulate Nuclear Gene Expression to Control Differentiation, Stem Cell Function, and Immune Response in Leukemia
Egan, G., Khan, D. H., Lee, J. B., Mirali, S., Zhang, L., & Schimmer, A. D. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1227 · Cited by 52
Menin regulates the serine biosynthetic pathway in Ewing sarcoma
Svoboda, L. K., Teh, S. S. K., Sud, S., Kerk, S. A., Zebolsky, A. L., Treichel, S., Thomas, D. G., Halbrook, C. J., Lee, H., Kremer, D. M., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5085 · Cited by 52
Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold
Kawai, J., Ota, M., Ohki, H., Toki, T., Suzuki, M., Shimada, T., Matsui, S., Inoue, H., Sugihara, C., Matsuhashi, N., et al. (2019) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.9b00069 · Cited by 50
An LC-MS chemical derivatization method for the measurement of five different one-carbon states of cellular tetrahydrofolate
Chen, L., Ducker, G. S., Lu, W., Teng, X., & Rabinowitz, J. D. (2017) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-017-0514-4 · Cited by 49
Self-citation
Targeting the DNA damage response and repair in cancer through nucleotide metabolism
Helleday, T., & Rudd, S. G. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13227 · Cited by 49
SHMT2 promotes cell viability and inhibits ROS-dependent, mitochondrial-mediated apoptosis via the intrinsic signaling pathway in bladder cancer cells
Zhang, Y., Liu, Z., Wang, X., Jian, H., Xiao, H., & Wen, T. (2022) · Cancer Gene Therapy · doi:10.1038/s41417-022-00470-5 · Cited by 47
Linking Serine/Glycine Metabolism to Radiotherapy Resistance
Sánchez‐Castillo, A., Vooijs, M., & Kampen, K. R. (2021) · Cancers · doi:10.3390/cancers13061191 · Cited by 47
Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis
Kiweler, N., Delbrouck, C., Pozdeev, V. I., Neises, L., Soriano‐Baguet, L., Eiden, K., Xian, F., Benzarti, M., Haase, L., Koncina, E., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30363-y · Cited by 46
Phenotypic profiling of solute carriers characterizes serine transport in cancer
Papalazarou, V., Newman, A. C., Uribe, A. H., Legrave, N. M., Falcone, M., Zhang, T., McGarry, L., Athineos, D., Shanks, E. J., Blyth, K., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00936-2 · Cited by 53
A spatiotemporal proteomic map of human adipogenesis
Klingelhuber, F., Frendo‐Cumbo, S., Omar‐Hmeadi, M., Massier, L., Kakimoto, P. A., Taylor, A. J., Couchet, M., Ribičić, S., Wabitsch, M., Messias, A. C., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01025-8 · Cited by 51
A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments
Chidley, C., Darnell, A. M., Gaudio, B. L., Lien, E. C., Barbeau, A. M., Heiden, M. G. V., & Sorger, P. K. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01402-1 · Cited by 45
Decoding the metabolic dialogue in the tumor microenvironment: from immune suppression to precision cancer therapies
Wang, R., Zhuang, J., Zhang, Q., Wu, W., Yu, X., Zhang, H., & Xie, Z. (2025) · Experimental Hematology and Oncology · doi:10.1186/s40164-025-00689-6 · Cited by 52
Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction
Nonaka, H., Nakanishi, Y., Kuno, S., Ota, T., Mochidome, K., Saito, Y., Sugihara, F., Takakusagi, Y., Aoki, I., Nagatoishi, S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08833-7 · Cited by 47
The Role of Metabolic Enzymes in the Regulation of Inflammation
Godfrey, W. H., & Kornberg, M. D. (2020) · Metabolites · doi:10.3390/metabo10110426 · Cited by 50
Reverse engineering the cancer metabolic network using flux analysis to understand drivers of human disease
Badur, M. G., & Metallo, C. M. (2017) · Metabolic Engineering · doi:10.1016/j.ymben.2017.11.013 · Cited by 44
Protein interaction and functional data indicate MTHFD2 involvement in RNA processing and translation
Koufaris, C., & Nilsson, R. (2018) · Cancer & Metabolism · doi:10.1186/s40170-018-0185-4 · Cited by 45
Single-Cell Transcriptome Analysis Reveals Estrogen Signaling Coordinately Augments One-Carbon, Polyamine, and Purine Synthesis in Breast Cancer
Zhu, D., Zhao, Z., Cui, G., Chang, S., Hu, L., See, Y. X., Lim, M. G. L., Guo, D., Chen, X., Poudel, B., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.093 · Cited by 48
Should we consider subcellular compartmentalization of metabolites, and if so, how do we measure them?
Wellen, K. E., & Snyder, N. W. (2019) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000580 · Cited by 48
Metabolic Alterations in Cancer Cells and the Emerging Role of Oncometabolites as Drivers of Neoplastic Change
Zhou, Z., Ibekwe, E., & Chornenkyy, Y. (2018) · Antioxidants · doi:10.3390/antiox7010016 · Cited by 44
MTHFD2 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating AKT/GSK‐3β/β‐catenin signalling
Shi, Y., Xu, Y., Yao, J., Yan, C., Su, H., Zhang, X. Z., Chen, E., & Ying, K. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16715 · Cited by 43
ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis
Hennequart, M., Pilley, S. E., Labuschagne, C. F., Coomes, J., Mervant, L., Driscoll, P. C., Legrave, N. M., Lee, Y., Kreuzaler, P. A., Macintyre, B., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112562 · Cited by 44
Histidine-Dependent Protein Methylation Is Required for Compartmentalization of CTP Synthase
Lin, W.-C., Chakraborty, A., Huang, S., Wang, P., Hsieh, Y., Chien, K., Lee, Y., Chang, C., Tang, H.-Y., Lin, Y.-T., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.08.007 · Cited by 41
Drosha-independent miR-6778–5p strengthens gastric cancer stem cell stemness via regulation of cytosolic one-carbon folate metabolism
Zhao, M., Hou, Y., Du, Y.-E., Yang, L., Qin, Y., Peng, M., Liu, S., Wan, X., Qiao, Y., Zeng, H., et al. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.02.040 · Cited by 41
SHMT2 regulates esophageal cancer cell progression and immune Escape by mediating m6A modification of c-myc
Qiao, Z., Li, Y., Cheng, Y., Li, S., & Liu, S. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01148-7 · Cited by 40
Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury
Du, C., Liu, C., Yu, K., Zhang, S., Fu, Z., Chen, X., Liao, W., Chen, J., Zhang, Y., Wang, X., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.07.009 · Cited by 42
One Carbon Metabolism and Mammalian Pregnancy Outcomes
Cai, S., Quan, S., Yang, G., Ye, Q., Chen, M., Yu, H., Wang, G., Wang, Y., Zeng, X., & Qiao, S. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202000734 · Cited by 43
Cellular pharmacodynamics of a novel pyrrolo[3,2-d]pyrimidine inhibitor targeting mitochondrial and cytosolic one-carbon metabolism
Dekhne, A. S., Ning, C., Nayeen, M. J., Shah, K., Kalpage, H., Frühauf, J., Wallace-Povirk, A., O’Connor, C., Hou, Z., Kim, S., et al. (2020) · Molecular Pharmacology · doi:10.1124/mol.119.117937 · Cited by 40
Targeting MTHFD2 to Exploit Cancer-Specific Metabolism and the DNA Damage Response
Ramos, L., Henriksson, M., Helleday, T., & Green, A. C. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-1290 · Cited by 38
Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain
McKee, S. E., Zhang, S., Chen, L., Rabinowitz, J. D., & Reyes, T. M. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14319 · Cited by 38
Self-citation
Classically activated macrophages undergo functionally significant nucleotide metabolism remodelling driven by nitric oxide
John, S. V., Seim, G. L., Flores, B. J. E., Votava, J. A., Urquiza, U. S., Arp, N. L., Steill, J., Freeman, J., Carnevale, L. N., Roberts, I., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01337-3 · Cited by 45
Targeting Homocysteine and Hydrogen Sulfide Balance as Future Therapeutics in Cancer Treatment
Majumder, A. (2023) · Antioxidants · doi:10.3390/antiox12081520 · Cited by 36
Mitochondrial MTHFD isozymes display distinct expression, regulation, and association with cancer
Nilsson, R., Nicolaidou, V., & Koufaris, C. (2019) · Gene · doi:10.1016/j.gene.2019.144032 · Cited by 36
Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer
Achreja, A., Yu, T., Mittal, A., Choppara, S., Animasahun, O. H., Nenwani, M., Wuchu, F., Meurs, N., Mohan, A., Jeon, J. H., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00636-3 · Cited by 33
Glycine decarboxylase is a transcriptional target of MYCN required for neuroblastoma cell proliferation and tumorigenicity
Alptekin, A., Ye, B., Yu, Y., Poole, C. J., van Riggelen, J., Zha, Y., & Ding, H. (2019) · Oncogene · doi:10.1038/s41388-019-0967-3 · Cited by 35
Autophagy facilitates adaptation of budding yeast to respiratory growth by recycling serine for one-carbon metabolism
May, A. I., Prescott, M., & Ohsumi, Y. (2020) · Nature Communications · doi:10.1038/s41467-020-18805-x · Cited by 36
Multienzyme interactions of the de novo purine biosynthetic protein PAICS facilitate purinosome formation and metabolic channeling
He, J., Zou, L.-N., Pareek, V., & Benkovic, S. J. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101853 · Cited by 34
CSN6 Mediates Nucleotide Metabolism to Promote Tumor Development and Chemoresistance in Colorectal Cancer
Zou, S., Qin, B., Yang, Z., Wang, W., Zhang, J., Zhang, Y., Meng, M., Feng, J., Xie, Y., Fang, L., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-2145 · Cited by 35
MTHFD2 reprograms macrophage polarization by inhibiting PTEN
Shang, M., Ni, L., Shan, X., Cui, Y., Hu, P., Ji, Z., Shen, L., Zhang, Y., Zhou, J., Chen, B., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112481 · Cited by 34
SLC25A32 sustains cancer cell proliferation by regulating flavin adenine nucleotide (FAD) metabolism
Santoro, V., Kovalenko, I., Vriens, K., Christen, S., Bernthaler, A., Haegebarth, A., Fendt, S., & Christian, S. (2020) · Oncotarget · doi:10.18632/oncotarget.27486 · Cited by 36
A comprehensive review on signaling attributes of serine and serine metabolism in health and disease
Wu, D., Zhang, K., Khan, F. A., Pandupuspitasari, N. S., Guan, K., Sun, F., & Huang, C. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.129607 · Cited by 35
Metformin Is a Pyridoxal-5′-phosphate (PLP)-Competitive Inhibitor of SHMT2
Tramonti, A., Cuyàs, E., Encinar, J. A., Pietzke, M., Paone, A., Verdura, S., Arbusà, A., Martı́n-Castillo, B., Giardina, G., Joven, J., et al. (2021) · Cancers · doi:10.3390/cancers13164009 · Cited by 31
Overexpression of cytosolic long noncoding RNA cytb protects against pressure-overload-induced heart failure via sponging microRNA-103-3p
Zhang, X., Yuan, S., Liu, J., Tang, Y., Wang, Y., Zhan, J., Fan, J., Nie, X., Zhao, Y., Zheng, W., et al. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.02.002 · Cited by 32
Metabolic modulation of transcription: The role of one-carbon metabolism
Lin, J.-M. G., Kourtis, S., Ghose, R., Lorente, N. P., Kubicek, S., & Sdelci, S. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.11.009 · Cited by 36
Biological, dietetic and pharmacological properties of vitamin B9
Siatka, T., Máťuš, M., Moravcová, M., Harčárová, P., Lomozová, Z., Matoušová, K., Suwanvecho, C., Krčmová, L. K., & Mladěnka, P. (2025) · npj Science of Food · doi:10.1038/s41538-025-00396-w · Cited by 44
Simplifying the B Complex: How Vitamins B6 and B9 Modulate One Carbon Metabolism in Cancer and Beyond
Franco, C. N., Seabrook, L. J., Nguyen, S. T., Leonard, J. T., & Albrecht, L. V. (2022) · Metabolites · doi:10.3390/metabo12100961 · Cited by 36
Newcastle Disease Virus Manipulates Mitochondrial MTHFD2-Mediated Nucleotide Metabolism for Virus Replication
Tang, N., Chen, P., Zhao, C., Liu, P., Tan, L., Song, C., Qiu, X., Liao, Y., Liu, X., Luo, T., et al. (2023) · Journal of Virology · doi:10.1128/jvi.00016-23 · Cited by 31
The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 via pyrimidine depletion
Dembitz, V., Tomić, B., Kodvanj, I., Simon, J. A., Bedalov, A., & Višnjić, D. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009396 · Cited by 30
Combinatorial targeting of MTHFD2 and PAICS in purine synthesis as a novel therapeutic strategy
Cheung, C. H. Y., Hsu, C., Tsuei, C.-Y., Kuo, T., Huang, C.-T., Hsu, W., Chung, Y.-H., Wu, H.-Y., Hsu, C., Huang, H., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2033-z · Cited by 31
Serine hydroxymethyltransferase 2: a novel target for human cancer therapy
Xie, M., & Pei, D. (2021) · Investigational New Drugs · doi:10.1007/s10637-021-01144-z · Cited by 30
Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer
Lee, H. M., Muhammad, N., Lieu, E. L., Cai, F., Mu, J., Ha, Y., Cao, G., Suchors, C., Joves, K., Chronis, C., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01066-z · Cited by 33
Self-citation
Aberrant mitochondrial function in ageing and cancer
Whitehall, J. C., & Greaves, L. C. (2019) · Biogerontology · doi:10.1007/s10522-019-09853-y · Cited by 34
The emerging role of one-carbon metabolism in T cells
Kurniawan, H., Kobayashi, T., & Brenner, D. (2021) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2020.12.001 · Cited by 32
The role of mitochondrial folate enzyme MTHFD1L in esophageal squamous cell carcinoma
Yang, Y., Yuan, Y., Hu, W., Shang, Q.-X., & Chen, L.-Q. (2017) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365521.2017.1407440 · Cited by 30
Self-citation
The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes
Esposito, M., Amory, J. K., & Kang, Y. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20240519 · Cited by 32
Self-citation
DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy
Lin, H.-P., Petersen, J. D., Gilsrud, A. J., Madruga, A., D’Silva, T. M., Huang, X., Shammas, M. K., Randolph, N., Johnson, K. R., Li, Y., et al. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00242-x · Cited by 28
Epigenetics and nutrition-related epidemics of metabolic diseases: Current perspectives and challenges
Hernández‐Aguilera, A., Fernández‐Arroyo, S., Cuyàs, E., Luciano‐Mateo, F., Cabré, N., Camps, J., López‐Miranda, J., Menéndez, J. A., & Joven, J. (2016) · Food and Chemical Toxicology · doi:10.1016/j.fct.2016.08.006 · Cited by 30
Metabolic determinants of germinal center B cell formation and responses
Wu, J., Zhou, J., Li, G. L., Sun, X., Xiang, C., Chen, H., & Jiang, P. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01690-6 · Cited by 28
Deletion of the neural tube defect–associated gene disrupts one-carbon and central energy metabolism in mouse embryos
Bryant, J. D., Sweeney, S., Sentandreu, E., Shin, M., Ipas, H., Xhemalçe, B., Momb, J., Tiziani, S., & Appling, D. R. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002180 · Cited by 28
Transcriptional and metabolic remodeling in clear cell renal cell carcinoma caused by ATF4 activation and the integrated stress response (ISR)
van der Mijn, J. C., Chen, Q., Laursen, K. B., Khani, F., Wang, X., Dorsaint, P., Sboner, A., Gross, S. S., Nanus, D. M., & Gudas, L. J. (2022) · Molecular Carcinogenesis · doi:10.1002/mc.23437 · Cited by 27
MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions
Lorente, N. P., & Sdelci, S. (2024) · npj Metabolic Health and Disease · doi:10.1038/s44324-024-00005-6 · Cited by 28
Serine and glycine physiology reversibly modulate retinal and peripheral nerve function
Lim, E. W., Fallon, R. J., Bates, C., Ideguchi, Y., Nagasaki, T., Handzlik, M. K., Joulia, E., Bonelli, R., Green, C. R., Ansell, B. R. E., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.07.021 · Cited by 27
Metabolic flux analysis and fluxomics-driven determination of reaction free energy using multiple isotopes
Xu, J. P., Martien, J. I., Gilbertson, C., Ma, J., Amador‐Noguez, D., & Park, J. O. (2020) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2020.02.018 · Cited by 27
Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells
Silva, A. C. B. S., Pérez-Valencia, J. A., Sciacovelli, M., Lalou, C., Sarlak, S., Tronci, L., Nikitopoulou, E., Mészáros, A., Frezza, C., Rossignol, R., et al. (2021) · Cancers · doi:10.3390/cancers13071727 · Cited by 28
Non‐canonical metabolic pathways in the malaria parasite detected by isotope‐tracing metabolomics
Cobbold, S. A., Tutor, M. V., Frasse, P., McHugh, E., Karnthaler, M., Creek, D. J., John, A. R. O., Tilley, L. M., Ralph, S. A., & McConville, M. J. (2021) · Molecular Systems Biology · doi:10.15252/msb.202010023 · Cited by 27
The Role of Single-Nucleotide Polymorphisms in the Function of Candidate Tumor Suppressor ALDH1L1
Krupenko, S. A., & Horita, D. A. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.01013 · Cited by 28
Metabolism pathway-based subtyping in endometrial cancer: An integrated study by multi-omics analysis and machine learning algorithms
Liu, X., Wang, W., Zhang, X., Liang, J., Dingqing, F., Li, Y., Xue, M., & Ling, B. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102155 · Cited by 28
Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing
Zarou, M. M., Rattigan, K. M., Sarnello, D., Shokry, E., Dawson, A., Ianniciello, A., Dunn, K. M., Copland, M., Sumpton, D. P., Vázquez, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46114-0 · Cited by 28
High Expression of Serine Hydroxymethyltransferase 2 Indicates Poor Prognosis of Gastric Cancer Patients
Shi, H., Fang, X., Li, Y., & Zhang, Y. (2019) · Medical Science Monitor · doi:10.12659/msm.917435 · Cited by 25
Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer
Wallace-Povirk, A., Hou, Z., Nayeen, M. J., Gangjee, A., & Matherly, L. H. (2021) · Cancers · doi:10.3390/cancers14010191 · Cited by 26

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: Ducker, Gregory S.
Chen, Li
Morscher, Raphael J.
Ghergurovich, Jonathan M.
Esposito, Mark
Teng, Xin
Kang, Yibin
Rabinowitz, Joshua D.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2016-06
Volume: 23
Issue: 6
Pages: 1140-1153
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2016.04.016
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 378 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: 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

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 ›

Are you an author, or do you see a problem with this page? Request a review

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks