Cited by 695Folate and B Vitamins ResearchMetabolism and Genetic DisordersBiochemical and Molecular Research

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Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism

Tibbetts, Anne S., Appling, Dean R.·2010·Annual Review of Nutrition

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Abstract

The recognition that mitochondria participate in folate-mediated one-carbon metabolism grew out of pioneering work beginning in the 1950s from the laboratories of D.M. Greenberg, C.G. Mackenzie, and G. Kikuchi. These studies revealed mitochondria as the site of oxidation of one-carbon donors such as serine, glycine, sarcosine, and dimethylglycine. Subsequent work from these laboratories and others demonstrated the participation of folate coenzymes and folate-dependent enzymes in these mitochondrial processes. Biochemical and molecular genetic approaches in the 1980s and 1990s identified many of the enzymes involved and revealed an interdependence of cytoplasmic and mitochondrial one-carbon metabolism. These studies led to the development of a model of eukaryotic one-carbon metabolism that comprises parallel cytosolic and mitochondrial pathways, connected by one-carbon donors such as serine, glycine, and formate. Sequencing of the human and other mammalian genomes has facilitated identification of the enzymes that participate in this intercompartmental one-carbon metabolism, and animal models are beginning to clarify the roles of the cytoplasmic and mitochondrial isozymes of these enzymes. Identifying the mitochondrial transporters for the one-carbon donors and elucidating how flux through these pathways is controlled are two areas ripe for exploration.

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Zhang, J., Lee, S. E., Yoon, J., Ku, B. J., Park, J. O., Kang, D. H., Heo, J. Y., & Kang, Y. E. (2025) · Molecules and Cells · doi:10.1016/j.mocell.2025.100262 · Cited by 9
“SHMT1 and SHMT2 participate in distinct steps of the folate cycle (Tibbetts and Appling, 2010).”
Association between ALDH1L1 gene polymorphism and neural tube defects in the Chinese Han population
Wu, L., Lü, X., Guo, J., Zhang, T., Wang, F., & Bao, Y. (2016) · Neurological Sciences · doi:10.1007/s10072-016-2527-8 · Cited by 9
“Folate onecarbon metabolism can affect tumorogenesis [15, 18, 19], vitamin B utilization [20], and cardiovascular and cerebrovascular disease risk.”
Background
Impact of Formate Supplementation on Body Weight and Plasma Amino Acids
Dhayade, S., Pietzke, M., Wiesheu, R., Tait-Mulder, J., Athineos, D., Sumpton, D. P., Coffelt, S. B., Blyth, K., & Vázquez, A. (2020) · Nutrients · doi:10.3390/nu12082181 · Cited by 9
Probing Folate-Responsive and Stage-Sensitive Metabolomics and Transcriptional Co-Expression Network Markers to Predict Prognosis of Non-Small Cell Lung Cancer Patients
Lin, Y., Chen, Y.-C., Chen, T.-E., Cheng, M., Lynn, K., Shah, P., Chen, J., & Huang, R.-F. S. (2022) · Nutrients · doi:10.3390/nu15010003 · Cited by 9
In situ profiling reveals metabolic alterations in the tumor microenvironment of ovarian cancer after chemotherapy
Corvigno, S., Badal, S., Spradlin, M., Keating, M. F., Pereira, I., Stur, E., Bayraktar, E., Foster, K. I., Bateman, N. W., Barakat, W., et al. (2023) · npj Precision Oncology · doi:10.1038/s41698-023-00454-0 · Cited by 9
“…glycine and serine from the tumor stroma, leading to the increased activity of GLDC. GLDC fuels one-carbon metabolism via glycine breakdown to form CO 2 , NH 3 , and 5,10-methylene-tetrahydrofolate (CH2-THF) 27 ; in particular, CH2-THF has been shown to be crucial for nucleotide synthesis 28,29 .”
Elimination of human folypolyglutamate synthetase alters programming and plasticity of somatic cells
Srivastava, A. C., Thompson, Y., Singhal, J., Stellern, J., Srivastava, A., Du, J., O'Connor, T. R., & Riggs, A. D. (2019) · The FASEB Journal · doi:10.1096/fj.201901721r · Cited by 9
“The poly glutamate chain lengths of the folates differ from1 cell type to another and within different organelles of a given cell, but inmost eukaryotic cells, the penta- and hexaglutamate formspredominate (1).”
BackgroundInfluential
Association of Methylenetetrahydrofolate Reductase C677T Gene Polymorphisms with Mild Cognitive Impairment Susceptibility: A Systematic Review and Meta-Analysis
Sun, J., Jiang, X., Zhao, M., Ma, L., Pei, H., Liu, N., & Li, H. (2021) · Behavioural Neurology · doi:10.1155/2021/2962792 · Cited by 9
“MTHFR, which depends on folate and vitamin B12, is a pivotal enzyme in one-carbon metabolism [44].”
Background
Genetic variants in ALDH1L1 and GLDC influence the serine-to-glycine ratio in Hispanic children
Krupenko, S. A., Cole, S. A., Hou, R., Haack, K., Laston, S., Mehta, N. R., Comuzzie, A. G., Butte, N. F., & Voruganti, V. S. (2022) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqac091 · Cited by 10
Plasma Choline, Nicotine Exposure, and Risk of Low Bone Mineral Density and Hip Fracture: The Hordaland Health Study
Øyen, J., Nygard, O. K., Gjesdal, C. G., Ueland, P. M., Apalset, E. M., Schartum-Hansen, H., Vollset, S. E., Meyer, K., & Tell, G. S. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2025 · Cited by 9
Downregulation of MTHFD2 Inhibits Proliferation and Enhances Chemosensitivity in Hepatocellular Carcinoma via PI3K/AKT Pathway
Wang, J., Yu, Z., Jiang, Y., Le, T., Wu, Y., Li, Z., Zhang, G., Wu, F., & Ma, H. (2024) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2901035 · Cited by 8
EP300-mediated H3 acetylation elevates MTHFD2 expression to reduce mitochondrial dysfunction in lipopolysaccharide-induced tubular epithelial cells
Hu, W. (2024) · Renal Failure · doi:10.1080/0886022x.2024.2369342 · Cited by 8
“…dehydrogenase 2 (MTHFD2) is a mitochondrial folate one-carbon (1 C) enzyme with methylene dehydrogenase and cyclohydrolase activity [11], which catalyzes the mitochondrial reaction in 1 C metabolism (also called the folate metabolic pathway), a metabolic process supporting E1A…”
Background
Interaction and regulation of the mitochondrial proteome – in health and disease
Palmfeldt, J. (2025) · Expert Review of Proteomics · doi:10.1080/14789450.2025.2451704 · Cited by 8
“The two processes give a complete oxidative/reductive cycle, which catabolizes serine in the mitochondria and synthesizes serine in the cytosol [47].”
The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity
Jiao, Z., Zhang, M., Ning, J., Yao, H., Yan, X., Wu, Z., Wu, D., Liu, Y., Zhang, M., Wang, L., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2412854122 · Cited by 8
“In mammalian cells, SHMT consists of two isozymes including cytosolic SHMT1 and mitochondrial SHMT2 ( 11 , 12 ).”
Deuterium Tracing to Interrogate Compartment-Specific NAD(P)H Metabolism in Cultured Mammalian Cells
Lim, E. W., Parker, S. J., & Metallo, C. M. (2019) · Methods in molecular biology · doi:10.1007/978-1-0716-0159-4_4 · Cited by 8
Expression and Prognostic Value Identification of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) in Brain Low-Grade Glioma
Shi, L.-F., Zhang, Q., Shou, X.-Y., & Niu, H. (2021) · International Journal of General Medicine · doi:10.2147/ijgm.s323858 · Cited by 8
Alterations in cellular metabolisms after Imatinib therapy: a review
Kumar, V., Singh, P., Gupta, S. K., Ali, V., Jyotirmayee, & Verma, M. (2022) · Medical Oncology · doi:10.1007/s12032-022-01699-8 · Cited by 8
“And through this regulatory activity of ATP and CTP, the balance between purines/pyrimidines is maintained as both types of nucleotides are required in DNA synthesis [77, 78].”
Background
Formaldehyde reacts with N-terminal proline residues to give bicyclic aminals
John, T., Pires, E., Hester, S. S., Salah, E., Hopkinson, R. J., & Schofield, C. J. (2023) · Communications Chemistry · doi:10.1038/s42004-022-00801-5 · Cited by 8
SLC25 Family Member Genetic Interactions Identify a Role for HEM25 in Yeast Electron Transport Chain Stability
Dufay, J. N., Fernández-Murray, J. P., & McMaster, C. R. (2017) · G3 Genes Genomes Genetics · doi:10.1534/g3.117.041194 · Cited by 8
“Growth impairment by simultaneous deletion of HEM25 and members of the SLC25 family Theabilityofayeastcell toutilizeglycineasanitrogensourcedependson the transport of glycine inside the mitochondria, which is mediated mostly by Hem25 followed by the catabolism of glycine into ammonia through the GCV (Figure 1B).”
BackgroundInfluential
Plasma metabolite profiles in healthy women differ after intervention with supplemental folic acid v. folate-rich foods
Hefni, M. E., Witthöft, C. M., & Moazzami, A. A. (2018) · Journal of Nutritional Science · doi:10.1017/jns.2018.22 · Cited by 8
“Increasing attention is being devoted to the role of folate in mediating one-carbon metabolism((4,5)).”
Background
Approaches to studying the genomic architecture of complex birth defects
Taiwo, T., Cao, X., Cabrera, R. M., Lei, Y., & Finnell, R. H. (2020) · Prenatal Diagnosis · doi:10.1002/pd.5760 · Cited by 8
Modulating redox homeostasis and cellular reprogramming through inhibited methylenetetrahydrofolate dehydrogenase 2 enzymatic activities in lung cancer
Chan, C.-H., Wu, C.-Y., Dubey, N. K., Wei, H.-J., Lu, J.-H., Mao, S., Liang, J. N., Liang, Y.-H., Cheng, H.-C., & Deng, W. (2020) · Aging · doi:10.18632/aging.103471 · Cited by 8
“MTHFD2 is a bifunctional enzyme that is integral to mitochondrial one-carbon metabolism, particularly in folate cycle, MTHFD2 could catalyze NAD dependent 5,10-Methy-lenetetrahydrofolate (5,10CH2-THF) dehydrogenase/ 5,10-methenyltetrahydrofolate (5,10-CH-THF) cyclohydrolase then form 10-formyltetrahydrofolate (10-CHO-…”
Background
NAD+-Consuming Enzymes in Stem Cell Homeostasis
Ji, X., Zheng, M., Yu, T., Kang, J., Fan, T., & Xu, B. (2023) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2023/4985726 · Cited by 8
Transcriptome Analysis of Effects of Folic Acid Supplement on Gene Expression in Liver of Broiler Chickens
Zhang, Y., Zhang, N., Liu, L., Wang, Y., Xing, J., & Li, X. (2021) · Frontiers in Veterinary Science · doi:10.3389/fvets.2021.686609 · Cited by 7
Relative contributions of endogenous and exogenous formaldehyde to formation of deoxyguanosine monoadducts and DNA-protein crosslink adducts of DNA in rat nasal mucosa
Conolly, R. B., Campbell, J. L., M.A., H. J. C. I., Schroeter, J. D., Kimbell, J. S., & Gentry, P. R. (2022) · Toxicological Sciences · doi:10.1093/toxsci/kfac119 · Cited by 7
“and nuclear compartments and is not well-mixed across the volume of the cell (Tibbetts and Appling 2010; Field et al., 2018).”
Background
Effect of preconception pictured-based health education and counseling on adherence to iron-folic acid supplementation to improve maternal pregnancy and birth outcome among women who plan to pregnant: “Randomized Control Trial”
Berhane, A., & Belachew, T. (2022) · Clinical Nutrition Open Science · doi:10.1016/j.nutos.2021.12.002 · Cited by 7
Rational Construction of a Mitochondria-Targeted Reversible Fluorescent Probe with Intramolecular FRET for Ratiometric Monitoring Sulfur Dioxide and Formaldehyde
Lyu, J., Wang, C., & Zhang, X. (2022) · Biosensors · doi:10.3390/bios12090715 · Cited by 7
“It is also an important metabolic intermediate coexisting in almost all cells [17] and can be used for the biosynthesis of purine and some other alkaloids [18].”
Background
Two maize homologs of mammalian proton-coupled folate transporter, ZmMFS_1–62 and ZmMFS_1–73, are essential to salt and drought tolerance
Hou, X., Lu, Z., Yu, T., Zhang, Y., Yao, Q., Zhang, C., Niu, Y., & Liang, Q. (2024) · Plant Physiology and Biochemistry · doi:10.1016/j.plaphy.2024.108623 · Cited by 7
Spermatozoal mRNAs expression implicated in embryonic development were influenced by dietary folate supplementation of breeder roosters by altering spermatozoal piRNA expression profiles
Wu, S., Guo, W., Yan, T., Zhou, J., Li, Y., Zhu, Y., Duan, Y., & Yang, X. (2019) · Theriogenology · doi:10.1016/j.theriogenology.2019.07.009 · Cited by 7
Alcohol dehydrogenase 5 of Helicoverpa armigera interacts with the CYP6B6 promoter in response to 2‐tridecanone
Zhao, J., Wei, Q., Gu, X., Ren, S., & Liu, X. (2019) · Insect Science · doi:10.1111/1744-7917.12720 · Cited by 7
Significant alteration of liver metabolites by AAV8.Urocortin 2 gene transfer in mice with insulin resistance
Kim, Y. C., Truax, A. D., Giamouridis, D., Lai, N. C., Guo, T., Hammond, H. K., & Gao, M. H. (2019) · PLoS ONE · doi:10.1371/journal.pone.0224428 · Cited by 7
Glutathione metabolism links FOXRED1 to NADH:ubiquinone oxidoreductase (complex I) deficiency: A hypothesis
Lemire, B. D. (2015) · Mitochondrion · doi:10.1016/j.mito.2015.07.009 · Cited by 7
“Cells with defects in themitochondrial folate transporter are glycine auxotrophs, emphasizing the relationship between folate, one-carbon metabolism and glycine (Tibbetts and Appling, 2010).”
Influential
Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial)
Ding, Y., Pedersen, E. R., Svingen, G. F. T., Helgeland, Ø., Gregory, J. F., Løland, K. H., Meyer, K., Tell, G. S., Ueland, P. M., & Nygard, O. K. (2016) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.116.001483 · Cited by 7
In situ interface reaction-enabled electrochemiluminescence imaging for single-cell formaldehyde release analysis
Zhou, J., & Liu, Y. (2024) · Sensors & Diagnostics · doi:10.1039/d4sd00177j · Cited by 6
Tissue-Specific Transcriptomic Profiling of Vitamin-Dependent Mitochondrial Pathways in Female Buffalo
Sadeesh, E. M., Lahamge, M. S., Singh, P., & Mohiddin, R. (2025) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-025-01979-w · Cited by 6
“This transcriptional profile supports renal roles in nucleotide synthesis, antioxidant defense, and methylation cycling processes underpinned by conserved mitochondrial 1C pathways [110, 111].”
Amino acid metabolic reprogramming in clear cell renal cell carcinoma: Pathogenic mechanisms and therapeutic targeting
Xie, J., Ni, F., Shao, J., Zhang, D., Guo, T., & Wang, X. W. (2026) · Cancer Letters · doi:10.1016/j.canlet.2026.218244 · Cited by 6
Metabolic control of cancer progression as novel targets for therapy
Talukdar, S., Emdad, L., Gogna, R., Das, S. K., & Fisher, P. B. (2021) · Advances in cancer research · doi:10.1016/bs.acr.2021.06.002 · Cited by 6
Serum metabolites of hypertension among Chinese adolescents aged 12–17 years
Sun, J., Ding, W., Liu, X., Zhao, M., & Xi, B. (2021) · Journal of Human Hypertension · doi:10.1038/s41371-021-00602-8 · Cited by 7
“Glycine transformed from serine can contribute to redox homeostasis [28], which is associated with Table 1.”
Background
Insight into the long-term impact of birth weight on intestinal development, microbial settlement, and the metabolism of weaned piglets
Trevisi, P., Negrini, C., Correa, F., Virdis, S., Laghi, L., Marcello, M., Conte, G., Mazzoni, M., & Luise, D. (2023) · Journal of Animal Science · doi:10.1093/jas/skad395 · Cited by 6
“Moreover, formate is a precursor of nucleotide synthesis as well as a growth-limiting factor (Tibbetts and Appling, 2010; Ducker and Rabinowitz, 2017).”
Background
The impact of common genetic variants in the mitochondrial glycine cleavage system on relevant metabolites
O'Reilly, J., Pangilinan, F., Hokamp, K., Ueland, P. M., Brosnan, J. T., Brosnan, M. E., Brody, L. C., & Molloy, A. M. (2018) · Molecular Genetics and Metabolism Reports · doi:10.1016/j.ymgmr.2018.05.006 · Cited by 6
“These enzymes act sequentially in the mitochondrion to cleave glycine obtained from the cytoplasm or from the breakdown of serine in the mitochondrion to produce N,Nmethylene tetrahydrofolate (CH2-THF), an active folate derivative that contributes to the transfer of one‐carbon units in cellular reactions [1].”
Background
Folate
Combs, G. F. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-381980-2.00016-5 · Cited by 6
Alterations on Cellular Redox States upon Infection and Implications for Host Cell Homeostasis
Mesquita, I., Vergnes, B., & Silvestre, R. (2018) · Experientia supplementum · doi:10.1007/978-3-319-74932-7_4 · Cited by 6

Authors: Tibbetts, A. S., & Appling, D. R.
Affiliations: The University of Texas at Austin (US)
ORCID: Appling, Dean R.
Venue: Annual Review of Nutrition
Publisher: Annual Reviews
Published: 2010-07-01
Volume: 30
Issue: 1
Pages: 57-81
ISSN: 0199-9885 (ISSN-L)
1545-4312
DOI: 10.1146/annurev.nutr.012809.104810
OpenAlex: W2145912883
Cited by: 692
References: 157
Citations by year: 2026: 42 · 2025: 40 · 2024: 40 · 2023: 53 · 2022: 70 · 2021: 55 · 2020: 61 · 2019: 61 · 2018: 55 · 2017: 33 · 2016: 51 · 2015: 26 · 2014: 33 · 2013: 28 · 2012: 27
FWCI: 3.02
Type: journal article
Language: en
Open access: closed
Locations: Annual Review of Nutrition (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords: mitochondrial metabolism, glycine oxidation, folate coenzymes, folate-dependent enzymes, serine, glycine, formate, isozymes, metabolic flux control
MeSH terms: Animals, Cell Nucleus, Cytoplasm, Folic Acid, Humans, Mammals, Mitochondria, One-Carbon Group Transferases

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Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism

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