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Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism
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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“The co-factor tetrahydrofolate (THF) is the carrier that mediates 1C transfer reactions for de novo nucleotide synthesis.66,67”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [67]
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“In the mitochondria, the reactions are carried Frontiers in Oncology | www.frontiersin.org 2 April 2020 | Volume 10 | Article 658 out by two MTHFD isozymes, MTHFD2 and MTHFD2L (11).”
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InfluentialRegulatory mechanisms of one-carbon metabolism enzymes
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“…types (Allegra et al., 1986; Matherly et al., 1987; Trent et al., 1991b) and is attributable to binding of folates to cellular proteins and sequestration of folate cofactors in cellular organelles (e.g., mitochondria) (Trent et al., 1991a; Matherly and Muench, 1990; Tibbetts and Appling, 2010).”
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“Mitochondria contain up to 40% of total cellular folate [26,27], and coupled with the fact that folate and its metabolites are normally found near the level required for use in folate dependent catalysis, a change in folate availability can have significant consequences [18].”
Methotrexate Normalizes Up‐Regulated Folate Pathway Genes in Rheumatoid Arthritis
Blits, M., Jansen, G., Assaraf, Y. G., van de Wiel, M. A., Lems, W. F., Nurmohamed, M. T., van Schaardenburg, D., Voskuyl, A. E., Wolbink, G., Vosslamber, S., et al. (2013) · Arthritis & Rheumatism · doi:10.1002/art.38094 · Cited by 67
“Given the notion that GGH is compartmentalized in the lysosome, and folylpolyglutamates reside in the cytoplasm and mitochondria (36), this implies that intercompartmental cross-talk may take place in folate homeostasis and the response to MTX.”
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
Vitamins and non-alcoholic fatty liver disease: A molecular insight
Raza, S., Tewari, A., Rajak, S., & Sinha, R. A. (2021) · Liver Research · doi:10.1016/j.livres.2021.03.004 · Cited by 74
“83,84 Dysregulated folate-dependent one-carbon metabolism has been implicated in NAFLD-related comorbidities including obesity, T2D, and metabolic syndrome.”
Formate: an essential metabolite, a biomarker, or more?
Lamarre, S. G., Morrow, G. P., MacMillan, L., Brosnan, M. E., & Brosnan, J. T. (2012) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2012-0552 · Cited by 67
Kao, T.-T., Chu, C.-Y., Lee, G., Hsiao, T., Cheng, N.-W., Chang, N., Chen, B., & Fu, T.-F. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.004 · Cited by 66
Hitzel, J., Lee, E., Zhang, Y., Bibli, S. I., Li, X., Zukunft, S., Pflüger, B., Hu, J., Schürmann, C., Vasconez, A. E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04602-0 · Cited by 68
Mito-Nuclear Communication by Mitochondrial Metabolites and Its Regulation by B-Vitamins
Janssen, J. J. E., Grefte, S., Keijer, J., & de Boer, V. C. J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00078 · Cited by 70
“Several key steps of folate metabolism occur in mitochondria, and 30–50% of all cellular folate is located within the mitochondria (Appling, 1991; Tibbetts and Appling, 2010).”
BackgroundPetrat, F., Boengler, K., Schulz, R., & de GROOT, H. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01711.x · Cited by 66
“Within cells, glycine is oxidatively (NAD+-dependently) degraded by the mitochondrial glycine cleavage system to CO2, NH4, NADH and a methylene group, which is accepted by tetrahydrofolate, thus forming N(5),N(10)-methylenetetrahydrofolate (Kikuchi et al., 2008; Tibbetts and Appling, 2010).”
BackgroundShin, M., Momb, J., & Appling, D. R. (2017) · Cancer & Metabolism · doi:10.1186/s40170-017-0173-0 · Cited by 66
Self-citationNrf2‐Mediated Metabolic Reprogramming in Cancer
Wang, Y., Chen, J., Liu, X., Zhao, R., & Zhe, H. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/9304091 · Cited by 72
Liu, R., Zeng, L.-W., Gong, R., Yuan, F., Shu, H.-B., & Li, S. (2021) · Nature Communications · doi:10.1038/s41467-021-24321-3 · Cited by 67
Alam, C., Aufreiter, S., Georgiou, C. J., Hoque, M. T., Finnell, R. H., O’Connor, D. L., Goldman, I. D., & Bendayan, R. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1907077116 · Cited by 63
“F are required for key biosynthetic processes in mammalian cells (1).”
BackgroundMethodInfluentialMetabolic reprogramming and interventions in angiogenesis
Liu, Y., Wu, Z., Li, Y., Chen, Y., Zhao, X., Wu, M., & Xia, Y. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.05.001 · Cited by 70
“Moreover, the de novo synthesis pathway that begins with a rate-limiting step controlled by PHGDH (phosphoglycerate dehydrogenase) [76], serine is linked to one-carbon metabolism, which could regulate redox homeostasis and nucleotide synthesis [77,78].”
Schaevitz, L. R., & Berger-Sweeney, J. E. (2012) · ILAR Journal · doi:10.1093/ilar.53.3-4.322 · Cited by 67
“Methylation reactions occur within the methionine cycle when methyltransferases transfer a methyl group from S-adenosyl-methionine (SAM 1 ), the universal methyl group donor, to a methyl group acceptor, including DNA, RNA, proteins, phospholipids, or neurotransmitters (Figure 1) (Chiang et al. 1996).”
BackgroundMethodInfluentialMitochondrial Metabolism in Major Neurological Diseases
Zhou, Z., Austin, G. L., Young, L. E. A., Johnson, L. A., & Sun, R. C. (2018) · Cells · doi:10.3390/cells7120229 · Cited by 67
“All three of these enzymes have mitochondrial isoforms expressed in a wide range of tissue types, suggesting the production of purine rings, at least in part, takes place in the mitochondria [44,45].”
BackgroundField, M. S., Kamynina, E., Watkins, D., Rosenblatt, D. S., & Stover, P. J. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1414555112 · Cited by 63
“The N-terminal domain encodes the active site for 5,10-methenylTHF cyclohydrolase (C) and dehydrogenase (D) activities, whereas the C-terminal domain contains 10-formylTHF synthetase activity; the active sites of the C and D activities are overlapping (3).”
BackgroundFormate rescues neural tube defects caused by mutations in Slc25a32
Kim, J., Lei, Y., Guo, J., Kim, S., Wlodarczyk, B. J., Cabrera, R. M., Lin, Y. L., Nilsson, T., Zhang, T., Ren, A., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1800138115 · Cited by 63
“As folate is required for multiple cellular processes, including nucleotide synthesis, DNA repair, genomic stability, mitochondrial protein synthesis, and methylation reactions including histone methylation, it is clear why deficiencies of one carbon (1C) donor molecules could contribute to failed NTC (4).”
BackgroundInfluentialALDH1L1 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
One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling
Corbin, J. M., & Ruiz-Echevarría, M. J. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17081208 · Cited by 67
“SAM inhibits methylene-tetrahydrofolate reductase (MTHFR), the enzyme that catalyzes formation of 5-methylTHF, a necessary cofactor to regenerate methionine and, ultimately, SAM levels [17].”
Backgrounddi Salvo, M. L., Contestabile, R., Paiardini, A., & Maras, B. (2013) · Medical Hypotheses · doi:10.1016/j.mehy.2013.02.008 · Cited by 62
Shin, M., Bryant, J. D., Momb, J., & Appling, D. R. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.555573 · Cited by 61
“Why might mammals possess these two distinct mitochondrial dehydrogenase/cyclohydrolase isozymes? It appears that under most conditions, the majority of 1C units for cytoplasmic processes are derived from mitochondrial formate (1).”
BackgroundSelf-citationFormate 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
Toyoda, Y., Erkut, C., Pan-Montojo, F. J., Boland, S., Stewart, M. P., Müller, D. J., Wurst, W., Hyman, A. A., & Kurzchalia, T. V. (2014) · Biology Open · doi:10.1242/bio.20149399 · Cited by 61
“Rather, other mitochondrial metabolism cycles, such as one- carbon metabolism (Tibbetts and Appling, 2010; Locasale, 2013) may be involved.”
BackgroundDekhne, 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
“SHMT1, like TS, is localized to both the cytosol and nucleus (5,6); however, nuclear SHMT1 does not appear to be an important source of C1 units for TS (6,10).”
BackgroundChen, H., Li, H., & Song, Q. (2018) · ACS Omega · doi:10.1021/acsomega.8b02590 · Cited by 58
Folate nutrition and blood–brain barrier dysfunction
Stover, P. J., Durga, J., & Field, M. S. (2017) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2017.01.006 · Cited by 59
Protein methylation in mitochondria
Małecki, J., Davydova, E., & Falnes, P. Ø. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101791 · Cited by 57
“Both AdoMet and AdoHcy take part in the socalled one-carbon (1C) cycle, which is intertwined with several metabolic pathways (118).”
BackgroundAn isotope-dilution, GC–MS assay for formate and its application to human and animal metabolism
Lamarre, S. G., MacMillan, L., Morrow, G. P., Randell, E. W., Pongnopparat, T., Brosnan, M. E., & Brosnan, J. T. (2014) · Amino Acids · doi:10.1007/s00726-014-1738-7 · Cited by 55
Marani, M., Paone, A., Fiascarelli, A., Macone, A., Gargano, M., Rinaldo, S., Giardina, G., Pontecorvi, V., Koes, D. R., McDermott, L. A., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6726 · Cited by 57
“The formate derived from ME-THF would then be exported to the cytosol where it is converted into folate-activated carbon units [27, 28].”
BackgroundHigh Folate, Perturbed One-Carbon Metabolism and Gestational Diabetes Mellitus
Williamson, J. M., Arthurs, A. L., Smith, M. D., Roberts, C. T., & Jankovic-Karasoulos, T. (2022) · Nutrients · doi:10.3390/nu14193930 · Cited by 56
“It is believed that the one-carbon metabolic pathway is localized in the mitochondria to uncouple this pathway from glycolysis [60,61].”
BackgroundFormate 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
Changing appetites: the adaptive advantages of fuel choice
Stanley, I. A., Ribeiro, S. M., Giménez-Cassina, A., Norberg, E., & Danial, N. N. (2013) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.07.010 · Cited by 57
Cai, C.-C., Zhu, J., Ye, L.-X., Dai, Y., Fang, M., Hu, Y., Pan, S., Chen, S., Li, P., Fu, X., et al. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/4248529 · Cited by 55
“Moreover, mitochondria oxidatively decompose glycine into CO2, NH4 , NADH, and a methylene group to create methylenetetrahydrofolate, which sustains homeostasis [22].”
Background
Metadata
- 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
- 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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