Glycine decarboxylase maintains mitochondrial protein lipoylation to support tumor growth
Open accessAbstract
The folic acid cycle mediates the transfer of one-carbon (1C) units to support nucleotide biosynthesis. While the importance of serine as a mitochondrial and cytosolic donor of folate-mediated 1C units in cancer cells has been thoroughly investigated, a potential role of glycine oxidation remains unclear. We developed an approach for quantifying mitochondrial glycine cleavage system (GCS) flux by combining stable and radioactive isotope tracing with computational flux decomposition. We find high GCS flux in hepatocellular carcinoma (HCC), supporting nucleotide biosynthesis. Surprisingly, other than supplying 1C units, we found that GCS is important for maintaining protein lipoylation and mitochondrial activity. Genetic silencing of glycine decarboxylase inhibits the lipoylation and activity of pyruvate dehydrogenase and impairs tumor growth, suggesting a novel drug target for HCC. Considering the physiological role of liver glycine cleavage, our results support the notion that tissue of origin plays an important role in tumor-specific metabolic rewiring.
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
Cites
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?
GLDC is a mitochondrial enzyme that catalyzes the first step of glycine catabolism and is hyperactive in various cancers.
“glycine decarboxylase (GLDC), a mitochondrial enzyme that catalyzes the first step of glycine catabolism and is hyperactive in various cancers [70–72].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [70]
The Results and Discussion section, “Hepatocellular carcinoma has high expression and metabolic flux of GCS” (page unavailable), identifies GLDC as a glycine-cleavage-system subunit and reports high GLDC expression in hepatocellular carcinoma and renal cancer. The paper also reports high glycine-cleavage flux in hepatocellular carcinoma, but high expression does not establish that GLDC is hyperactive across various cancers. Our copy describes mitochondrial glycine catabolism through the system without explicitly identifying GLDC’s reaction as its first step. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., et al. (2012) · Nature · doi:10.1038/nature11003 · Cited by 7,950 · see citing works
The GTEx Consortium atlas of genetic regulatory effects across human tissues
The GTEx Consortium, Aguet, F., Anand, S., Ardlie, K. G., Gabriel, S., Getz, G. A., Graubert, A., Hadley, K., Handsaker, R. E., Huang, K. H., et al. (2020) · Science · doi:10.1126/science.aaz1776 · Cited by 5,547 · see citing works
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791 · see citing works
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 · see citing works
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 · see citing works
Reductive carboxylation supports growth in tumour cells with defective mitochondria
Mullen, A. R., Wheaton, W. W., Jin, E. S., Chen, P.-H., Sullivan, L. B., Cheng, T., Yang, Y., Linehan, W. M., Chandel, N. S., & DeBerardinis, R. J. (2012) · Nature · doi:10.1038/nature10642 · Cited by 1,328 · see citing works
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 · see citing works
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 · see citing works
Self-citationThe Cancer Genome Atlas: Creating Lasting Value beyond Its Data
Hutter, C., & Zenklusen, J. C. (2018) · Cell · doi:10.1016/j.cell.2018.03.042 · Cited by 871 · see citing works
Zhang, W. C., Shyh-Chang, N., Yang, H., Rai, A., Umashankar, S., Ma, S., Soh, B. S., Sun, L. L., Tai, B. C., Nga, M. E., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.050 · Cited by 660 · see citing works
Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism
Hanada, K. (2003) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(03)00059-3 · Cited by 618 · see citing works
Modulating the therapeutic response of tumours to dietary serine and glycine starvation
Maddocks, O. D. K., Athineos, D., Cheung, E. C., Lee, P., Zhang, T., van den Broek, N. J. F., Mackay, G. M., Labuschagne, C. F., Gay, D., Kruiswijk, F., et al. (2017) · Nature · doi:10.1038/nature22056 · Cited by 603 · see citing works
Tissue of origin dictates branched-chain amino acid metabolism in mutant <i>Kras</i> -driven cancers
Mayers, J. R., Torrence, M. E., Danai, L. V., Papagiannakopoulos, T., Davidson, S. M., Bauer, M. R., Lau, A. N., Ji, B. W., Dixit, P. D., Hosios, A. M., et al. (2016) · Science · doi:10.1126/science.aaf5171 · Cited by 582 · see citing works
Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells
Labuschagne, C. F., van den Broek, N. J. F., Mackay, G. M., Vousden, K. H., & Maddocks, O. D. K. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.045 · Cited by 576 · see citing works
LC‐MS Data Processing with MAVEN: A Metabolomic Analysis and Visualization Engine
Clasquin, M. F., Melamud, E., & Rabinowitz, J. D. (2012) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1411s37 · Cited by 507 · see citing works
Lipoic acid metabolism and mitochondrial redox regulation
Solmonson, A., & DeBerardinis, R. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.tm117.000259 · Cited by 492 · see citing works
Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway
Ducker, G. S., Chen, L., Morscher, R. J., Ghergurovich, J. M., Esposito, M., Teng, X., Kang, Y., & Rabinowitz, J. D. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.016 · Cited by 419 · see citing works
Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia
Kikuchi, G., Motokawa, Y., Yoshida, T., & Hiraga, K. (2008) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.84.246 · Cited by 381 · see citing works
SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
Kim, D., Fiske, B. P., Birsoy, K., Freinkman, E., Kami, K., Possemato, R. L., Chudnovsky, Y., Pacold, M. E., Chen, W. W., Cantor, J. R., et al. (2015) · Nature · doi:10.1038/nature14363 · Cited by 368 · see citing works
Mitochondrial translation requires folate-dependent tRNA methylation
Morscher, R. J., Ducker, G. S., Li, H., Mayer, J., Gitai, Z., Sperl, W., & Rabinowitz, J. D. (2018) · Nature · doi:10.1038/nature25460 · Cited by 278 · see citing works
Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis
Pollari, S., Käkönen, S.-M., Edgren, H., Wolf, M., Kohonen, P., Sara, H., Guise, T., Nees, M., & Kallioniemi, O. (2011) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-0848-5 · Cited by 269 · see citing works
Minton, D. R., Nam, M., McLaughlin, D. J., Shin, J., Bayraktar, E. C., Alvarez, S., Sviderskiy, V. O., Papagiannakopoulos, T. Y., Sabatini, D. M., Birsoy, K., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.01.024 · Cited by 192 · see citing works
PHGDH amplification and altered glucose metabolism in human melanoma
Mullarky, E., Mattaini, K. R., Heiden, M. G. V., Cantley, L. C., & Locasale, J. W. (2011) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2011.00919.x · Cited by 147 · see citing works
Pai, Y. J., Leung, K., Savery, D., Hutchin, T. P., Prunty, H., Heales, S., Brosnan, M. E., Brosnan, J. T., Copp, A. J., & Greene, N. D. E. (2015) · Nature Communications · doi:10.1038/ncomms7388 · Cited by 144 · see citing works
Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway
Ducker, G. S., Chen, L., Morscher, R. J., Ghergurovich, J. M., Esposito, M., Teng, X., Kang, Y., & Rabinowitz, J. D. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.011 · Cited by 91 · see citing works
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 · see citing works
Self-citationCao, X., Zhu, L., Song, X., Hu, Z., & Cronan, J. E. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1805862115 · Cited by 53 · see citing works
Zhang, W. C., Shyh‐Chang, N., He, Y., Rai, A., Umashankar, S., Ma, S., Soh, B.-S., Sun, L. L., Tai, B. C., Nga, M. E., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.024 · Cited by 48 · see citing works
Cell biology, physiology and enzymology of phosphatidylserine decarboxylase
Bartolomeo, F. D., Wagner, A., & Daum, G. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.09.007 · Cited by 46 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Metabolic reprogramming in the tumor microenvironment of liver cancer
Lin, J., Rao, D., Zhang, M., & Gao, Q. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01527-8 · Cited by 251 · see citing works
“In HCC cells, glycine-derived 1C units support purine and pyrimidine biosynthesis and tumor progression through glycine cleavage system (GCS) flux [73].”
BackgroundAcetylation: a new target for protein degradation in cancer
Crawford, C. E. W., & Burslem, G. M. (2025) · Trends in Cancer · doi:10.1016/j.trecan.2025.01.013 · Cited by 20 · see citing works
- Authors
- Mukha, D., Fokra, M., Feldman, A., Sarvin, B., Sarvin, N., Nevo-Dinur, K., Besser, E., Hallo, E., Aizenshtein, E., Schug, Z. T., & Shlomi, T.
- Affiliations
- The Wistar Institute (US)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Shlomi, Tomer
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2022-05
- Volume
- 34
- Issue
- 5
- Pages
- 775-782.e9
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC9583459
- OpenAlex
- W4225296420
- Cited by
- 69
- References
- 29
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 16 · 2023: 11 · 2022: 4
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 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)
- PubMed Central (acceptedVersion)
- Funders
- Gujarat Cancer Society (2H, 2I)
- National Institutes of Health (NCI DP2 CA249950-01, P30 CA010815)
- European Research Council (714738)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Keywords
- glycine decarboxylase, glycine cleavage system, protein lipoylation, pyruvate dehydrogenase, hepatocellular carcinoma, one-carbon units, nucleotide synthesis, tumor growth, therapeutic target, isotope tracing, flux decomposition
- MeSH terms
- Folic Acid, Glycine, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Nucleotides, Mitochondrial Proteins, Glycine Dehydrogenase (Decarboxylating), Lipoylation
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
