Asparagine signals mitochondrial respiration and can be targeted to impair tumour growth
Open accessAbstract
Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP via the electron transport chain (ETC), respiration is required for the generation of TCA cycle-derived biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Because mTORC1 coordinates availability of biosynthetic precursors with anabolic metabolism, including nucleotide synthesis, a link between respiration and mTORC1 is fitting. Here we show that in addition to depleting intracellular aspartate, ETC inhibition depletes aspartate-derived asparagine and impairs mTORC1 activity. Providing exogenous asparagine restores mTORC1 activity, nucleotide synthesis, and proliferation in the context of ETC inhibition without restoring intracellular aspartate in a panel of cancer cell lines. As a therapeutic strategy, the combination of ETC inhibitor metformin, which limits tumour asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumour asparagine consumption, effectively impairs tumour growth in several mouse models of cancer. Because environmental asparagine is sufficient to restore proliferation with respiration impairment, both in vitro and in vivo , our findings suggest that asparagine synthesis is a fundamental purpose of mitochondrial respiration. Moreover, the results suggest that asparagine signals active respiration to mTORC1 to communicate biosynthetic precursor sufficiency and promote anabolism.
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Asparagine functions as an exchange factor needed for uptake of other amino acids required for mTORC1 activation and for enhanced nucleotide biosynthesis under mitochondrial electron transport chain impairment.
“Recently, asparagine has been reported to function as an exchange factor needed for the uptake of other amino acids that are required for mTORC1 activation53 and for enhanced nucleotide biosynthesis under mitochondrial electron chain transport system impairment54.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [54]
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Cites
A cross-platform toolkit for mass spectrometry and proteomics
Chambers, M., MacLean, B., Burke, R., Amodei, D., Ruderman, D., Neumann, S., Gatto, L., Fischer, B., Pratt, B. S., Egertson, J. D., et al. (2012) · Nature Biotechnology · doi:10.1038/nbt.2377 · Cited by 4,038 · see citing works
Pluskal, T., Castillo, S., Villar‐Briones, A., & Orešič, M. (2010) · BMC Bioinformatics · doi:10.1186/1471-2105-11-395 · Cited by 3,852 · see citing works
Newgard, C. B., An, J., Bain, J. R., Muehlbauer, M. J., Stevens, R. D., Lien, L. F., Haqq, A. M., Shah, S. H., Arlotto, M., Slentz, C. A., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.02.002 · Cited by 3,165 · see citing works
Activation of a metabolic gene regulatory network downstream of mTOR complex 1
Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.022 · Cited by 2,020 · see citing works
Human Cells Lacking mtDNA: Repopulation with Exogenous Mitochondria by Complementation
King, M. P., & Attardi, G. M. (1989) · Science · doi:10.1126/science.2814477 · Cited by 1,659 · see citing works
Birsoy, K., Wang, T., Chen, W. W., Freinkman, E., Abu-Remaileh, M., & Sabatini, D. M. (2015) · Cell · doi:10.1016/j.cell.2015.07.016 · Cited by 1,388 · see citing works
Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation
(1990) · Trends in Genetics · doi:10.1016/0168-9525(90)90040-d · Cited by 1,386 · see citing works
Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells
Sullivan, L. B., Gui, D. Y., Hosios, A. M., Bush, L. N., Freinkman, E., & Vander Heiden, M. G. (2015) · Cell · doi:10.1016/j.cell.2015.07.017 · Cited by 1,173 · see citing works
Mammalian TOR: a homeostatic ATP sensor
Dennis, P. B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S. C., & Thomas, G. (2001) · Science · doi:10.1126/science.1063518 · Cited by 962 · see citing works
Dowling, R. J. O., Zakikhani, M., Fantus, I. G., Pollak, M., & Sonenberg, N. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2310 · Cited by 933 · see citing works
Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.014 · Cited by 889 · see citing works
Quirós, P. M., Prado, M. A., Zamboni, N., D’Amico, D., Williams, R. W., Finley, D., Gygi, S. P., & Auwerx, J. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201702058 · Cited by 832 · see citing works
Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1
Ben-Sahra, I., Howell, J. J., Asara, J. M., & Manning, B. D. (2013) · Science · doi:10.1126/science.1228792 · Cited by 739 · see citing works
Mitochondrial stress is relayed to the cytosol by an OMA1–DELE1–HRI pathway
Guo, X., Aviles, G., Liu, Y., Tian, R., Unger, B. A., Lin, Y.-H. T., Wiita, A. P., Xu, K., Correia, M. A., & Kampmann, M. (2020) · Nature · doi:10.1038/s41586-020-2078-2 · Cited by 674 · see citing works
de Haar-Holleman, A., Cheok, M. H.-C., den Boer, M. L., Yang, W., Veerman, A. J. P., Kazemier, K. M., Pei, D., Cheng, C., Pui, C., Relling, M. V., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa033513 · Cited by 629 · see citing works
Asparagine bioavailability governs metastasis in a model of breast cancer
Knott, S., Wagenblast, E., Khan, S., Kim, S. Y., Soto, M., Wagner, M., Turgeon, M., Fish, L., Erard, N., Gable, A. L., et al. (2018) · Nature · doi:10.1038/nature25465 · Cited by 534 · see citing works
Self-citationA pathway coordinated by DELE1 relays mitochondrial stress to the cytosol
Fessler, E., Eckl, E.-M., Schmitt, S., Mancilla, I. A., Meyer-Bender, M., Hanf, M., Philippou‐Massier, J., Krebs, S., Zischka, H., & Jae, L. T. (2020) · Nature · doi:10.1038/s41586-020-2076-4 · Cited by 514 · see citing works
Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor
Krall, A. S., Xu, S., Graeber, T. G., Braas, D., & Christofk, H. R. (2016) · Nature Communications · doi:10.1038/ncomms11457 · Cited by 504 · see citing works
Self-citationMyers, O. D., Sumner, S., Li, S., Barnes, S., & Du, X. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.7b00947 · Cited by 435 · see citing works
Balsa, E., Soustek, M. S., Thomas, A. J., Cogliati, S., García‐Poyatos, C., Martín-García, E., Jedrychowski, M. P., Gygi, S. P., Enrı́quez, J. A., & Puigserver, P. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.03.031 · Cited by 317 · see citing works
Metabolite Spectral Accuracy on Orbitraps
Su, X., Lu, W., & Rabinowitz, J. D. (2017) · Analytical Chemistry · doi:10.1021/acs.analchem.7b00396 · Cited by 270 · see citing works
Zhang, X., Fryknäs, M., Hernlund, E., Fayad, W., Milito, A. D., Olofsson, M. H., Gogvadze, V. G., Dang, L. H., Påhlman, S., Kunz‐Schughart, L. A., et al. (2014) · Nature Communications · doi:10.1038/ncomms4295 · Cited by 253 · see citing works
Therapeutic Concentrations of Metformin: A Systematic Review
Kajbaf, F., Broe, M. E. D., & Lalau, J. (2015) · Clinical Pharmacokinetics · doi:10.1007/s40262-015-0323-x · Cited by 155 · see citing works
Regulation of asparagine synthetase gene expression by amino acid starvation.
Gong, S. S., Guerrini, L., & Basilico, C. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.12.6059 · Cited by 93 · see citing works
Lorenzi, P. L., Llamas, J., Gunsior, M., Ozbun, L. L., Reinhold, W. C., Varma, S., Ji, H., Kim, H., Hutchinson, A. A., Kohn, E. C., et al. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0589 · Cited by 91 · see citing works
Rajeshkumar, N. V., Yabuuchi, S., Pai, S. G., Oliveira, E. D., Kamphorst, J. J., Rabinowitz, J. D., Tejero, H., Al‐Shahrour, F., Hidalgo, M. M., Maitra, A., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1115 · Cited by 90 · see citing works
Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma
Hettmer, S., Schinzel, A. C., Tchessalova, D., Schneider, M., Parker, C. L., Bronson, R. T., Richards, N. G. J., Hahn, W. C., & Wagers, A. J. (2015) · eLife · doi:10.7554/elife.09436 · Cited by 59 · see citing works
Hunt, R. J., Granat, L., McElroy, G. S., Ranganathan, R., Chandel, N. S., & Bateman, J. M. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201904148 · Cited by 49 · see citing works
Metabolomics Strategy Reveals Subpopulation of Liposarcomas Sensitive to Gemcitabine Treatment
Braas, D., Ahler, E., Tam, B., Nathanson, D. A., Riedinger, M., Benz, M., Smith, K. B., Eilber, F. C., Witte, O. N., Tap, W. D., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0197 · Cited by 32 · see citing works
Self-citationPyruvate blocks expression of sensitivity to antimycin A and chloramphenicol
Harris, M. (1980) · Somatic Cell Genetics · doi:10.1007/bf01538969 · Cited by 30 · see citing works
Lactic Acidosis With Therapeutic Metformin Blood Level in a Low-Risk Diabetic Patient
Al-Jebawi, A. F., LASSMAN, M. N., & Abourizk, N. N. (1998) · Diabetes Care · doi:10.2337/diacare.21.8.1364 · Cited by 29 · see citing works
Wuu, J.-A., Wen, L. Y., Chuang, T. Y., & Chang, G. G. (1988) · Clinical Chemistry · doi:10.1093/clinchem/34.8.1610 · Cited by 24 · see citing works
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Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
The biological underpinnings of therapeutic resistance in pancreatic cancerPreprint
Beatty, G. L., Werba, G., Lyssiotis, C. A., & Simeone, D. M. (2021) · Genes & Development · doi:10.1101/gad.348523.121 · Cited by 133 · see citing works
“2B; Halbrook et al. 2020; Krall et al. 2020).”
Self-citationTargeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis
Sharma, S., Agnihotri, N., & Kumar, S. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114943 · Cited by 42 · see citing works
The MEMIC is an ex vivo system to model the complexity of the tumor microenvironment
Janská, L., Anandi, L., V, Kirchberger, N. C., Marinkovic, Z. S., Schachtner, L. T., Guzelsoy, G., & Carmona‐Fontaine, C. (2021) · Disease Models & Mechanisms · doi:10.1242/dmm.048942 · Cited by 14 · see citing works
“, 2011), and asparagine (Halbrook et al., 2020; Krall et al., 2020; Pavlova et al., 273 2018), as well as diet-derived essential amino acids, vitamins, and lipids (Bose et al.”
Davidsen, K., & Sullivan, L. B. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1251 · Cited by 7 · see citing works
- Authors
- Krall, A. S., Mullen, P. J., Surjono, F., Momcilovic, M., Schmid, E. W., Halbrook, C. J., Thambundit, A., Mittelman, S. D., Lyssiotis, C. A., Shackelford, D. B., Knott, S. R. V., & Christofk, H. R.
- Affiliations
- University of California, Los Angeles (US)
- Cedars-Sinai Medical Center (US)
- University of Michigan (US)
- Corresponding author
- Christofk, Heather R.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2020-03-18
- OpenAlex
- W3010868473
- Cited by
- 5
- References
- 32
- Citations by year
- 2022: 1 · 2021: 2 · 2020: 2
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- American Cancer Society (RSG-18-186-01, RSG-16-111-01-MPC)
- UCLA Health System
- Jazz Pharmaceuticals
- Jonsson Comprehensive Cancer Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- asparagine, mitochondrial respiration, mTORC1, electron transport inhibition, aspartic acid, nucleotide synthesis, TCA cycle, tumor cell proliferation, metformin, L-asparaginase, tumor growth, biosynthetic precursors, anabolism
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