Increased demand for NAD(+) relative to ATP drives aerobic glycolysis
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Abstract
Abstract Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is a hallmark of proliferative metabolism that is observed across many organisms and conditions. To better understand why aerobic glycolysis is associated with cell proliferation, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase mitochondrial pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the nicotinamide adenine dinucleotide cofactor ratio (NAD+/NADH). This change in NAD+/NADH ratio is caused by an increase in mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling mitochondrial respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when the demand for NAD+ to support oxidation reactions exceeds the demand for ATP consumption in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation despite available oxygen. This argues that cells engage in aerobic glycolysis when the cellular demand for NAD+ is in excess of the cellular demand for ATP.
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Cell proliferation can be impaired when demand for mitochondrial NAD+ exceeds that of ATP, which may explain why highly proliferative cells often engage in aerobic glycolysis over pyruvate oxidation and OXPHOS even with sufficient oxygen.
“These results indicate that cell proliferation can be impaired when the demand for mitochondrial NAD+ exceeds that of ATP and may explain why highly proliferative cells often engage in aerobic glycolysis over pyruvate oxidation and OXPHOS, even in the presence of sufficient oxygen (138).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [138]
Increasing flux through OXPHOS by increasing ATP consumption reverses the growth inhibitory effects of PDHC activation.
“Increasing flux through OXPHOS by increasing ATP consumption reverses the growth inhibitory effects of PDHC activation (138).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [138]
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Cites
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · see citing works
Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425 · see citing works
The Warburg Effect: How Does it Benefit Cancer Cells?
Liberti, M. V., & Locasale, J. W. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.12.001 · Cited by 5,150 · see citing works
Why Do Cancers Have High Aerobic Glycolysis?
Gatenby, R. A., & Gillies, R. J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1478 · Cited by 4,784 · see citing works
Regulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744 · see citing works
Kim, J.-W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.002 · Cited by 3,905 · see citing works
CRISPR-Mediated Modular RNA-Guided Regulation of Transcription in Eukaryotes
Gilbert, L. A., Larson, M. H., Morsut, L., Liu, Z., Brar, G. A., Torres, S. E., Stern-Ginossar, N., Brandman, O., Whitehead, E. H., Doudna, J. A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.044 · Cited by 3,696 · see citing works
On Respiratory Impairment in Cancer Cells
Warburg, O. H. (1956) · Science · doi:10.1126/science.124.3215.269 · Cited by 3,472 · see citing works
Otto Warburg's contributions to current concepts of cancer metabolism
Koppenol, W. H., Bounds, P. L., & Dang, C. V. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3038 · Cited by 3,427 · see citing works
Assessing mitochondrial dysfunction in cells
Brand, M. D., & Nicholls, D. G. (2011) · Biochemical Journal · doi:10.1042/bj20110162 · Cited by 2,436 · see citing works
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L., & Denko, N. C. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.01.012 · Cited by 2,267 · see citing works
Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R. S., & Chandel, N. S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003428107 · Cited by 1,742 · see citing works
Glucose feeds the TCA cycle via circulating lactate
Hui, S., Ghergurovich, J. M., Morscher, R. J., Jang, C., Teng, X., Lu, W., Esparza, L. A., Reya, T., Zhan, L., Yanxiang Guo, J., et al. (2017) · Nature · doi:10.1038/nature24057 · Cited by 1,721 · see citing works
Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648 · see citing works
Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice
Sonveaux, P., Végran, F., Schroeder, T., Wergin, M., Verrax, J., Rabbani, Z. N., Saedeleer, C. J. D., Kennedy, K. M., Diepart, C., Jordan, B. F., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36843 · Cited by 1,635 · see citing works
Fantin, V. R., St-Pierre, J., & Leder, P. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.04.023 · Cited by 1,635 · see citing works
Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression
Le, A., Cooper, C. R., Gouw, A. M., Dinavahi, R., Maitra, A., Deck, L. M., Royer, R. E., Jagt, D. L. V., Semenza, G. L., & Dang, C. V. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914433107 · Cited by 1,528 · see citing works
Ying, W. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1672 · Cited by 1,494 · see citing works
Metabolic pathways promoting cancer cell survival and growth
Boroughs, L. K., & DeBerardinis, R. J. (2015) · Nature Cell Biology · doi:10.1038/ncb3124 · Cited by 1,459 · see citing works
LeBleu, V. S., O’Connell, J. T., Herrera, K. N. G., Wikman, H., Pantel, K., Haigis, M. C., de Carvalho, F. M., Damascena, A. S., Chinen, L. T. D., Rocha, R. M., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3039 · Cited by 1,412 · 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
Cooperation and Competition in the Evolution of ATP-Producing Pathways
Pfeiffer, T., Schuster, S., & Bonhoeffer, S. (2001) · Science · doi:10.1126/science.1058079 · Cited by 1,365 · see citing works
Lactate Metabolism in Human Lung Tumors
Faubert, B., Li, K. Y., Cai, L., Hensley, C. T., Kim, J., Zacharias, L. G., Yang, C., Do, Q. N., Doucette, S., Burguete, D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.019 · Cited by 1,343 · see citing works
Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function
Viale, A., Pettazzoni, P., Lyssiotis, C. A., Ying, H., Sánchez, N., Marchesini, M., Carugo, A., Green, T., Seth, S., Giuliani, V., et al. (2014) · Nature · doi:10.1038/nature13611 · Cited by 1,259 · see citing works
The Control of the Metabolic Switch in Cancers by Oncogenes and Tumor Suppressor Genes
Levine, A. J., & Puzio-Kuter, A. M. (2010) · Science · doi:10.1126/science.1193494 · Cited by 1,243 · see citing works
Mitochondrial Membrane Potential Probes and the Proton Gradient: A Practical Usage Guide
Perry, S. W., Norman, J. P., Barbieri, J., Brown, E. B., & Gelbard, H. A. (2011) · BioTechniques · doi:10.2144/000113610 · Cited by 1,196 · 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
Self-citationMetformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis
Wheaton, W. W., Weinberg, S. E., Hamanaka, R. B., Soberanes, S., Sullivan, L. B., Anso, E., Glasauer, A., Dufour, E., Mutlu, G. M., Budigner, G. S., et al. (2014) · eLife · doi:10.7554/elife.02242 · Cited by 1,105 · see citing works
Self-citationA hierarchy of ATP-consuming processes in mammalian cells
Buttgereit, F., & Brand, M. D. (1995) · Biochemical Journal · doi:10.1042/bj3120163 · Cited by 929 · see citing works
Horlbeck, M. A., Gilbert, L. A., Villalta, J. E., Adamson, B., Pak, R. A., Chen, Y., Fields, A. P., Park, C. Y., Corn, J. E., Kampmann, M., et al. (2016) · eLife · doi:10.7554/elife.19760 · Cited by 894 · see citing works
The Crabtree Effect: A Regulatory System in Yeast
DEKEN, R. H. D. (1966) · Journal of General Microbiology · doi:10.1099/00221287-44-2-149 · Cited by 880 · see citing works
Tan, A. S., Baty, J. W., Dong, L.-F., Bezawork-Geleta, A., Endaya, B., Goodwin, J., Bajzikova, M., Kovarova, J., Peterka, M., Yan, B., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.003 · Cited by 785 · see citing works
Overflow metabolism in Escherichia coli results from efficient proteome allocation
Basan, M., Hui, S., Okano, H., Zhang, Z., Shen, Y., Williamson, J. R., & Hwa, T. (2015) · Nature · doi:10.1038/nature15765 · Cited by 785 · see citing works
Metabolic Modulation of Glioblastoma with Dichloroacetate
Michelakis, E. D., Sutendra, G., Dromparis, P., Webster, L., Haromy, A., Niven, E. B., Maguire, C., Gammer, T.-L., Mackey, J. R., Fulton, D. S., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000677 · Cited by 722 · see citing works
Bonora, M., Patergnani, S., Rimessi, A., De Marchi, E., Suski, J. M., Bononi, A., Giorgi, C., Marchi, S., Missiroli, S., Poletti, F., et al. (2012) · Purinergic Signalling · doi:10.1007/s11302-012-9305-8 · Cited by 644 · see citing works
Hosios, A. M., Hecht, V. C., Danai, L. V., Johnson, M. O., Rathmell, J. C., Steinhauser, M. L., Manalis, S. R., & Vander Heiden, M. G. (2016) · Developmental Cell · doi:10.1016/j.devcel.2016.02.012 · Cited by 641 · see citing works
Self-citationA key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence
Kaplon, J., Zheng, L., Meissl, K., Chaneton, B., Selivanov, V. A., Mackay, G., van der Burg, S. H., Verdegaal, E. M. E., Cascante, M., Shlomi, T., et al. (2013) · Nature · doi:10.1038/nature12154 · Cited by 633 · see citing works
�ber den Stoffwechsel der Carcinomzelle
Warburg, O. (1924) · Die Naturwissenschaften · doi:10.1007/bf01504608 · Cited by 631 · see citing works
Control of respiration and ATP synthesis in mammalian mitochondria and cells
Brown, G. C. (1992) · Biochemical Journal · doi:10.1042/bj2840001 · Cited by 598 · see citing works
Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells
Lewis, C. A., Parker, S. J., Fiske, B. P., McCloskey, D., Gui, D. Y., Green, C. R., Vokes, N. I., Feist, A. M., Vander Heiden, M. G., & Metallo, C. M. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.008 · Cited by 562 · see citing works
Self-citationOn respiratory impairment in cancer cells
Weinhouse, S. (1956) · Science · doi:10.1126/science.124.3215.267 · Cited by 554 · see citing works
Titov, D. V., Cracan, V., Goodman, R. P., Peng, J., Grabarek, Z., & Mootha, V. K. (2016) · Science · doi:10.1126/science.aad4017 · Cited by 518 · see citing works
Xie, H., Hanai, J.-I., Ren, J.-G., Kats, L., Burgess, K., Bhargava, P., Signoretti, S., Billiard, J., Duffy, K. J., Grant, A., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.003 · Cited by 516 · see citing works
Imaging cytosolic NADH-NAD(+) redox state with a genetically encoded fluorescent biosensor
Hung, Y. P., Albeck, J. G., Tantama, M., & Yellen, G. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.08.012 · Cited by 509 · see citing works
Heiden, M. G. V., Chandel, N. S., Schumacker, P. T., & Thompson, C. B. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80307-x · Cited by 505 · see citing works
Diaz-Ruiz, R., Rigoulet, M., & Devin, A. (2011) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.08.010 · Cited by 486 · see citing works
Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours
Garcia-Bermudez, J., Baudrier, L., La, K., Zhu, X. G., Fidelin, J., Sviderskiy, V. O., Papagiannakopoulos, T., Molina, H., Snuderl, M., Lewis, C. A., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0118-z · Cited by 442 · see citing works
Self-citationMitochondrial dysfunction remodels one-carbon metabolism in human cells
Bao, X. R., Ong, S., Goldberger, O., Peng, J., Sharma, R., Thompson, D. A., Vafai, S. B., Cox, A. G., Marutani, E., Ichinose, F., et al. (2016) · eLife · doi:10.7554/elife.10575 · Cited by 439 · see citing works
Pyruvate Dehydrogenase Complex Activity Controls Metabolic and Malignant Phenotype in Cancer Cells
McFate, T., Mohyeldin, A., Lu, H., Thakar, J. H., Henriques, J., Halim, N. D., Wu, H., Schell, M. J., Tsang, T. M., Teahan, O., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801765200 · Cited by 383 · see citing works
Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis
Rabinovich, S., Adler, L., Yizhak, K., Sarver, A., Silberman, A., Agron, S., Stettner, N., Sun, Q., Brandis, A., Helbling, D., et al. (2015) · Nature · doi:10.1038/nature15529 · Cited by 382 · see citing works
Increasing NADH oxidation reduces overflow metabolism in Saccharomyces cerevisiae
Vemuri, G. N., Eiteman, M. A., McEwen, J. E., Lisbeth Olsson, A., & Nielsen, J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607469104 · Cited by 373 · see citing works
Coordinated regulation of protein synthesis and degradation by mTORC1
Zhang, Y., Nicholatos, J. W., Dreier, J. R., Ricoult, S. J. H., Widenmaier, S. B., Hotamışlıgil, G. S., Kwiatkowski, D. J., & Manning, B. D. (2014) · Nature · doi:10.1038/nature13492 · Cited by 349 · see citing works
Aspartate is an endogenous metabolic limitation for tumour growth
Sullivan, L. B., Luengo, A., Danai, L. V., Bush, L. N., Diehl, F. F., Hosios, A. M., Lau, A. N., Elmiligy, S., Malstrom, S. E., Lewis, C. A., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0125-0 · Cited by 339 · see citing works
Self-citationMitochondrial fusion supports increased oxidative phosphorylation during cell proliferation
Yao, C.-H., Wang, R., Wang, Y., Kung, C.-P., Weber, J. D., & Patti, G. J. (2019) · eLife · doi:10.7554/elife.41351 · Cited by 338 · see citing works
Aerobic glycolysis during lymphocyte proliferation
Wang, T., Marquardt, C. A., & Foker, J. E. (1976) · Nature · doi:10.1038/261702a0 · Cited by 333 · see citing works
Hitosugi, T., Fan, J., Chung, T., Lythgoe, K., Wang, X., Xie, J., Ge, Q., Gu, T.-L., Polakiewicz, R. D., Roesel, J. L., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.10.015 · Cited by 329 · see citing works
Gui, D. Y., Sullivan, L. B., Luengo, A., Hosios, A. M., Bush, L. N., Gitego, N., Davidson, S. M., Freinkman, E., Thomas, C. J., & Vander Heiden, M. G. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.006 · Cited by 323 · see citing works
Self-citationCatabolic efficiency of aerobic glycolysis: The Warburg effect revisited
Vázquez, A., Liu, J., Zhou, Y., & Oltvai, Z. N. (2010) · BMC Systems Biology · doi:10.1186/1752-0509-4-58 · Cited by 320 · see citing works
Regulation of pyruvate dehydrogenase kinase and phosphatase by acetyl-CoA/CoA and NADH/NAD ratios
Pettit, F. H., Pelley, J. W., & Reed, L. J. (1975) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(75)80185-9 · Cited by 315 · see citing works
Pyruvate Kinase Isoform Expression Alters Nucleotide Synthesis to Impact Cell Proliferation
Lunt, S. Y., Muralidhar, V., Hosios, A. M., Israelsen, W. J., Gui, D. Y., Newhouse, L., Ogrodzinski, M. P., Hecht, V. C., Xu, K., Acevedo, P. N. M., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.10.027 · Cited by 258 · see citing works
Self-citationH+ transport is an integral function of the mitochondrial ADP/ATP carrier
Bertholet, A. M., Chouchani, E. T., Kazak, L., Angelin, A., Fedorenko, A., Long, J. Z., Vidoni, S., Garrity, R., Cho, J., Terada, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1400-3 · Cited by 256 · see citing works
Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites
KOLOBOVA, E. A., Tuganova, A., Boulatnikov, I. G., & Popov, K. M. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3580069 · Cited by 254 · 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
Bioenergetics and the problem of tumor growth.
Racker, E. (1972) · PubMed · Cited by 252 · see citing works
Korotchkina, L. G., & Patel, M. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103069200 · Cited by 246 · see citing works
Kato, M., Li, J., Chuang, J. L., et al. (2007) · Structure · doi:10.1016/j.str.2007.07.001 · Cited by 222 · see citing works
Fang, M., Shen, Z., Huang, S., Zhao, L., Chen, S., Mak, T. W., & Wang, X. (2010) · Cell · doi:10.1016/j.cell.2010.10.010 · Cited by 222 · see citing works
Rumsey, W. L., Schlosser, C., Nuutinen, E. M., Robiolio, M., & Wilson, D. F. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55409-0 · Cited by 211 · see citing works
Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites
KOLOBOVA, E. A., Tuganova, A., Boulatnikov, I. G., et al. (2001) · Biochemical Journal · doi:10.1042/bj3580069 · Cited by 200 · see citing works
Glycolytic reliance promotes anabolism in photoreceptors
Chinchore, Y., Begaj, T., Wu, D., Drokhlyansky, E., & Cepko, C. L. (2017) · eLife · doi:10.7554/elife.25946 · Cited by 191 · see citing works
Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer
Kennedy, K. M., Scarbrough, P. M., Ribeiro, A., Richardson, R., Yuan, H., Sonveaux, P., Landon, C. D., Chi, J.-T., Pizzo, S., Schroeder, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0075154 · Cited by 190 · see citing works
Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferationPreprint
Grassian, A. R., Metallo, C. M., Coloff, J. L., Stephanopoulos, G. N., & Brugge, J. S. (2011) · Genes & Development · doi:10.1101/gad.16771811 · Cited by 178 · see citing works
Aerobic glycolysis and lymphocyte transformation
Hume, D. A., Radik, J., Ferber, E., & Weidemann, M. J. (1978) · Biochemical Journal · doi:10.1042/bj1740703 · Cited by 172 · see citing works
Matheson, N. J., Sumner, J., Wals, K., Rapiteanu, R., Weekes, M. P., Vigan, R., Weinelt, J., Schindler, M., Antrobus, R., Costa, A. S. H., et al. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.09.003 · Cited by 169 · see citing works
Self-citationTargeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth
Schöckel, L., Glasauer, A., Basit, F., Bitschar, K., Truong, H., Erdmann, G., Algire, C., Hägebarth, A., Willems, P. H., Kopitz, C., et al. (2015) · Cancer & Metabolism · doi:10.1186/s40170-015-0138-0 · Cited by 161 · see citing works
Diehl, F. F., Lewis, C. A., Fiske, B. P., & Vander Heiden, M. G. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0108-x · Cited by 159 · see citing works
Self-citationThe redox requirements of proliferating mammalian cells
Hosios, A. M., & Heiden, M. G. V. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.tm117.000239 · Cited by 147 · see citing works
Exogenous Fatty Acids Are the Preferred Source of Membrane Lipids in Proliferating Fibroblasts
Yao, C.-H., Fowle-Grider, R., Mahieu, N. G., Liu, G., Chen, Y., Wang, R., Singh, M., Potter, G. S., Gross, R. W., Schaefer, J., et al. (2016) · Cell chemical biology · doi:10.1016/j.chembiol.2016.03.007 · Cited by 142 · see citing works
Molecular Oxygen Modulates Cytochrome c Oxidase Function
Chandel, N. S., Budinger, G. R. S., & Schumacker, P. T. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.31.18672 · Cited by 139 · see citing works
Extracellular serine controls epidermal stem cell fate and tumour initiation
Baksh, S. C., Todorova, P. K., Gur-Cohen, S., Hurwitz, B., Ge, Y., Novak, J. S. S., Tierney, M. T., dela Cruz-Racelis, J., Fuchs, E., & Finley, L. W. S. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0525-9 · Cited by 128 · see citing works
Regulatory Mechanisms in Carbohydrate Metabolism
Scholnick, P. L., Lang, D., & Racker, E. (1973) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)43686-7 · Cited by 103 · see citing works
Munyon, W. H., & Merchant, D. J. (1959) · Experimental Cell Research · doi:10.1016/0014-4827(59)90069-2 · Cited by 93 · see citing works
Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells
Naguib, A., Mathew, G., Reczek, C. R., Watrud, K. E., Ambrico, A. J., Herzka, T. M., Casanova‐Salas, I., Lee, M. F., El-Amine, N., Zheng, W., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.032 · Cited by 93 · see citing works
AZD7545 is a selective inhibitor of pyruvate dehydrogenase kinase 2
Morrell, J., Orme, J. P., Butlin, R. J., Roche, T. E., Mayers, R. M., & Kilgour, E. (2003) · Biochemical Society Transactions · doi:10.1042/bst0311168 · Cited by 86 · see citing works
Zabka, T. S., Singh, J., Dhawan, P., Liederer, B. M., Oeh, J., Kauss, M. A., Xiao, Y., Zak, M., Lin, T., McCray, B., et al. (2014) · Toxicological Sciences · doi:10.1093/toxsci/kfu268 · Cited by 83 · see citing works
Role and Regulation of Glucose Metabolism in Proliferating Cells
Hume, D., & Weidemann, M. J. (1979) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/62.1.3 · Cited by 81 · see citing works
Brand, K., Leibold, W., Luppa, P., Schoerner, C., & Schulz, A. (1986) · Immunobiology · doi:10.1016/s0171-2985(86)80086-9 · Cited by 80 · see citing works
Limits of aerobic metabolism in cancer cells
Fernández-de-Cossio-Díaz, J., & Vázquez, A. (2017) · Scientific Reports · doi:10.1038/s41598-017-14071-y · Cited by 77 · see citing works
Vazquez, A., & Oltvai, Z. N. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019538 · Cited by 70 · see citing works
Kurmi, K., Hitosugi, S., Yu, J., Boakye‐Agyeman, F., Wiese, E. K., Larson, T. R., Dai, Q., Machida, Y., Lou, Z., Wang, L., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.08.008 · Cited by 70 · see citing works
New Aspects of Mitochondrial Uncoupling Proteins (UCPs) and Their Roles in Tumorigenesis
Robbins, D. F., & Zhao, Y. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12085285 · Cited by 69 · see citing works
Role of Uncoupling Proteins in Cancer
Valle, A., Oliver, J., & Roca, P. (2010) · Cancers · doi:10.3390/cancers2020567 · Cited by 67 · see citing works
Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth
Liu, M., Wang, Y., Yang, C., Ruan, Y., Bai, C., Chu, Q., Cui, Y., Chen, C., Ying, G., & Li, B. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20191226 · Cited by 56 · see citing works
The contribution of ATP turnover by the Na+/K+-ATPase to the rate of respiration of hepatocytes
Nobes, C. D., Lakin‐Thomas, P. L., & Brand, M. D. (1989) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(89)80236-1 · Cited by 55 · see citing works
MFSD7C switches mitochondrial ATP synthesis to thermogenesis in response to heme
Li, Y., Ivica, N. A., Dong, T., Papageorgiou, D. P., He, Y., Brown, D. R., Kleyman, M., Hu, G., Chen, W. W., Sullivan, L. B., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18607-1 · Cited by 50 · see citing works
Self-citationHowell, N., & Sager, R. (1979) · Somatic Cell and Molecular Genetics · doi:10.1007/bf01542645 · Cited by 41 · see citing works
Metabolism of renal tumors in situ and during ischemia.
Dh, W., Ha, K., Stubbs, M., et al. (1970) · PubMed · Cited by 29 · see citing works
Merker, M. P., Audi, S. H., Bongard, R. D., Lindemer, B. J., & Krenz, G. S. (2005) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00302.2005 · Cited by 26 · see citing works
Kawashima, M., Bensaad, K., Zois, C. E., Barberis, A., Bridges, E., Wigfield, S., Lagerholm, B. C., Dmitriev, R. I., Tokiwa, M., Toi, M., et al. (2020) · Cancer & Metabolism · doi:10.1186/s40170-020-00219-4 · Cited by 20 · see citing works
[Ethyl alcohol production and growth of baker's yeast cultured under aerobic conditions].
Lemoigne, M., Jp, A., & Millet, J. (1954) · PubMed · Cited by 14 · see citing works
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Sorted by citations
The hallmarks of cancer metabolism: still emerging
Pavlova, N. N., Zhu, J., & Thompson, C. B. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.01.007 · Cited by 1,418 · see citing works
Regulation and function of the mammalian tricarboxylic acid cycle
Arnold, P. K., & Finley, L. W. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102838 · Cited by 535 · see citing works
A non-canonical tricarboxylic acid cycle underlies cellular identity
Arnold, P. K., Jackson, B. T., Paras, K. I., Brunner, J. S., Hart, M. L., Newsom, O. J., Alibeckoff, S. P., Endress, J., Drill, E., Sullivan, L. B., et al. (2022) · Nature · doi:10.1038/s41586-022-04475-w · Cited by 304 · see citing works
Self-citationCellular ATP demand creates metabolically distinct subpopulations of mitochondria
Ryu, K. W., Fung, T. S., Baker, D. C., Saoi, M., Park, J., Febres-Aldana, C. A., Aly, R. G., Cui, R., Sharma, A., Fu, Y., et al. (2024) · Nature · doi:10.1038/s41586-024-08146-w · Cited by 284 · see citing works
100 years of the Warburg effect: A cancer metabolism endeavor
Fendt, S.-M. (2024) · Cell · doi:10.1016/j.cell.2024.06.026 · Cited by 223 · see citing works
Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells
Wang, Y., Stancliffe, E., Fowle-Grider, R., Wang, R., Wang, C., Schwaiger-Haber, M., Shriver, L. P., & Patti, G. J. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.07.007 · Cited by 180 · see citing works
Carbon source availability drives nutrient utilization in CD8+ T cells
Kaymak, I., Luda, K. M., Duimstra, L. R., Ma, E. H., Longo, J., Dahabieh, M. S., Faubert, B., Oswald, B. M., Watson, M. J., Kitchen-Goosen, S. M., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.07.012 · Cited by 160 · see citing works
Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited
Li, Z., Ji, B. W., Dixit, P. D., Tchourine, K., Lien, E. C., Hosios, A. M., Abbott, K. L., Rutter, J. C., Westermark, A. M., Gorodetsky, E. F., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00588-8 · Cited by 81 · see citing works
The Warburg Effect is the result of faster ATP production by glycolysis than respiration
Kukurugya, M. A., Rosset, S., & Titov, D. V. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2409509121 · Cited by 81 · see citing works
CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma
Chen, Y., Zhu, Z., Wu, X., Li, H., Guan, W., & Ren, H. (2024) · Cell Death Discovery · doi:10.1038/s41420-023-01777-4 · Cited by 6 · see citing works
- Authors
- Luengo, A., Li, Z., Gui, D. Y., Sullivan, L. B., Zagorulya, M., Do, B. T., Ferreira, R., Naamati, A., Ali, A., Lewis, C. A., Thomas, C. J., Spranger, S., Matheson, N. J., & Vander Heiden, M. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Fred Hutch Cancer Center (US)
- Harvard University (US)
- University of Cambridge (GB)
- Whitehead Institute for Biomedical Research (US)
- National Institutes of Health (US)
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 81
- Issue
- 4
- Pages
- 691-707.e6
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC8315838
- OpenAlex
- W3113834486
- Cited by
- 547
- References
- 100
- Citations by year
- 2026: 90 · 2025: 139 · 2024: 113 · 2023: 92 · 2022: 69 · 2021: 44
- FWCI
- 17.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Chalmers Research (Chalmers University of Technology) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation
- Howard Hughes Medical Institute
- Medical Research Council
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- aerobic glycolysis, NAD+/NADH ratio, pyruvate dehydrogenase complex, pyruvate oxidation, cell proliferation, mitochondrial membrane potential, mitochondrial electron transport chain, NAD+ regeneration, uncoupled respiration, ATP turnover, glucose metabolism
- MeSH terms
- A549 Cells, Adenosine Triphosphate, Aerobiosis, Glucose, Glycolysis, HeLa Cells, Humans, NAD, Oxidation-Reduction
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 ›
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