Akt regulation of glycolysis mediates bioenergetic stability in epithelial cells
Open accessPublished version of a preprint
Abstract
Abstract Cells use multiple feedback controls to regulate metabolism in response to nutrient and signaling inputs. However, feedback creates the potential for unstable network responses. We examined how concentrations of key metabolites and signaling pathways interact to maintain homeostasis in proliferating human cells, using fluorescent reporters for AMPK activity, Akt activity, and cytosolic NADH/NAD + redox. Across various conditions including metabolic (glycolytic or mitochondrial) inhibition or cell proliferation, we observed distinct patterns of AMPK activity, including stable adaptation and highly dynamic behaviors such as periodic oscillations and irregular fluctuations, indicating a failure to reach a steady state. Fluctuations in AMPK activity, Akt activity, and cytosolic NADH/NAD + redox state were temporally linked in individual cells adapting to metabolic perturbations. By monitoring single-cell dynamics in each of these contexts, we identified PI3K/Akt regulation of glycolysis as a multifaceted modulator of single-cell metabolic dynamics that is required to maintain metabolic stability in proliferating cells.
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?
A number of studies have demonstrated important roles of both AKT and mTOR in up-regulating glycolysis and respiration in various tissues.
“In turn, a number of studies have demonstrated the important roles of both AKT and mTOR in up-regulating glycolysis and respiration in various tissues [54,55,56,57,58].”
From 20-Hydroxyecdysone Boosts Energy Production and Biosynthetic Processes in Non-Transformed Mouse Cells (2024) · cites this paper as [54]
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
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
Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor
Brunet, A., Bonni, A., Zigmond, M. J., Lin, M. Z., Juo, P., Hu, L. S., Anderson, M. J., Arden, K. C., Blenis, J., & Greenberg, M. E. (1999) · Cell · doi:10.1016/s0092-8674(00)80595-4 · Cited by 6,535 · 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
TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914 · see citing works
AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., & Shaw, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.003 · Cited by 3,849 · 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
A guide to choosing fluorescent proteins
Shaner, N. C., Steinbach, P. A., & Tsien, R. Y. (2005) · Nature Methods · doi:10.1038/nmeth819 · Cited by 2,823 · see citing works
Visualizing Spatiotemporal Dynamics of Multicellular Cell-Cycle Progression
Sakaue-Sawano, A., Kurokawa, H., Morimura, T., Hanyu, A., Hama, H., Osawa, H., Kashiwagi, S., Fukami, K., Miyata, T., Miyoshi, H., et al. (2008) · Cell · doi:10.1016/j.cell.2007.12.033 · Cited by 2,123 · see citing works
Robust single particle tracking in live cell time-lapse sequences
Jaqaman, K., Loerke, D., Mettlen, M., Kuwata, H., Grinstein, S., Schmid, S., & Danuser, G. (2008) · Nature Methods · doi:10.1038/nmeth.1237 · Cited by 2,045 · see citing works
Cellular energy utilization and molecular origin of standard metabolic rate in mammals
Rolfe, D. F., & Brown, G. C. (1997) · Physiological Reviews · doi:10.1152/physrev.1997.77.3.731 · Cited by 2,021 · see citing works
Debnath, J., Muthuswamy, S. K., & Brugge, J. S. (2003) · Methods · doi:10.1016/s1046-2023(03)00032-x · Cited by 2,001 · see citing works
Self-citationSupporting 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
Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation
Sano, H., Kane, S., Sano, E., Mı̂inea, C. P., Asara, J. M., Lane, W. S., Garner, C. W., & Lienhard, G. E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300063200 · Cited by 964 · see citing works
A 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
Real-time imaging of the intracellular glutathione redox potential
Gutscher, M., Pauleau, A.-L., Marty, L., Brach, T., Wabnitz, G. H., Samstag, Y., Meyer, A. J., & Dick, T. P. (2008) · Nature Methods · doi:10.1038/nmeth.1212 · Cited by 894 · see citing works
DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein
Tran, H. G., Brunet, A., Grenier, J. M., Datta, S. R., Fornace, A. J., DiStefano, P. S., Chiang, L. W., & Greenberg, M. E. (2002) · Science · doi:10.1126/science.1068712 · Cited by 860 · see citing works
Yu, Y., Yoon, S.-O., Poulogiannis, G., Yang, Q., Ma, X. M., Villén, J., Kubica, N., Hoffman, G. R., Cantley, L. C., Gygi, S. P., et al. (2011) · Science · doi:10.1126/science.1199484 · Cited by 855 · see citing works
Encoding and Decoding Cellular Information through Signaling Dynamics
Purvis, J. E., & Lahav, G. (2013) · Cell · doi:10.1016/j.cell.2013.02.005 · Cited by 805 · see citing works
AMPK and mTOR in Cellular Energy Homeostasis and Drug Targets
Inoki, K., Kim, J., & Guan, K. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134537 · Cited by 800 · see citing works
Structure-guided evolution of cyan fluorescent proteins towards a quantum yield of 93%
Goedhart, J., von Stetten, D., Noirclerc‐Savoye, M., Lelimousin, M. G., Joosen, L., Hink, M. A., van Weeren, L., Gadella, T. W. J., & Royant, A. (2012) · Nature Communications · doi:10.1038/ncomms1738 · Cited by 790 · see citing works
A hyperactive piggyBac transposase for mammalian applications
Yusa, K., Zhou, L., Li, M. A., Bradley, A., & Craig, N. L. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008322108 · Cited by 776 · see citing works
AMPK: a key regulator of energy balance in the single cell and the whole organism
Hardie, D. G. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.116 · Cited by 709 · see citing works
Wieman, H. L., Wofford, J. A., & Rathmell, J. C. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-07-0593 · Cited by 593 · see citing works
Development of an optimized backbone of FRET biosensors for kinases and GTPases
Komatsu, N., Aoki, K., Yamada, M., Yukinaga, H., Fujita, Y., Kamioka, Y., & Matsuda, M. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-01-0072 · Cited by 580 · 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
Frequency-Modulated Pulses of ERK Activity Transmit Quantitative Proliferation Signals
Albeck, J. G., Mills, G. B., & Brugge, J. S. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.11.002 · Cited by 490 · see citing works
Self-citationTantama, M., Martínez‐François, J. R., Mongeon, R., & Yellen, G. (2013) · Nature Communications · doi:10.1038/ncomms3550 · Cited by 486 · see citing works
Self-citationA genetically encoded fluorescent reporter of ATP:ADP ratio
Berg, J., Hung, Y. P., & Yellen, G. (2009) · Nature Methods · doi:10.1038/nmeth.1288 · Cited by 481 · see citing works
Self-citationZhao, Y., Hu, Q., Cheng, F., Su, N., Wang, A., Zou, Y., Hu, H., Chen, X., Hai‐Meng, Z. H. O. U., Huang, X., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.04.009 · Cited by 434 · see citing works
Akt-dependent transformation: there is more to growth than just surviving
Plas, D. R., & Thompson, C. B. (2005) · Oncogene · doi:10.1038/sj.onc.1209097 · Cited by 427 · see citing works
Hu, H., Juvekar, A., Lyssiotis, C. A., Lien, E. C., Albeck, J. G., Oh, D., Varma, G., Hung, Y. P., Ullas, S., Lauring, J. D., et al. (2016) · Cell · doi:10.1016/j.cell.2015.12.042 · Cited by 374 · see citing works
Self-citationAerobic glycolysis during lymphocyte proliferation
Wang, T., Marquardt, C. A., & Foker, J. E. (1976) · Nature · doi:10.1038/261702a0 · Cited by 333 · see citing works
Elkabets, M., Vora, S., Juric, D., Morse, N., Mino-Kenudson, M., Muranen, T., Tao, J., Campos, A. B., Rodon, J., Ibrahim, Y. H., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005747 · Cited by 332 · see citing works
Hexokinase-II Positively Regulates Glucose Starvation-Induced Autophagy through TORC1 Inhibition
Roberts, D. J., Tan‐Sah, V. P., Ding, E., Smith, J. M., & Miyamoto, S. (2014) · Molecular Cell · doi:10.1016/j.molcel.2013.12.019 · Cited by 330 · see citing works
Oscillations of glycolytic intermediates in yeast cells
Ghosh, A. K., & Chance, B. (1964) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(64)90357-2 · Cited by 305 · see citing works
High Precision Isotope Ratio Monitoring Techniques in Mass Spectrometry
Brand, W. A. (1996) · Journal of Mass Spectrometry · doi:10.1002/(sici)1096-9888(199603)31:3 · Cited by 299 · see citing works
Building and breeding molecules to spy on cells and tumors
Tsien, R. Y. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.11.025 · Cited by 295 · see citing works
Oscillations of Membrane Current and Excitability Driven by Metabolic Oscillations in Heart Cells
O'Rourke, B. P., Ramza, B. M., & Marbán, E. (1994) · Science · doi:10.1126/science.8052856 · Cited by 281 · see citing works
Insulin, Glucagon, and Glucose Exhibit Synchronous, Sustained Oscillations in Fasting Monkeys
Goodner, C. J., Walike, B. C., Koerker, D. J., Ensinck, J. W., Brown, A. C. L., Chideckel, E. W., Palmer, J. P., & Kalnasy, L. W. (1977) · Science · doi:10.1126/science.401543 · Cited by 281 · see citing works
Ahn, W. S., & Antoniewicz, M. R. (2011) · Metabolic Engineering · doi:10.1016/j.ymben.2011.07.002 · Cited by 263 · see citing works
Sustained oscillations in living cells
Danø, S., Sørensen, P. G., & Hynne, F. (1999) · Nature · doi:10.1038/46329 · Cited by 249 · see citing works
Roberts, D. J., Tan‐Sah, V. P., Smith, J. M., & Miyamoto, S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.482026 · Cited by 243 · see citing works
Glycolytic Oscillations and Limits on Robust Efficiency
Chandra, F. A., Buzi, G., & Doyle, J. C. (2011) · Science · doi:10.1126/science.1200705 · Cited by 217 · see citing works
Presley, S. J., Willig, M. R., Castro-Arellano, I., & Weaver, S. C. (2009) · Journal of Mammalogy · doi:10.1644/08-mamm-a-089.1 · Cited by 212 · see citing works
Bioenergetic Profile Experiment using C2C12 Myoblast Cells
Nicholls, D. G., Darley-Usmar, V. M., Wu, M., Jensen, P. B., Rogers, G. W., & Ferrick, D. A. (2010) · Journal of Visualized Experiments · doi:10.3791/2511 · Cited by 186 · see citing works
Schmidt, M. (2009) · Frontiers in Neuroenergetics · doi:10.3389/neuro.14.001.2009 · Cited by 171 · see citing works
A Fluorescent Reporter of AMPK Activity and Cellular Energy Stress
Tsou, P., Zheng, B., Hsu, C., Sasaki, A. T., & Cantley, L. C. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.03.006 · Cited by 158 · see citing works
Identifying single-cell molecular programs by stochastic profiling
Janes, K. A., Wang, C., Holmberg, K. J., Cabral, K., & Brugge, J. S. (2010) · Nature Methods · doi:10.1038/nmeth.1442 · Cited by 130 · see citing works
Self-citationTime delays, oscillations, and chaos in physiological control systems
Glass, L., Beuter, A. C., & Larocque, D. (1988) · Mathematical Biosciences · doi:10.1016/0025-5564(88)90060-0 · Cited by 121 · see citing works
Multiple Nuclei Tracking Using Integer Programming for Quantitative Cancer Cell Cycle Analysis
Li, F., Zhou, X., Ma, J., & Wong, S. T. C. (2009) · IEEE Transactions on Medical Imaging · doi:10.1109/tmi.2009.2027813 · Cited by 119 · see citing works
Sparta, B., Pargett, M., Minguet, M., Distor, K., Bell, G. R. R., & Albeck, J. G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.662247 · Cited by 113 · see citing works
Self-citationWorster, D. T., Schmelzle, T., Solimini, N. L., Lightcap, E. S., Millard, B. L., Mills, G. B., Brugge, J. S., & Albeck, J. G. (2012) · Science Signaling · doi:10.1126/scisignal.2001986 · Cited by 83 · see citing works
Self-citationNovellasdemunt, L., Tato, I., Navarro‐Sabaté, À., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.455998 · Cited by 81 · see citing works
Multiplexed Fluorescence Imaging of ERK and Akt Activities and Cell-cycle Progression
Maryu, G., Matsuda, M., & Aoki, K. (2016) · Cell Structure and Function · doi:10.1247/csf.16007 · Cited by 76 · see citing works
Hung, Y. P., & Yellen, G. (2013) · Methods in molecular biology · doi:10.1007/978-1-62703-622-1_7 · Cited by 66 · see citing works
Self-citationTornheim, K., & Lowenstein, J. M. (1973) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)44058-1 · Cited by 62 · see citing works
Tantama, M., Hung, Y. P., & Yellen, G. (2012) · Progress in brain research · doi:10.1016/b978-0-444-59426-6.00012-4 · Cited by 62 · see citing works
Self-citationRam, T. G., Kokeny, K. E., Dilts, C. A., et al. (1995) · Journal of Cellular Physiology · doi:10.1002/jcp.1041630320 · Cited by 62 · see citing works
Chou, H.-F., Berman, N., & Ipp, E. (1992) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1992.262.6.e800 · Cited by 60 · see citing works
Glycolytic Oscillations in Isolated Rabbit Ventricular Myocytes
Yang, J., Yang, L., Qu, Z., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804794200 · Cited by 54 · see citing works
Mapping growth-factor-modulated Akt signaling dynamics
Gross, S. M., & Rotwein, P. S. (2016) · Journal of Cell Science · doi:10.1242/jcs.183764 · Cited by 37 · see citing works
Birtwistle, M. R., von Kriegsheim, A., Kida, K., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027823 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kondo, H., Ratcliffe, C. D. H., Hooper, S., Ellis, J., MacRae, J. I., Hennequart, M., Dunsby, C. W., Anderson, K. I., & Sahai, E. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108750 · Cited by 109 · see citing works
Shuvalov, O., Kirdeeva, Y., Fefilova, E., Daks, A., Fedorova, O., Parfenyev, S., Nazarov, A., Vlasova, Y., Krasnov, G. S., & Barlev, N. A. (2024) · Antioxidants · doi:10.3390/antiox13111349 · Cited by 9 · see citing works
- Authors
- Hung, Y. P., Teragawa, C., Kosaisawe, N., Gillies, T. E., Pargett, M., Minguet, M., Distor, K., Rocha-Gregg, B. L., Coloff, J. L., Keibler, M. A., Stephanopoulos, G., Yellen, G., Brugge, J. S., & Albeck, J. G.
- Affiliations
- Brigham and Women's Hospital (US)
- University of California, Davis (US)
- Harvard University (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Albeck, John G
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-12-14
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5730373
- OpenAlex
- W2619981145
- Cited by
- 74
- References
- 63
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 6 · 2023: 7 · 2022: 8 · 2021: 15 · 2020: 11 · 2019: 7 · 2018: 2 · 2017: 1
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Congressionally Directed Medical Research Programs (W81XWH-08-1-0609)
- National Cancer Institute (5-R01-CA105134-07)
- National Institute of Neurological Disorders and Stroke (R01-NS055031)
- Stuart HQ and Victoria Quan (Predoctoral Fellowship)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- 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
- Keywords
- Akt signaling, AMPK, glycolysis, metabolic homeostasis, PI3K/Akt signaling, metabolic oscillations, epithelial cells, cell proliferation, mitochondrial inhibition
- MeSH terms
- Cell Line, Energy Metabolism, Epithelial Cells, Gene Expression Regulation, Glycolysis, Humans, NAD, Phosphatidylinositol 3-Kinases, Cell Proliferation, Proto-Oncogene Proteins c-akt, AMP-Activated Protein Kinases
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
