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NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration

Nature Cell Biology volume 13, pages 1272–1279 (2011)Cite this article

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Abstract

Cell proliferation is a metabolically demanding process1,2. It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth1,2. NF-κB/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis3, but whether NF-κB regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-κB organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation. The metabolic reorganization that results from NF-κB inhibition overcomes the requirement for tumour suppressor mutation in oncogenic transformation and impairs metabolic adaptation in cancer in vivo. This NF-κB-dependent metabolic pathway involves stimulation of oxidative phosphorylation through upregulation of mitochondrial synthesis of cytochrome c oxidase 2 (SCO2; ref. 4). Our findings identify NF-κB as a physiological regulator of mitochondrial respiration and establish a role for NF-κB in metabolic adaptation in normal cells and cancer.

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Figure 1: NF-κB counters reprogramming to aerobic glycolysis and promotes metabolic adaptation to nutrient starvation.
Figure 2: p53 mediates NF-κB-dependent protection against glucose starvation.
Figure 3: SCO2 mediates NF-κB-dependent protection against glucose-starvation-induced PCD.
Figure 4: RelA suppresses oncogenic transformation by regulating energy metabolism.
Figure 5: NF-κB promotes metabolic adaptation in cancer in vivo.

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Acknowledgements

We thank M. Pagano, F. Dazzi, P. Ashton-Rickardt, F. Marelli-Berg and G. Screaton for critical comments on the manuscript. We also thank K. Ryan (Beatson Institute for Cancer Research, Glasgow, UK) for the eGFP–LC3 plasmid; T. Lindsten and C. B. Thompson (University of Pennsylvania, Philadelphia, USA) for the immortalized Bax−/−/Bak−/− MEFs; D. Trono (Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland) for the pWPT lentiviral vector; C. Chevtzoff and D. G. Hardie for assistance with the use of the Seahorse machine; and K. R. Chng for assistance with the analyses of the p53 promoter. C.M. was supported in part by a fellowship from AIRC (Italy). S.C.L. is supported by a scholarship from A*STAR (Singapore). M.M. is supported by a fellowship from the Pasteur Institute, Cenci Bolognetti Foundation (Italy). This work was supported by NIH grants R01 CA084040 and R01 CA098583 and Cancer Research UK grant C26587/A8839 to G.F., and NIH grant R01 CA123067 to N.S.C.

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Author notes

  1. Claudio Mauro and Shi Chi Leow: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Section of Inflammation and Signal Transduction, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK

    Claudio Mauro, Shi Chi Leow, Anil K. Thotakura, Laura Tornatore, Marta Moretti & Guido Franzoso

  2. Laboratory of NF-κB Signaling, Proteos, Singapore 138673, Singapore

    Shi Chi Leow & Vinay Tergaonkar

  3. Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA

    Elena Anso & Navdeep S. Chandel

  4. Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK

    Sonia Rocha

  5. Department of Experimental Medicine, Sapienza University, Rome 00161, Italy

    Marta Moretti & Enrico De Smaele

  6. Department of Immunology, Moffitt Cancer Center, Tampa, Florida 33612, USA

    Amer A. Beg

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Contributions

C.M. first observed the glucose addiction exhibited by RelA-null cells. C.M. and S.C.L. carried out the further experimental characterization of this phenomenon and most of the analyses shown. E.A. and S.R. carried out the oxygen consumption assays. A.K.T. carried out the cell-cycle analysis and helped with in vivo studies. L.T. carried out the immunoblot analyses of apoptosis and autophagy and the in vitro metabolic analyses of CT-26 cells. E.D.S. and A.A.B. generated the early passage p 53−/− and RelA−/− MEFs, respectively, as well as the early passage wild-type controls from littermates. G.F., C.M. and S.C.L. wrote the manuscript and conceived the experiments. N.S.C. and V.T. contributed to the design of some of the experiments and made substantial critical revision to the manuscript. C.M., E.A., A.K.T., L.T. and M.M. carried out the experiments during revision of the manuscript. All authors discussed and revised the manuscript.

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Correspondence to Guido Franzoso.

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Mauro, C., Leow, S., Anso, E. et al. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nat Cell Biol 13, 1272–1279 (2011). https://doi.org/10.1038/ncb2324

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