title: NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration.
abstract: Cell proliferation is a metabolically demanding process. It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth. NF-κB/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis, 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. ). 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.
authors.affiliation: Section of Inflammation and Signal Transduction, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mauro
authors.forename: Shi Chi
authors.initials: SC
authors.lastname: Leow
authors.forename: Elena
authors.initials: E
authors.lastname: Anso
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
authors.forename: Anil K
authors.initials: AK
authors.lastname: Thotakura
authors.forename: Laura
authors.initials: L
authors.lastname: Tornatore
authors.forename: Marta
authors.initials: M
authors.lastname: Moretti
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Guido
authors.initials: G
authors.lastname: Franzoso
mesh_terms: D000222:Adaptation, Physiological; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019069:Cell Respiration; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D006019:Glycolysis; D006706:Homeostasis; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D018832:Molecular Chaperones; D009336:Necrosis; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D034622:RNA Interference; D013997:Time Factors; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D018832:Molecular Chaperones; C498143:RELA protein, human; C498144:Rela protein, mouse; C511423:SCO2 protein, mouse; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D005947:Glucose