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

Nat Cell Biol. 2011 Aug 28;13(10):1272-9. doi: 10.1038/ncb2324.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cell Respiration*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Electron Transport Complex IV / metabolism
  • Energy Metabolism*
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Glucose / deficiency
  • Glucose / metabolism
  • Glycolysis
  • Homeostasis
  • Lactic Acid / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Mitochondria / metabolism*
  • Necrosis
  • Oxidative Phosphorylation
  • Oxygen Consumption
  • RNA Interference
  • Time Factors
  • Transcription Factor RelA / deficiency
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transfection
  • Tumor Burden
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • Bak1 protein, mouse
  • Bax protein, mouse
  • RELA protein, human
  • Rela protein, mouse
  • SCO2 protein, mouse
  • Transcription Factor RelA
  • Tumor Suppressor Protein p53
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • Lactic Acid
  • Adenosine Triphosphate
  • Electron Transport Complex IV
  • Glucose