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.