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

TY - JOUR

T1 - NF-kappa B controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration

AU - Mauro, Claudio

AU - Leow, Shi Chi

AU - Anso, Elena

AU - Rocha, Sonia

AU - Thotakura, Anil K.

AU - Tornatore, Laura

AU - Moretti, Marta

AU - De Smaele, Enrico

AU - Beg, Amer A.

AU - Tergaonkar, Vinay

AU - Chandel, Navdeep S.

AU - Franzoso, Guido

PY - 2011/10

Y1 - 2011/10

N2 - Cell proliferation is a metabolically demanding process(1,2). It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth(1,2). NF-kappa B/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis(3), but whether NF-kappa B regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-kappa B organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondria! respiration. NF-kappa B inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation. The metabolic reorganization that results from NF-kappa B inhibition overcomes the requirement for tumour suppressor mutation in oncogenic transformation and impairs metabolic adaptation in cancer in vivo. This NF-kappa B-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-kappa B as a physiological regulator of mitochondrial respiration and establish a role for NF-kappa B in metabolic adaptation in normal cells and cancer.

AB - Cell proliferation is a metabolically demanding process(1,2). It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth(1,2). NF-kappa B/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis(3), but whether NF-kappa B regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-kappa B organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondria! respiration. NF-kappa B inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation. The metabolic reorganization that results from NF-kappa B inhibition overcomes the requirement for tumour suppressor mutation in oncogenic transformation and impairs metabolic adaptation in cancer in vivo. This NF-kappa B-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-kappa B as a physiological regulator of mitochondrial respiration and establish a role for NF-kappa B in metabolic adaptation in normal cells and cancer.

KW - TNF-ALPHA

KW - TUMOR-SUPPRESSOR

KW - MOUSE MODEL

KW - CELL-DEATH

KW - P53

KW - APOPTOSIS

KW - CANCER

KW - TRANSFORMATION

KW - GROWTH

KW - RAS

U2 - 10.1038/ncb2324

DO - 10.1038/ncb2324

M3 - Article

C2 - 21968997

SN - 1465-7392

VL - 13

SP - 1272-U234

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 10

ER -