p53 regulates mitochondrial respiration.
The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.
Matoba
Satoaki
S
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Kang
Ju-Gyeong
JG
Patino
Willmar D
WD
Wragg
Andrew
A
Boehm
Manfred
M
Gavrilova
Oksana
O
Hurley
Paula J
PJ
Bunz
Fred
F
Hwang
Paul M
PM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D019069:Cell Respiration; D002470:Cell Survival; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006019:Glycolysis; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D009154:Mutation; D010101:Oxygen Consumption; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D034741:RNA, Small Interfering; D011995:Recombination, Genetic; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D002352:Carrier Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D011506:Proteins; D034741:RNA, Small Interfering; C489345:SCO1 protein, human; C400285:SCO2 protein, human; C511423:SCO2 protein, mouse; D016159:Tumor Suppressor Protein p53; D000255:Adenosine Triphosphate; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV