K-ras super(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis

Increased aerobic glycolysis and oxidative stress are important features of cancer cell metabolism, but the underlying biochemical and molecular mechanisms remain elusive. Using a tetracycline inducible model, we show that activation of K-ras super(G12V) causes mitochondrial dysfunction, leading to...

Full description

Saved in:
Bibliographic Details
Published in:Cell research 2012-02, Vol.22 (2), p.399-412
Main Authors: Hu, Yumin, Lu, Weiqin, Chen, Gang, Wang, Peng, Chen, Zhao, Zhou, Yan, Ogasawara, Marcia, Trachootham, Dunyaporn, Feng, Li, Pelicano, Helene, Chiao, Paul J, Keating, Michael J, Garcia-Manero, Guillermo, Huang, Peng
Format: Article
Language:English
Subjects:
Adaptations
Cancer
Electron transport
Glycolysis
K-Ras protein
Membrane permeability
Membrane potential
Metabolism
Mitochondrial permeability transition pore
Molecular modelling
Oxidative phosphorylation
Oxidative stress
Reactive oxygen species
Tetracyclines
Transformation
Transformed cells
Tumors
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Increased aerobic glycolysis and oxidative stress are important features of cancer cell metabolism, but the underlying biochemical and molecular mechanisms remain elusive. Using a tetracycline inducible model, we show that activation of K-ras super(G12V) causes mitochondrial dysfunction, leading to decreased respiration, elevated glycolysis, and increased generation of reactive oxygen species. The K-RAS protein is associated with mitochondria, and induces a rapid suppression of respiratory chain complex-I and a decrease in mitochondrial transmembrane potential by affecting the cyclosporin-sensitive permeability transition pore. Furthermore, pre-induction of K-ras super(G12V) expression in vitro to allow metabolic adaptation to high glycolytic metabolism enhances the ability of the transformed cells to form tumor in vivo. Our study suggests that induction of mitochondrial dysfunction is an important mechanism by which K-ras super(G12V) causes metabolic changes and ROS stress in cancer cells, and promotes tumor development.
ISSN:1001-0602
DOI:10.1038/cr.2011.145