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Molecular and Cellular Biology, August 2009, p. 4495-4507, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.01868-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence{triangledown} ,{dagger}

Olga Moiseeva, Véronique Bourdeau, Antoine Roux, Xavier Deschênes-Simard, and Gerardo Ferbeyre*

Département de Biochimie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Québec H3C 3J7, Canada

Received 8 December 2008/ Returned for modification 6 January 2009/ Accepted 3 June 2009

The expression of oncogenic ras in normal human cells quickly induces an aberrant proliferation response that later is curtailed by a cell cycle arrest known as cellular senescence. Here, we show that cells expressing oncogenic ras display an increase in the mitochondrial mass, the mitochondrial DNA, and the mitochondrial production of reactive oxygen species (ROS) prior to the senescent cell cycle arrest. By the time the cells entered senescence, dysfunctional mitochondria accumulated around the nucleus. The mitochondrial dysfunction was accompanied by oxidative DNA damage, a drop in ATP levels, and the activation of AMPK. The increase in mitochondrial mass and ROS in response to oncogenic ras depended on intact p53 and Rb tumor suppression pathways. In addition, direct interference with mitochondrial functions by inhibiting the expression of the Rieske iron sulfur protein of complex III or the use of pharmacological inhibitors of the electron transport chain and oxidative phosphorylation was sufficient to trigger senescence. Taking these results together, this work suggests that mitochondrial dysfunction is an effector pathway of oncogene-induced senescence.

* Corresponding author. Mailing address: Université de Montréal, Département de Biochimie, E-515, C.P. 6128, Succ. Centre-Ville, Montréal, Qc H3C 3J7, Canada. Phone: (514) 343-7571. Fax: (514) 343-2210. E-mail: g.ferbeyre{at}umontreal.ca

{triangledown} Published ahead of print on 15 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2009, p. 4495-4507, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.01868-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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