Mitochondrial dysfunction contributes to oncogene-induced senescence.
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.
Moiseeva
Olga
O
Département de Biochimie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Québec H3C3J7, Canada.
Bourdeau
Véronique
V
Roux
Antoine
A
Deschênes-Simard
Xavier
X
Ferbeyre
Gerardo
G
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology; D004249:DNA Damage; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D050259:Genes, Mitochondrial; D011905:Genes, ras; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D017382:Reactive Oxygen Species; C037989:Rieske iron-sulfur protein; D000263:Adenylate Kinase; D018631:ras Proteins; D014450:Electron Transport Complex III