FIG. 9.

Mitochondrial dysfunction as an effector mechanism of OIS and replicative senescence (short telomeres). The oncogenic activity of the Ras/mitogen-activated protein kinase pathway induces a replication stress (12) and mitochondrial biogenesis leading to DNA damage and the activation of the p53 and Rb pathways. The activity of these tumor suppressors converge in the mitochondria to induce a senescence effector pathway characterized here as a metabolic checkpoint and oxidative stress. This is not a linear pathway, since the effects of mitochondrial dysfunction can activate the p53 and Rb pathways, generating positive feedback mechanisms that we propose contribute to keeping cells senescent.