Although mitochondrial stress is a key determinant of cellular homeostasis, the intracellular mechanisms by which this stress is communicated to the nucleus and its impact on cell fate decisions are not well defined. In this study, we report that activation of mTORC1 signaling triggered by mitochondrial-generated reactive oxygen species (ROS) results in activation of the senescence program. We show that exposure of human fibroblasts to nucleoside analogs commonly used in antiretroviral therapies, and known to induce mitochondrial dysfunction, increases mitochondrial ROS and leads to a rise in intracellular ROS concomitant with activation of mTORC1. In this setting, it appears that mTORC1 activates senescence through HDM2 phosphorylation, facilitating a p53-mediated response. Inhibition of mTORC1 by rapamycin decreases HDM2 phosphorylation and blocks activation of the senescence program in human cells. In addition, decreasing mitochondrial ROS directly blocks mTORC1 signaling and prevents the onset of senescence. Consistent with these results, both total and mitochondrial-specific ROS increased in cells undergoing replicative senescence along with ribosomal p70 phosphorylation. The results reveal a novel link between mitochondrial dysfunction, mTORC1 signaling, and the senescence program.
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