Nacarelli Timothy, Azar Ashley, Sell Christian
Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102, United States.
Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102, United States.
Free Radic Biol Med. 2016 Jun;95:133-54. doi: 10.1016/j.freeradbiomed.2016.03.008. Epub 2016 Mar 23.
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.
尽管线粒体应激是细胞稳态的关键决定因素，但这种应激传递至细胞核的细胞内机制及其对细胞命运决定的影响尚不清楚。在本研究中，我们报告由线粒体产生的活性氧（ROS）触发的mTORC1信号激活导致衰老程序的激活。我们表明，将人类成纤维细胞暴露于抗逆转录病毒疗法中常用的核苷类似物（已知其可诱导线粒体功能障碍）会增加线粒体ROS，并导致细胞内ROS升高，同时伴随mTORC1的激活。在这种情况下，mTORC1似乎通过HDM2磷酸化激活衰老，促进p53介导的反应。雷帕霉素抑制mTORC1可降低HDM2磷酸化，并阻断人类细胞中衰老程序的激活。此外，降低线粒体ROS可直接阻断mTORC1信号并防止衰老的发生。与这些结果一致，在经历复制性衰老的细胞中，总ROS和线粒体特异性ROS均增加，同时核糖体p70磷酸化也增加。这些结果揭示了线粒体功能障碍、mTORC1信号和衰老程序之间的新联系。
