Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish
Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish
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DOI：
10.7554/elife.54935
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发表时间：
2020-05-19
期刊：
影响因子：
7.7
通讯作者：
Ferreira, Miguel Godinho
中科院分区：
文献类型：
--
作者：
El Mai, Mounir;Marzullo, Marta;Ferreira, Miguel Godinho
在生命周期中，端粒逐渐缩短与细胞增殖受限、基因组不稳定和衰老有关。细胞凋亡和衰老是不可逆细胞损伤的两种主要结果。在这里，我们展示了端粒酶缺陷斑马鱼衰老过程中这两种细胞命运的转变。在年轻的端粒酶突变体中，增殖组织表现出DNA损伤和p53依赖性细胞凋亡，但没有衰老。然而，这些组织在老年动物中表现出细胞性丧失和衰老成为主要。组织改变伴随着AKT信号介导的促增殖刺激。AKT激活后，FoxO转录因子被磷酸化并转移出细胞核。这导致SOD2表达减少，导致ROS增加和线粒体功能障碍。这些改变导致p15/16生长停滞和衰老。我们认为，在端粒缩短后，早期凋亡导致细胞耗竭和代偿性增殖不足。组织损伤后，mTOR/AKT被激活，导致线粒体功能障碍和p15/16依赖性衰老。
Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, proliferative tissues exhibit DNA damage and p53-dependent apoptosis, but no senescence. However, these tissues in older animals display loss of cellularity and senescence becomes predominant. Tissue alterations are accompanied by a pro-proliferative stimulus mediated by AKT signaling. Upon AKT activation, FoxO transcription factors are phosphorylated and translocated out of the nucleus. This results in reduced SOD2 expression causing an increase of ROS and mitochondrial dysfunction. These alterations induce p15/16 growth arrest and senescence. We propose that, upon telomere shortening, early apoptosis leads to cell depletion and insufficient compensatory proliferation. Following tissue damage, the mTOR/AKT is activated causing mitochondrial dysfunction and p15/16-dependent senescence.