p53 regulates mitochondrial dynamics by inhibiting Drp1 translocation into mitochondria during cellular senescence
p53 regulates mitochondrial dynamics by inhibiting Drp1 translocation into mitochondria during cellular senescence
复制标题
p53通过抑制细胞衰老期间Drp 1移位到线粒体来调节线粒体动力学
DOI：
10.1096/fj.201901747rr
复制
发表时间：
2020-02-01
期刊：
影响因子：
4.8
通讯作者：
Yun, Jeanho
中科院分区：
文献类型：
--
作者：
Kim, Young Yeon;Um, Jee-Hyun;Yun, Jeanho
细胞衰老通过消除癌前细胞作为肿瘤发生的重要屏障。以往的研究表明肿瘤抑制因子p53在细胞衰老中起重要作用，但p53如何诱导细胞衰老尚不完全清楚。我们发现p53在细胞衰老之前促进了高度相互连接和延长的线粒体的形成。抑制线粒体伸长对p53表达的抑制抑制了细胞衰老，这表明线粒体伸长是诱导p53依赖性衰老所必需的。p53诱导的线粒体伸长导致线粒体功能障碍和细胞内活性氧（ROS）水平的增加，ROS是细胞衰老的重要介质。机制上，Drp1 Ser637的抑制性磷酸化在p53表达时增加，抑制Drp1转位到线粒体。p53的转录功能对于控制Drp1的抑制性磷酸化至关重要，而p21则不是必需的。蛋白激酶A （PKA）活性与p53介导的Drp1 Ser637磷酸化和线粒体功能障碍有关。综上所述，这些结果表明p53通过PKA-Drp1通路调节线粒体动力学，诱导细胞衰老。
Cellular senescence acts as an important barrier to tumorigenesis by eliminating precancerous cells. Previous studies have shown an essential role of the tumor suppressor p53 in cellular senescence, but how p53 induces cellular senescence is not fully understood. We found that p53 promoted the formation of highly interconnected and elongated mitochondria prior to the onset of cellular senescence. The inhibition of mitochondrial elongation upon p53 expression suppressed cellular senescence, suggesting that mitochondrial elongation is required for the induction of p53-dependent senescence. p53-induced mitochondrial elongation resulted in mitochondrial dysfunction and subsequent increases in intracellular reactive oxygen species (ROS) levels, an important mediator of cellular senescence. Mechanistically, the inhibitory phosphorylation of Drp1 Ser637 increased upon p53 expression, suppressing the translocation of Drp1 into mitochondria. The transcriptional function of p53 was crucial for controlling the inhibitory phosphorylation of Drp1, whereas p21 was nonessential. Protein kinase A (PKA) activity was responsible for p53-mediated Drp1 Ser637 phosphorylation and mitochondrial dysfunction. Taken together, these results suggest that p53 regulates mitochondrial dynamics through the PKA-Drp1 pathway to induce cellular senescence.