Peripheral Neuropathy Research Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
Department of Biochemistry, College of Medicine, Dong-A University, Busan, Republic of Korea.
FASEB J. 2021 Feb;35(2):e21319. doi: 10.1096/fj.202002007R.
The tumor suppressor p53 is known as a critical mediator of many cellular processes, including cellular senescence, but its role in mitochondrial dynamics is not fully understood. We have previously shown that p53 regulates mitochondrial dynamics via the PKA-Drp1 pathway to induce cellular senescence. In this study, to further understand the role of p53-dependent regulation of mitochondrial dynamics, the effect of p53 expression on mitochondrial morphology was examined in various cancer cell lines and normal human cells. We found that p53 induced remarkable mitochondrial elongation and cellular senescence in various cancer cells regardless of their p53 status. p53 also induced mitochondrial elongation in various human primary normal cells, suggesting that p53-mediated mitochondrial elongation is a general phenomenon. Moreover, we found that p53 plays an essential role in mitochondrial elongation in H-Ras-induced cellular senescence and in the replicative senescence of normal human cells. Treatment with the MDM-2 antagonist Nutlin-3a also induced mitochondrial elongation through the PKA-Drp1 pathway in IMR90 normal human cells. Furthermore, the inhibition of PKA activity in late-passage normal cells significantly reduced both mitochondrial elongation and cellular senescence, suggesting that the p53-PKA pathway is essential for maintaining the senescence phenotype in normal cells. Together, these results further confirm the direct regulation of mitochondrial dynamics by p53 and the important role of p53-mediated mitochondrial elongation in cellular senescence.
肿瘤抑制因子 p53 被认为是许多细胞过程的关键介质，包括细胞衰老，但它在线粒体动力学中的作用尚未完全阐明。我们之前已经表明，p53 通过 PKA-Drp1 途径调节线粒体动力学，以诱导细胞衰老。在这项研究中，为了进一步了解 p53 依赖性调节线粒体动力学的作用，研究了 p53 表达对各种癌细胞系和正常人类细胞中线粒体形态的影响。我们发现，p53 诱导各种癌细胞中线粒体显著伸长和细胞衰老，无论其 p53 状态如何。p53 还诱导各种人类原代正常细胞中线粒体伸长，表明 p53 介导的线粒体伸长是一种普遍现象。此外，我们发现 p53 在 H-Ras 诱导的细胞衰老和正常人细胞的复制性衰老中对线粒体伸长起着至关重要的作用。用 MDM-2 拮抗剂 Nutlin-3a 处理也通过 PKA-Drp1 途径在 IMR90 正常人类细胞中诱导线粒体伸长。此外，在晚期传代正常细胞中抑制 PKA 活性显著减少线粒体伸长和细胞衰老，表明 p53-PKA 途径对于维持正常细胞的衰老表型至关重要。总之，这些结果进一步证实了 p53 对线粒体动力学的直接调节以及 p53 介导的线粒体伸长在细胞衰老中的重要作用。
