Premium
p53‐mediated regulation of mitochondrial dynamics plays a pivotal role in the senescence of various normal cells as well as cancer cells
Author(s) -
Kim Young Yeon,
Um JeeHyun,
Shin Dong Jin,
Jeong Dae Jin,
Hong Young Bin,
Yun Jeanho
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202002007r
Subject(s) - microbiology and biotechnology , senescence , cancer cell , dynamics (music) , cancer , chemistry , biology , genetics , psychology , pedagogy
Abstract 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.