p53‐mediated regulation of mitochondrial dynamics plays a pivotal role in the senescence of various normal cells as well as cancer cells

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.

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

“…This inhibitory action is part of its tumor suppressor effect. P53-dependent Protein kinase A (PKA) activation has also been linked to mitochondrial elongation [332,333]. On the contrary, a recent study showed that mitochondrial fusion protein OPA1 is cleaved by p53 via another inner mitochondrial membrane protein, OMA1, resulting in bax/bak-dependent apoptosis induction.…”

p53 Regulates Mitochondrial Dynamics in Vascular Smooth Muscle Cell Calcification

“…A number of studies have revealed an important role for p53 overexpression in the induction of senescence and alteration of mitochondrial dynamics in a variety of cell types. It has been shown that p53 directly modulates the mitochondrial function in a human endometrial carcinoma cell-line, whereby infection with p53 adenovirus induced a significant decrease in mitochondrial membrane potential and induced mitochondrial fusion preceding cellular senescence [ 15 , 53 ]. Furthermore, it has been demonstrated that p53 activation and overexpression promote cellular senescence in a range of cells, including human bladder carcinoma cells and fibroblasts [ 15 , 46 ].…”

microRNA-Mediated Encoding and Decoding of Time-Dependent Signals in Tumorigenesis

“…P53 is one of the main actors on which cells rely to determine their fate following DNA damage [ 80 ]. Cell cycle arrest, apoptosis, or senescence can be promoted depending on whether p53 exhibits a transient or a pulsing expression [ 87 , 88 , 89 , 90 ].…”