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p53 regulates mitochondrial dynamics by inhibiting Drp1 translocation into mitochondria during cellular senescence
Author(s) -
Kim Young Yeon,
Um JeeHyun,
Yoon JeongHyun,
Lee DaYe,
Lee Yoon Jung,
Kim Dong Hyun,
Park JooIn,
Yun Jeanho
Publication year - 2020
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.201901747rr
Subject(s) - senescence , microbiology and biotechnology , mitochondrion , biology , phosphorylation , mitochondrial fission , carcinogenesis , reactive oxygen species , biochemistry , gene
Abstract 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.