Mitochondrial nucleoid remodeling and biogenesis are regulated by the p53-p21(WAF1)-PKC zeta pathway in p16(INK4a)-silenced cells
- Authors
- Lee, Yun Yeong; Choi, Yeon Seung; Kim, Do Wan; Cheong, Jae Youn; Song, Kye Yong; Ryu, Min Sook; Lim, In Kyoung
- Issue Date
- 30-Apr-2020
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- senescence; p53-p21-PKC zeta activation; p16INK4a silence; mitochondria; nucleoid remodeling
- Citation
- AGING-US, v.12, no.8, pp 6700 - 6732
- Pages
- 33
- Journal Title
- AGING-US
- Volume
- 12
- Number
- 8
- Start Page
- 6700
- End Page
- 6732
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/44211
- DOI
- 10.18632/aging.103029
- ISSN
- 1945-4589
- Abstract
- Mitochondrial dysfunction is linked to age-related senescence phenotypes. We report here the pathway increasing nucleoid remodeling and biogenesis in mitochondria during the senescence of foreskin human diploid fibroblasts (fs-HDF) and WI-38 cells. Replicative senescence in fs-HDF cells increased mitochondria! nucleoid remodeling as indicated by 5-bromo-2'-deoxyuridine (BrdU) incorporation and mitochondrial transcription factor A (TFAM) expression in enlarged and fused mitochondria. Mitochondrial nucleoid remodeling was accompanied by mitochondrial biogenesis in old cells, and the expression levels of OXPHOS complex-I, -IV and -V subunits, PGC1 alpha and NRF1 were greatly increased compared to young cells. Activated protein kinase C zeta (PKC zeta) increased mitochondrial activity and expressed phenotypes of delayed senescence in fs-HDF cells, but not in WI-38 cells. The findings were reproduced in the doxorubicin-induced senescence of young fs-HDF and WI-38 cells via the PKC zeta-LKB1-AMPK signaling pathway, which was regulated by the p53-p21(WAF1) pathway when p16(INK4a) was silenced. The signaling enhanced PGC-1 alpha-NRF1-TFAM axis in mitochondria, which was demonstrated by Ingenuity Pathway Analysis of young and old fs-HDF cells. Activation of the p53-p21(WAF1 )pathway and silencing of p16(INK4a) are responsible for mitochondrial reprogramming in senescent cells, which may be a compensatory mechanism to promote cell survival under senescence stress.
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