Research Paper Volume 12, Issue 8 pp 6700—6732
Mitochondrial nucleoid remodeling and biogenesis are regulated by the p53-p21WAF1-PKCζ pathway in p16INK4a-silenced cells
- 1 Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 16499, Korea
- 2 Department of Biomedical Sciences, The Graduate School, Ajou University, Suwon 16499, Korea
- 3 Department of Otolaryngology, Ajou University School of Medicine, Suwon 16499, Korea
- 4 Omics Center, Ajou University School of Medicine, Suwon 16499, Korea
- 5 Department of Gastroenterology, Ajou University of Medicine, Suwon 16499, Korea
- 6 Department of Pathology, Chung-Ang University College of Medicine, Seoul 156-756, Korea
received: August 29, 2019 ; accepted: February 22, 2020 ; published: April 24, 2020 ;https://doi.org/10.18632/aging.103029
How to Cite
Copyright © 2020 Lee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 mitochondrial 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, PGC-1α and NRF1 were greatly increased compared to young cells. Activated protein kinase C zeta (PKCζ) 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 PKCζ-LKB1-AMPK signaling pathway, which was regulated by the p53-p21WAF1 pathway when p16INK4a was silenced. The signaling enhanced PGC-1α-NRF1-TFAM axis in mitochondria, which was demonstrated by Ingenuity Pathway Analysis of young and old fs-HDF cells. Activation of the p53-p21WAF1 pathway and silencing of p16INK4a are responsible for mitochondrial reprogramming in senescent cells, which may be a compensatory mechanism to promote cell survival under senescence stress.
fs-HDF: foreskin-derived human diploid fibroblast; ROS: Reactive oxygen species; SA-β-gal: Senescence-associated β-galactosidase; OXPHOS: Oxidative phosphorylation; OCR: Oxygen consumption rate; PKCζ: protein kinase C-zeta; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TFAM: Transcription factor A mitochondrial; NRF1: Nuclear respiratory factor 1; LKB1: liver kinase B1; AMPK: Adenosine monophosphate-activated protein kinase; IPA: Ingenuity Pathway Analysis; PDs: Number of population doublings; DTs: doubling times of cells.