Mitochondrial nucleoid remodeling and biogenesis are regulated by the p53-p21WAF1-PKCζ pathway in p16INK4a-silenced cells

Aging (Albany NY). 2020 Apr 24;12(8):6700-6732. doi: 10.18632/aging.103029. Epub 2020 Apr 24.

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 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.

Keywords: mitochondria; nucleoid remodeling; p16INK4a silence; p53-p21-PKCζ activation; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Cellular Senescence* / drug effects
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA, Mitochondrial / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Doxorubicin / pharmacology
  • Fibroblasts / metabolism
  • Gene Silencing
  • Humans
  • Mitochondria / genetics*
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Nuclear Respiratory Factor 1 / metabolism
  • Organelle Biogenesis*
  • Oxidative Phosphorylation
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Protein Kinase C / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Topoisomerase II Inhibitors / pharmacology
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • NRF1 protein, human
  • Nuclear Respiratory Factor 1
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • TFAM protein, human
  • Topoisomerase II Inhibitors
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Doxorubicin
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • protein kinase C zeta
  • Protein Kinase C
  • AMP-Activated Protein Kinase Kinases