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
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinase Kinases
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Cellular Senescence* / drug effects
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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DNA, Mitochondrial / metabolism
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Doxorubicin / pharmacology
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Fibroblasts / metabolism
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Gene Silencing
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Humans
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Mitochondria / genetics*
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Mitochondria / metabolism*
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Mitochondrial Proteins / genetics*
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Mitochondrial Proteins / metabolism
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Nuclear Respiratory Factor 1 / metabolism
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Organelle Biogenesis*
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Oxidative Phosphorylation
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
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Protein Kinase C / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction
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Topoisomerase II Inhibitors / pharmacology
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Tumor Suppressor Protein p53 / metabolism
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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DNA, Mitochondrial
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DNA-Binding Proteins
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Mitochondrial Proteins
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NRF1 protein, human
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Nuclear Respiratory Factor 1
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PPARGC1A protein, human
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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TFAM protein, human
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Topoisomerase II Inhibitors
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Transcription Factors
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Tumor Suppressor Protein p53
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Doxorubicin
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Protein Serine-Threonine Kinases
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STK11 protein, human
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protein kinase C zeta
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Protein Kinase C
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AMP-Activated Protein Kinase Kinases