Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Prolonged disturbance of proteostasis induces cellular senescence via temporal mitochondrial dysfunction and enhanced mitochondrial biogenesis in human fibroblasts

View ORCID ProfileYasuhiro Takenaka, Ikuo Inoue, View ORCID ProfileTakanari Nakano, View ORCID ProfileMasaaki Ikeda, View ORCID ProfileYoshihiko Kakinuma
doi: https://doi.org/10.1101/2020.01.22.916221
Yasuhiro Takenaka
Department of Physiology, Graduate School of Medicine, Nippon Medical School, Tokyo, JapanDepartment of Diabetes and Endocrinology, Saitama Medical University, Saitama, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Yasuhiro Takenaka
Ikuo Inoue
Department of Diabetes and Endocrinology, Saitama Medical University, Saitama, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Takanari Nakano
Department of Biochemistry, Saitama Medical University, Saitama, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Takanari Nakano
Masaaki Ikeda
Department of Physiology, Saitama Medical University, Saitama, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Masaaki Ikeda
Yoshihiko Kakinuma
Department of Physiology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Yoshihiko Kakinuma
  • For correspondence: yasuhiro-takenaka@nms.ac.jp
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Proteolytic activities decline with age, resulting in the accumulation of aggregated proteins in aged organisms. To investigate how disturbance of proteostasis causes cellular senescence in proliferating cells, we developed a stress-induced premature senescence (SIPS) model, in which normal human fibroblast MRC-5 cells were treated with either the proteasome inhibitor MG132 or V-ATPase inhibitor bafilomycin A1 (BAFA1). After 5 days of drug treatment, cells showed morphological and functional changes associated with aging along with DNA damage response. Time-course studies revealed significant increase in intracellular and mitochondrial reactive oxygen species (ROS) during and after drug treatment. We also found temporal downregulation of mitochondrial membrane potential during drug treatment, followed by an increase in mitochondrial mass, especially after drug treatment. Notable upregulation of PGC-1α and TFAM proteins confirmed enhanced mitochondrial biogenesis. Furthermore, the protein levels of SOD2 and GPx4, mitochondrial antioxidant enzymes, in the mitochondrial fraction were specifically reduced on day 1 of the treatment. Co-treatment with rapamycin along with MG132 or BAFA1 partially attenuated induction of SIPS by suppressing generation of excess ROS and mitochondrial biogenesis. In conclusion, the present study revealed that disturbance of proteostasis by the inhibitors changes the distribution of nuclear-encoded mitochondrial antioxidant enzymes at an early period of the treatment, which induces mitochondrial ROS and temporal mitochondrial dysfunction. ROS in turn activates stress responses pathways, followed by PGC-1α-mediated mitochondrial biogenesis. Hence, the excessive ROS continuously generated by increased mitochondria can cause deleterious damage to nuclear DNA, cell cycle arrest, and eventual cellular senescence.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
Back to top
PreviousNext
Posted January 23, 2020.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Prolonged disturbance of proteostasis induces cellular senescence via temporal mitochondrial dysfunction and enhanced mitochondrial biogenesis in human fibroblasts
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
Share
Prolonged disturbance of proteostasis induces cellular senescence via temporal mitochondrial dysfunction and enhanced mitochondrial biogenesis in human fibroblasts
Yasuhiro Takenaka, Ikuo Inoue, Takanari Nakano, Masaaki Ikeda, Yoshihiko Kakinuma
bioRxiv 2020.01.22.916221; doi: https://doi.org/10.1101/2020.01.22.916221
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Prolonged disturbance of proteostasis induces cellular senescence via temporal mitochondrial dysfunction and enhanced mitochondrial biogenesis in human fibroblasts
Yasuhiro Takenaka, Ikuo Inoue, Takanari Nakano, Masaaki Ikeda, Yoshihiko Kakinuma
bioRxiv 2020.01.22.916221; doi: https://doi.org/10.1101/2020.01.22.916221

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cell Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (1647)
  • Biochemistry (2738)
  • Bioengineering (1907)
  • Bioinformatics (10243)
  • Biophysics (4183)
  • Cancer Biology (3217)
  • Cell Biology (4538)
  • Clinical Trials (135)
  • Developmental Biology (2840)
  • Ecology (4460)
  • Epidemiology (2041)
  • Evolutionary Biology (7231)
  • Genetics (5475)
  • Genomics (6813)
  • Immunology (2388)
  • Microbiology (7480)
  • Molecular Biology (2992)
  • Neuroscience (18584)
  • Paleontology (136)
  • Pathology (472)
  • Pharmacology and Toxicology (780)
  • Physiology (1149)
  • Plant Biology (2706)
  • Scientific Communication and Education (680)
  • Synthetic Biology (888)
  • Systems Biology (2846)
  • Zoology (468)