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Mitochondrial fatty acid oxidation drives senescence

Shota Yamauchi1,2, Yuki Sugiura3, Junji Yamaguchi4,5

  • 1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

Science Advances
|October 25, 2024
PubMed

Insights

DNA damage response signaling to mitochondria triggers cellular senescence. This process involves BNIP3, enhanced fatty acid oxidation, and p16INK4a expression, highlighting mitochondria

Area of Science:

  • Cellular biology
  • Mitochondrial metabolism
  • Aging research

Background:

  • Cellular senescence is a crucial stress-induced cell cycle arrest implicated in tumor suppression and aging.
  • While nuclear DNA damage is known to induce senescence, the precise mechanisms linking it to this process remain largely unknown.
  • Understanding the signaling pathways that connect DNA damage to senescence is vital for aging and cancer research.

Purpose of the Study:

  • To elucidate the mechanisms by which DNA damage response signaling triggers cellular senescence.
  • To investigate the role of mitochondria in mediating the senescence response to DNA damage.
  • To identify novel targets for therapeutic intervention in senescence-related conditions.

Main Methods:

  • Utilized a genome-wide small interfering RNA screen to identify key proteins involved in senescence induction.
  • Employed techniques including Western blotting, metabolomics (stable isotope labeling), and cell-based assays to analyze mitochondrial function and gene expression.
  • Investigated the role of the ataxia telangiectasia mutated (ATM) kinase and the BNIP3 protein in the DNA damage response pathway.

Main Results:

  • Identified the outer mitochondrial protein BNIP3 as a crucial mediator of senescence induction following DNA damage.
  • Demonstrated that DNA damage response signaling phosphorylates BNIP3, leading to increased mitochondrial cristae and enhanced fatty acid oxidation (FAO).
  • Showed that increased FAO boosts histone acetylation and upregulates the expression of the cyclin-dependent kinase inhibitor p16INK4a, driving senescence.
  • Pharmacological activation of FAO alone was sufficient to induce senescence in vitro and in vivo.

Conclusions:

  • Mitochondrial energy metabolism, specifically enhanced fatty acid oxidation, plays a critical role in the induction of cellular senescence.
  • The DNA damage response pathway converges on mitochondria, utilizing BNIP3 and FAO to promote senescence.
  • Mitochondrial energy metabolism represents a potential therapeutic target for controlling cellular senescence in aging and cancer.

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