2. Academic Validation
  3. Mitochondrial fatty acid oxidation drives senescence

Mitochondrial fatty acid oxidation drives senescence

  • Sci Adv. 2024 Oct 25;10(43):eado5887. doi: 10.1126/sciadv.ado5887.
Shota Yamauchi 1 2,  Yuki Sugiura 3,  Junji Yamaguchi 4 5,  Xiangyu Zhou 1 2,  Satoshi Takenaka 1 6,  Takeru Odawara 1,  Shunsuke Fukaya 1,  Takao Fujisawa 1 6,  Isao Naguro 1,  Yasuo Uchiyama 5,  Akiko Takahashi 2,  Hidenori Ichijo 1 6
Affiliations

Affiliations

  • 1 Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 2 Division of Cellular Senescence, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
  • 3 Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.
  • 4 Laboratory of Morphology and Image Analysis, Biomedical Research Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
  • 5 Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
  • 6 Cell Signaling and Stress Responses Laboratory, Advanced Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
PMID: 39454000 DOI: 10.1126/sciadv.ado5887
Abstract

Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl-coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.

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