Mitochondrial fatty acid oxidation drives senescence.

Shota Yamauchi, Yuki Sugiura, Junji Yamaguchi, Xiangyu Zhou, Satoshi Takenaka, Takeru Odawara, Shunsuke Fukaya, Takao Fujisawa, Isao Naguro, Yasuo Uchiyama, Akiko Takahashi, Hidenori Ichijo

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

Paper

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 p16

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper explores the mechanisms linking mitochondrial function and fatty acid oxidation to cellular senescence, which is a key process in aging. By identifying the role of BNIP3 and its connection to the DNA damage response, the research contributes to understanding the biological processes that underlie aging and senescence. However, while the findings are solid and provide insights into the metabolic changes associated with senescence, they do not present a major breakthrough or transformative implications for longevity research. Thus, the impact is rated as limited but still significant.

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