Fatty acid desaturation guides cellular decisions between ferroptosis and cellular senescence

When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such decisions are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here we show that senescent cells increase levels of multiple membrane-bound pol...

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Vydané v:bioRxiv
Hlavní autori: Kuehnemann, Chisaka, Jezak, Samantha, Mogck, Bronwyn, Kura, Niharika, Che, Yuheng, Vaittinen, Maija, Siokas, Ioannis, Tariq, Rushmeen, Deshpande, Sharvari, Guthrie, Carlyn, Tan, Xuejuan, Aimontche, Eliezer, Zheng, Tong, Greenberg, Andrew S., Wang, Xiang-Dong, Kitazawa, Koji, Dolnikowsi, Gregory, Cheng, Yong, Matthan, Nirupa R., Ramanthan, Arvind, Pihlajamaki, Jussi, Korstanje, Ron, Wiley, Christopher D.
Médium: Paper
Jazyk:English
Vydavateľské údaje: Cold Spring Harbor Laboratory 03.10.2024
Vydanie:1.1
Predmet:
Cell Biology
senescence
ferroptosis
PUFA
DGLA
senolytic
aging
FADS1
desaturases
ISSN:2692-8205
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Popis
Shrnutí:When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such decisions are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here we show that senescent cells increase levels of multiple membrane-bound polyunsaturated fatty acids (PUFAs), but a specific PUFA, dihomo-gamma-linolenic acid (DGLA, 20:3ω-3) is reduced. Exogenous repletion of DGLA or inhibition of delta-5-desaturase, the enzyme that metabolizes DGLA, instead results in cell death by ferroptosis. Senescent cells had elevated levels of other fezzroptosis sensitizers, including labile iron and expression of lipoxygenases – but also increased Gpx4 levels to prevent ferroptosis. Oral DGLA lowered senescent cell burden in aged mice and improved age-related functional outcomes. Finally, obese humans with lowered DGLA desaturation rates showed lower markers of adipose tissue senescence. Together, our data implicate DGLA and its desaturation as a major driver of decisions between senescence and ferroptosis.
Bibliografia:Competing Interest Statement: CW is an inventor on patents related to the elimination of senescent cells using DGLA, D5D inhibitors, and other ferroptosis inducers. The content is the sole responsibility of the authors and does not necessarily represent the official views of the USDA.
ISSN:2692-8205
DOI:10.1101/2024.10.03.616257