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Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis

Masaldan, Shashank, Clatworthy, Sharnel A.S., Gamell, Cristina, Meggyesy, Peter M., Rigopoulos, Antonia-Tonia, Haupt, Sue, Haupt, Ygal, Denoyer, Delphine, Adlard, Paul A., Bush, Ashley I. and Cater, Michael A. 2018, Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis, Redox biology, vol. 14, pp. 100-115, doi: 10.1016/j.redox.2017.08.015.

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Title Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis
Author(s) Masaldan, ShashankORCID iD for Masaldan, Shashank orcid.org/0000-0003-4960-4983
Clatworthy, Sharnel A.S.
Gamell, Cristina
Meggyesy, Peter M.
Rigopoulos, Antonia-Tonia
Haupt, Sue
Haupt, Ygal
Denoyer, DelphineORCID iD for Denoyer, Delphine orcid.org/0000-0001-8932-5116
Adlard, Paul A.
Bush, Ashley I.
Cater, Michael A.
Journal name Redox biology
Volume number 14
Start page 100
End page 115
Total pages 16
Publisher Elsevier
Place of publication Amsterdam, The Netherlands
Publication date 2018-04
ISSN 2213-2317
Keyword(s) Ageing
Autophagy
Ferritin
Ferritinophagy
Ferroptosis
Iron
Senescence
Summary Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins. For instance, ferritin (iron storage) levels provided a robust biomarker of cellular senescence, for associated iron accumulation and for resistance to iron-induced toxicity. Cellular senescence preceded iron accumulation and was not perturbed by sustained iron chelation (deferiprone). Iron accumulation in senescent cells was driven by impaired ferritinophagy, a lysosomal process that promotes ferritin degradation and ferroptosis. Lysosomal dysfunction in senescent cells was confirmed through several markers, including the build-up of microtubule-associated protein light chain 3 (LC3-II) in autophagosomes. Impaired ferritin degradation explains the iron accumulation phenotype of senescent cells, whereby iron is effectively trapped in ferritin creating a perceived cellular deficiency. Accordingly, senescent cells were highly resistant to ferroptosis. Promoting ferritin degradation by using the autophagy activator rapamycin averted the iron accumulation phenotype of senescent cells, preventing the increase of TfR1, ferritin and intracellular iron, but failed to re-sensitize these cells to ferroptosis. Finally, the enrichment of senescent cells in mouse ageing hepatic tissue was found to accompany iron accumulation, an elevation in ferritin and mirrored our observations using cultured senescent cells.
Language eng
DOI 10.1016/j.redox.2017.08.015
Field of Research 060199 Biochemistry and Cell Biology not elsewhere classified
060104 Cell Metabolism
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2017, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution Non-Commercial No-Derivatives licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30102603

Document type: Journal Article
Collections: School of Life and Environmental Sciences
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.