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Redox Biol. 2018 Apr;14:100-115. doi: 10.1016/j.redox.2017.08.015. Epub 2017 Sep 1.

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

Author information

1
Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.
2
Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
3
Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
4
Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
5
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.
6
Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: mcater@deakin.edu.au.

Abstract

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.

KEYWORDS:

Ageing; Autophagy; Ferritin; Ferritinophagy; Ferroptosis; Iron; Senescence

PMID:
28888202
PMCID:
PMC5596264
DOI:
10.1016/j.redox.2017.08.015
[Indexed for MEDLINE]
Free PMC Article

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