Elsevier

Redox Biology

Volume 14, April 2018, Pages 100-115
Redox Biology

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

https://doi.org/10.1016/j.redox.2017.08.015Get rights and content
Under a Creative Commons license
open access

Highlights

  • Altered iron homeostasis in senescent cells is driven by impaired ferritinophagy.

  • Impaired ferritinophagy causes functional cellular iron deficiency.

  • senescent cells are resistant to iron mediated cell death including ferroptosis.

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

Senescence
Iron
Ferritinophagy
Ferroptosis
Ferritin
Autophagy
Ageing

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