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

Shashank Masaldan, Sharnel A.S. Clatworthy, Cristina Gamell, Peter M. Meggyesy, Antonia Tonia Rigopoulos, Sue Haupt, Ygal Haupt, Delphine Denoyer, Paul A Adlard, Ashley Ian Bush, Michael A Cater

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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.

Original languageEnglish
Pages (from-to)100-115
Number of pages16
JournalRedox Biology
Volume14
DOIs
Publication statusPublished - 1 Apr 2018
Externally publishedYes

Keywords

  • Ageing
  • Autophagy
  • Ferritin
  • Ferritinophagy
  • Ferroptosis
  • Iron
  • Senescence

Cite this

Masaldan, S., Clatworthy, S. A. S., Gamell, C., Meggyesy, P. M., Rigopoulos, A. T., Haupt, S., Haupt, Y., Denoyer, D., Adlard, P. A., Bush, A. I., & Cater, M. A. (2018). Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biology, 14, 100-115. https://doi.org/10.1016/j.redox.2017.08.015