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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cellular Senescence / drug effects*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Ferritins / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Iron / analysis
  • Iron / metabolism
  • Iron / toxicity*
  • Lysosomes / metabolism
  • Mass Spectrometry
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells


  • Cyclin-Dependent Kinase Inhibitor p16
  • Ferritins
  • Iron