Elsevier

Redox Biology

Volume 16, June 2018, Pages 322-331
Redox Biology

Research Paper
Copper accumulation in senescent cells: Interplay between copper transporters and impaired autophagy

https://doi.org/10.1016/j.redox.2018.03.007Get rights and content
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Highlights

  • Copper accumulation is a feature of cellular senescence.

  • Elevated copper in senescent cells is associated with impaired autophagic-lysosomal function.

  • Restoration/preservation of lysosomal function attenuates copper accumulation.

  • Both Atp7a and autophagic-lysosomal function are required for copper export.

Abstract

Cellular senescence is characterized by irreversible growth arrest incurred through either replicative exhaustion or by pro-oncogenic cellular stressors (radioactivity, oxidative stress, oncogenic activation). The enrichment of senescent cells in tissues with age has been associated with tissue dyshomeostasis and age-related pathologies including cancers, neurodegenerative disorders (e.g. Alzheimer's, Parkinson's, etc.) and metabolic disorders (e.g. diabetes). We identified copper accumulation as being a universal feature of senescent cells [mouse embryonic fibroblasts (MEF), human prostate epithelial cells and human diploid fibroblasts] in vitro. Elevated copper in senescent MEFs was accompanied by elevated levels of high-affinity copper uptake protein 1 (Ctr1), diminished levels of copper-transporting ATPase 1 (Atp7a) (copper export) and enhanced antioxidant defence reflected by elevated levels of glutathione (GSH), superoxide dismutase 1 (SOD1) and glutaredoxin 1 (Grx1). The levels of intracellular copper were further increased in senescent MEFs cultured in copper supplemented medium and in senescent Mottled Brindled (Mobr) MEFs lacking functional Atp7a. Finally, we demonstrated that the restoration/preservation of autophagic-lysosomal degradation in senescent MEFs following rapamycin treatment correlated with attenuation of copper accumulation in these cells despite a further decrease in Atp7a levels. This study for the first time establishes a link between Atp7a and the autophagic-lysosomal pathway, and a requirement for both to effect efficient copper export. Such a connection between cellular autophagy and copper homeostasis is significant, as both have emerged as important facets of age-associated degenerative disease.

Keywords

Senescence
Copper
Ageing
Homeostasis
Autophagy

Cited by (0)

1

Co-senior authors.