Copper accumulation in senescent cells: Interplay between copper transporters and impaired autophagy.
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.
['Masaldan|Shashank|S|', 'Clatworthy|Sharnel A S|SAS|', 'Gamell|Cristina|C|', 'Smith|Zoe M|ZM|', 'Francis|Paul S|PS|', 'Denoyer|Delphine|D|', 'Meggyesy|Peter M|PM|', 'Fontaine|Sharon La|S|', 'Cater|Michael A|MA|']
D000818:Animals D001343:Autophagy D027682:Cation Transport Proteins D016922:Cellular Senescence D003300:Copper D000079923:Copper Transporter 1 D000073840:Copper-Transporting ATPases D004847:Epithelial Cells D005347:Fibroblasts D054477:Glutaredoxins D005978:Glutathione D006706:Homeostasis D006801:Humans D008247:Lysosomes D008297:Male D051379:Mice D011467:Prostate D000072105:Superoxide Dismutase-1
Copper Senescence Autophagy Ageing Homeostasis