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

Masaldan, Shashank, Clatworthy, Sharnel AS, Gamell, Cristina, Smith, Zoe M, Francis, Paul S, Denoyer, Delphine, Meggyesy, Peter M, La Fontaine, Sharon and Cater, Michael A 2018, Copper accumulation in senescent cells: Interplay between copper transporters and impaired autophagy, Redox biology, vol. 16, pp. 322-331, doi: 10.1016/j.redox.2018.03.007.

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Title Copper accumulation in senescent cells: Interplay between copper transporters and impaired autophagy
Author(s) Masaldan, ShashankORCID iD for Masaldan, Shashank orcid.org/0000-0003-4960-4983
Clatworthy, Sharnel AS
Gamell, Cristina
Smith, Zoe M
Francis, Paul SORCID iD for Francis, Paul S orcid.org/0000-0003-4165-6922
Denoyer, DelphineORCID iD for Denoyer, Delphine orcid.org/0000-0001-8932-5116
Meggyesy, Peter M
La Fontaine, SharonORCID iD for La Fontaine, Sharon orcid.org/0000-0002-9948-074X
Cater, Michael A
Journal name Redox biology
Volume number 16
Start page 322
End page 331
Total pages 10
Publisher Elsevier
Place of publication Amsterdam, The Netherlands
Publication date 2018-06
ISSN 2213-2317
2213-2317
Keyword(s) Ageing
Autophagy
Copper
Homeostasis
Senescence
Summary 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.
Language eng
DOI 10.1016/j.redox.2018.03.007
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2018, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution Non-Commercial No-Derivatives licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30107064

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.