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

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    Author
    Masaldan, S; Clatworthy, SAS; Gamell, C; Smith, ZM; Francis, PS; Denoyer, D; Meggyesy, PM; La Fontaine, S; Cater, MA
    Date
    2018-06-01
    Source Title
    Redox Biology
    Publisher
    ELSEVIER SCIENCE BV
    University of Melbourne Author/s
    Gamell-Fulla, Cristina; Cater, Michael; Masaldan, Shashank
    Affiliation
    Clinical Pathology
    Bio21
    Florey Department of Neuroscience and Mental Health
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Masaldan, S., Clatworthy, S. A. S., Gamell, C., Smith, Z. M., Francis, P. S., Denoyer, D., Meggyesy, P. M., La Fontaine, S. & Cater, M. A. (2018). Copper accumulation in senescent cells: Interplay between copper transporters and impaired autophagy. REDOX BIOLOGY, 16, pp.322-331. https://doi.org/10.1016/j.redox.2018.03.007.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253499
    DOI
    10.1016/j.redox.2018.03.007
    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.

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