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

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.

Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration

“…protein (Ingold et al, 2017, Xie et al, 2016, Tarangelo et al, 2018, Gnanapradeepan et al, 2018, Li et al, 2012, Wang et al, 2016, Masaldan et al, 2018a, Masaldan et al, 2018b.…”

Hallmarks of Aging: An Autophagic Perspective

“…In addition, senescent MEF cells accumulate copper due to higher import and lower export, enhancing antioxidant defense mechanisms. In addition, rapamycin treatment can prevent and reverse copper accumulation, suggesting that autophagy mediates the copper homeostasis (136). Along the same lines, primary cultures from human fibroblasts depleted for Atg7, Atg12, or Lamp2 showed cell cycle arrest and high levels of SA-β-Gal staining, a characteristic feature of replicative senescence cells (137).…”

Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

“…Senescent cells in vitro display aberrant iron homeostasis [82], and there are some indications that their abundance influences iron levels in ageing tissue [82,93,94]. Senescent cells display elevated iron and a concomitant increase in ferritin and markers of oxidative stress in vitro [82,93,94,95]. Iron is known to promote the induction of senescence in cultured microglia [96].…”