MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes.
Senescence is a state of growth arrest resulting mainly from telomere attrition and oxidative stress. It ultimately leads to cell death. We have previously shown that, in keratinocytes, senescence is induced by NF-kappaB activation, MnSOD upregulation and H(2)O(2) overproduction. We have also shown that senescent keratinocytes do not die by apoptosis but as a result of high macroautophagic activity that targets the primary vital cell components. Here, we investigated the mechanisms that activate this autophagic cell death program. We show that corpses occurring at the senescence plateau display oxidatively-damaged mitochondria and nucleus that colocalize with autophagic vacuoles. The occurrence of such corpses was decreased by specifically reducing the H(2)O(2) level with catalase, and, conversely, reproduced by overexpressing MnSOD or applying subtoxic doses of H(2)O(2). This H(2)O(2)-induced cell death did occur through autophagy since it was accompanied by an accumulation of autophagic vesicles as evidenced by Lysotracker staining, LC3 vesiculation and transmission electron microscopy. Most importantly, it was partly abolished by 3-methyladenine, the specific inhibitor of autophagosome formation, and by anti-Atg5 siRNAs. Taken together these results suggest that autophagic cell death is activated in senescent keratinocytes because of the upregulation of MnSOD and the resulting accumulation of oxidative damages to nucleus and mitochondria.
Deruy
Emeric
E
Université Lille Nord de France, Lille, France.
Gosselin
Karo
K
Vercamer
Chantal
C
Martien
Sébastien
S
Bouali
Fatima
F
Slomianny
Christian
C
Bertout
Julie
J
Bernard
David
D
Pourtier
Albin
A
Abbadie
Corinne
C
D001343:Autophagy; D016923:Cell Death; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase