Increased resistance of lipofuscin-loaded prematurely senescent fibroblasts to starvation-induced programmed cell death.
Alterations of cellular structures often found in ageing cells is mainly the result of production of reactive oxygen species and a consequence of aerobic life. Both oxidative stress and decreased degradative capacity of lysosomal system cause accumulation of intralysosomal age-related pigment called lipofuscin. To investigate the influence of lipofuscin on cell function, we compared survival of lipofuscin-loaded and control human fibroblasts following complete starvation induced by exposure to phosphate-buffered saline (PBS). Starving of control fibroblasts resulted in lysosomal alkalinisation, relocation of cathepsin D to the cytosol, caspase-3 activation and, finally, cell death, which became evident 72 h after the start of exposure to PBS. Increase of lysosomal pH was significantly less prominent in lipofuscin-loaded cells than in controls and was accompanied neither by leakage of cathepsin D nor by caspase-3 activation even 96 h after the initiation of starvation. Suppression of autophagy by 3-methyladenine (3-MA) accelerated cell death, while inhibition of cathepsin D delayed it, implying an important role of autophagy in cell survival during starvation and showing the involvement of lysosomes in starvation-induced cell death. Disturbed apoptotic response found in lipofuscin-loaded cells can be interpreted as an example of hormesis--an adaptation to low doses of otherwise harmful agents, in this case of lipofuscin, which has a protective effect at moderate amounts but becomes toxic at large quantities.
Stroikin
Yuri
Y
Faculty of Health Sciences, Division of Experimental Pathology, Department of Neuroscience and Locomotion, Linköping University, Sweden. yuri.stroikin@inr.liu.se
Johansson
Uno
U
Asplund
Sofia
S
Ollinger
Karin
K
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D016895:Culture Media, Serum-Free; D006801:Humans; D008062:Lipofuscin / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism
D016895:Culture Media, Serum-Free; D008062:Lipofuscin; C025946:3-methyladenine; C505407:CASP3 protein, human; D053148:Caspase 3; D002402:Cathepsin D; D000225:Adenine