Aggregates of oxidized proteins (lipofuscin) induce apoptosis through proteasome inhibition and dysregulation of proapoptotic proteins.
Cellular senescence may be accompanied by accumulation of large aggregates of oxidized proteins, also known as lipofuscin. The hypothesis that cellular accumulation of lipofuscin-like materials (LIP) results in cell death as a result of proteasome inhibition was examined. Rat neonatal cardiomyocytes were incubated with synthetic LIP for up to 48 h. This was accompanied by increases in cellular autofluorescence (207% by 48 h; p < 0.05) and electron microscopic evidence of internalization of LIP particles. LIP incubation resulted in loss of viability (-46% by 48 h; p < 0.05) through apoptotic cell death. Although 20S-proteasome activity was increased by 74% after 6 h, both 20S- and 26S-proteasome activities were decreased after 48 h of incubation (-54% (p < 0.05) and -50%, respectively), accompanied by large increases in ubiquitinated proteins. Several proteasome-regulated proapoptotic proteins, including c-Jun (2.9-fold; p < 0.05), Bax (1.8-fold; p < 0.05), and p27(kip1) (3.2-fold; p < 0.05), were observed to be increased by 48 h. Observation of ubiquitinated homologues of Bax and p27(kip1) suggested that part of the increase was due to decreased proteasomal degradation of these proteins. The results of this study are consistent with the conclusion that accumulation of LIP results in inhibition of the proteasome, which initiates an apoptotic cascade as a result of dysregulation of several proapoptotic proteins.
Powell
Saul R
SR
Department of Medicine, Long Island Jewish Medical Center Campus of the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, NY 11042, USA. spowell@lij.edu
Wang
Ping
P
Divald
Andras
A
Teichberg
Saul
S
Haridas
Viraga
V
McCloskey
Thomas W
TW
Davies
Kelvin J A
KJ
Katzeff
Harvey
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005260:Female; D005609:Free Radicals; D008062:Lipofuscin / Q000378:metabolism / Q000502:physiology*; D008854:Microscopy, Electron; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D025801:Ubiquitin / Q000378:metabolism
D005609:Free Radicals; D008062:Lipofuscin; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D000255:Adenosine Triphosphate