Proteasome inhibition enhances lipofuscin formation.
Lipofuscin, a hallmark of aged nondividing cells, is an undegradable autofluorescent intralysosomal substance composed essentially of oxidized, cross-linked proteins. To test whether impaired activity of proteasomes-which, along with lysosomes, belong to major cellular proteolytic systems-may contribute to lipofuscinogenesis, we exposed growth-arrested human fibroblasts to subapoptotic doses (2 and 5 nM) of a highly specific proteasome inhibitor, MG-262. This resulted in accelerated lipofuscin accumulation (especially when MG-262 exposure was combined with mild hyperoxia-i.e., cultivation at 40% ambient oxygen versus 8% for controls); and enhanced immunostaining for ubiquitin, reflecting accumulation of modified cytosolic proteins subjected for degradation, and cathepsin L, reflecting enlargement of the lysosomal compartment. These data suggest that insufficient proteasomal function may contribute to lipofuscinogenesis by a compensatory increase in the amount of proteins that are difrected for lysosomal degradation. The findings may be helpful for the understanding of cellular aging as well as diseases associated with intralysosomal accumulation of undegradable material.
Terman
Alexei
A
Division of Pathology II, Faculty of Health Sciences, Linköping University, SE-58185, Linköping, Sweden. alete@pat.liu.se
Sandberg
Sara
S
D015415:Biomarkers; D001897:Boronic Acids / Q000494:pharmacology*; D002478:Cells, Cultured; D016922:Cellular Senescence; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005347:Fibroblasts; D006801:Humans; D008062:Lipofuscin / Q000096:biosynthesis*; D009097:Multienzyme Complexes / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D012867:Skin
D015415:Biomarkers; D001897:Boronic Acids; D008062:Lipofuscin; C423917:MG 262; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex