RESUMO
Lipofuscin, a highly oxidized aggregate, consists of covalently cross-linked proteins, lipids, and sugar residues and is one of the major life-span-limiting factors in postmitotic aging cells. An artificial model of this material, showing characteristics and effects comparable to those of the natural form, has turned out to be very useful for in vitro studies. Artificial lipofuscin was used to investigate its effects on the viability of human fibroblasts, its rate of uptake, and its ability to inhibit the proteasomal system. The inhibition of the proteasomal system is one of the major aspects of the cytotoxic effects of lipofuscin. We present here that this proteasomal inhibition is due to proteasomal binding to the lipofuscin surface motifs, degradable by protease K. Furthermore, removal of the surface peptide structures by protease K strongly reduces the cytotoxic effects of lipofuscin and binding of cellular proteins and proteasomes to intracellular protein aggregates.
Assuntos
Lipofuscina/metabolismo , Inibidores de Proteassoma , Células Cultivadas , Senescência Celular/fisiologia , Endopeptidase K/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Lipofuscina/síntese química , Lipofuscina/farmacologia , Oxirredução , Estresse Oxidativo/fisiologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
The kinetics of lipofuscin growth in diseased retinal pigment epithelium cells is investigated using Monte Carlo simulations and scaling theory on a cluster aggregation model. The model captures the essential physics of lipofuscin growth in the cells. A remarkable feature is that small particles may be removed from the cells while the larger ones become fixed and grow by aggregation. Model simulations are compared to the number of lipofuscin granules in eyes with early age-related degeneration.
