Lipofuscin

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lipofuscin

In unstressed situations protein homeostasis is balanced by folding and stabilization of proteins by chaperones of the Hsp family and the controlled degradation of proteins by the proteasomal system. Under stress conditions and, therefore, most notably during aging the balance between protein damage and clearance of damaged proteins is disturbed leading to a malfunctioning of proteostasis and an accumulating mass of oxidized proteins, aggregate and aggresome formation and finally to the accumulation of highly cross-linked materials such as lipofuscin. Accumulation of aggregates in postmitotic cells seems to be especially dramatic, since they are not able to dilute this material by cell division.

A Schiff base reaction product of ethanolamine and all-transretinal named A2-E (N-retinylidene-N-retinylethanolamine) was identified as the major fluorophor of ocular lipofuscin. A2-E accumulate during the autophagy of oxidized lipoprotein complexes. A2-E is an inhibitor of the ATP-driven proton pump located in the lysosomal membrane. Such inhibition of proton transport to the lysosomal lumen results in an increase of the lysosomal pH with subsequent inhibition of lysosomal hydrolases. All this processes lead to lipofuscin formation. Lipofuscin is accepted to consist of oxidized proteins (30–70%) as well as lipids (20–50%). Although, the 20S proteasome is relatively resistant towards oxidants both in vitro and in vivo, it was shown that oxidized protein aggregates are able to inhibit the proteolytic activity of the 20S proteasome.

Intracellular effects of lipofuscin in a cell are very different. By using an artificial lipofuscin it could be shown, that lipofuscin is a prominent source of oxidants and is able to incorporate iron in a redox-active manner. It could be shown that artificial lipofuscin and particularly iron-loaded artificial lipofuscin increase caspase-3 activity if taken up by cells and, therefore, apoptosis. Another major characteristic of lipofuscin is its ability to inhibit the degradation of oxidized proteins by competitively binding to proteolytic enzymes and this activates the complement system and inflammatory response. And as a result of inactivation of lysosomes by A2-E and early lipofuscin due to reduced intralysosomal acidity and hydrolase activity macroautophagy is decreased and so late lipofuscin is accumulated at periphery of postmitotic cells and causes different age-related pathologies.