Mechanisms of lipofuscin/ceroid accumulation and its impact on the function of the lysosomal system
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
The accumulation of lipofuscin - an electron-dense, autofluorescent, polymeric, intralysosomal substance - is a recognized hallmark of aging postmitotic cells. Ceroid- a substance very close, or perhaps even identical, to lipofuscin - is a characteristic of various pathological processes, such as lysosomal storage diseases, malnutrition, atherosclerosis, oxidative stress, ionizing radiation, etc. Although the mechanisms of lipofuscin formation are now rather well understood (Brunk et al., 1992), what causes it to accumulate within aging postmitotic cells (namely, the role of its possibly impaired degradation/exocytosis) is still disputed. Moreover, little is known about whether lipofuscin accumulation interferes with normal cellular functions, perhaps it even promotes cell death and age-associated pathologies. The role, if any, of ceroid accumulation in the pathogenesis of many diseases also is not clear.
To gain a better insight into the mechanisms of lipofuscin/ceroid accumulation, and to test whether this accumulation has any negative impact on cellular functions, especially on the autophagocytotic process, we decided to study: (l) the role of oxidative stress (normobaric hyperoxia) and/or lysosomal protease inhibition (leupeptin treatment) in lipofuscin/ceroid accumulation in cultured AG-1518 human fibroblasts and neonatal rat cardiac myocytes; (2) the fate of formed lipofuscin/ceroid after the cessation of oxidative stress and/or protease inhibition; (3) the possible reversal of lipofuscin/ceroid accumulation in vitro with an anti-aging drug centrophenoxine; (4) the survival of lipofuscin/ceroid-loaded fibroblasts under amino acid starvation; (5) the effect of lipofuscin/ceroid accumulation on autophagocytosis and intralysosomal degradation; and (6) the sensitivity of lipofuscin/ceroid-loaded fibroblasts to oxidative stress.
We have shown that: (1) both oxidative stress and lysosomal protease inhibition accelerated lipofuscin/ceroid formation, however the effects of these two factors increased dramatically when they acted concurrently; (2) protease-inhibition by itself does not lead to lipofuscin/ceroid formation, but rather allows the prolonged time needed for oxidative modification of autophagocytosed material; (3) lipofuscin/ceroid inclusions formed due to oxidative stress and protease inhibition do not disappear either after returning the cultured cells to normal conditions, during amino acid starvation, or under the influence of centrophenoxine; (4) lipofuscin/ceroid-loaded cells exposed to amino acid starvation show decreased survival time and diminished autophagocytosis; (5) exposure of fibroblasts with various amounts of lipofuscin/ceroid to naphthazarin (a redox cycling quinone producing 0 2 ·-and H20 2) results in selective survival of cells with lower quantities of the pigment; and (6) lipofuscin/ceroid-rich cells have an expanded lysosomal compartment with increased amounts of cathepsin D.
The results suggest that: (i) lipofuscin/ceroid forms within secondary lysosomes due to oxidative damage of autophagocytosed material resulting in cross-linking of protein residues by aldehydes formed from decomposed peroxidized unsaturated lipids; (ii) lipofuscin/ceroid is not substantially eliminated from non-dividing cells by degradation or exocytosis, which explains the progressive accumulation of lipofuscin in postmitotic cells with age; and (iii) a heavy lipofuscin/ceroid loading of cells interferes with normal lysosomal functions by making them less able to autophagocytose and more sensitive to oxidative stress, conceivably due to increased amounts of lysosomal enzymes (potential mediators of oxidative damage) and/or due to a possible catalyzing role of lipofuscin/ceroid-associated iron.
Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 1999. , 52 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 606
Aging, Autophagocytosis, Centrophenoxine, Ceroid, Lipofuscin, Lysosomes, Oxidative stress
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-28080Local ID: 12844ISBN: 91-7219-560-6OAI: oai:DiVA.org:liu-28080DiVA: diva2:248631
1999-10-08, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
von Zglinicki, Thomas, Professor
Papers, included in the Ph.D. thesis, are not registered and included in the posts from 1999 and backwards.2009-10-082009-10-082012-07-31Bibliographically approved