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Lysosome-targeted stress reveals increased stability of lipofuscin-containing lysosomes
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
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2008 (English)In: Age (Omaha), ISSN 0161-9152, E-ISSN 1574-4647, Vol. 30, no 1, 31-42 p.Article in journal (Refereed) Published
Abstract [en]

Cellular ageing is associated with accumulation of undegradable intralysosomal material, called lipofuscin. In order to accelerate the lipofuscin-accumulation, confluent, growth arrested human fibroblasts were cultured under hyperoxic conditions. To provide a better insight into the effects of lipofuscin on cellular functions, we compared lysosomal stability in control and lipofuscin-loaded human fibroblasts under conditions of lysosome-targeted stress induced by exposure to either the lysosomotropic detergent MSDH or the redox-cycling quinone naphthazarin. We show that lysosomal damage, assessed by acridine-orange relocation, translocation of cathepsin D to the cytosol, and alkalinization of lysosomes is more pronounced in control than in lipofuscin-loaded fibroblasts. Finding that lysosomal integrity was less affected or even preserved in case of lipofuscin-loaded cells enables us to suggest that lipofuscin exerts lysosome-stabilizing properties.

Place, publisher, year, edition, pages
Springer, 2008. Vol. 30, no 1, 31-42 p.
Keyword [en]
alkalinization, autophagolysosomes, bafilomycin A1, cathepsin D, MSDH, naphthazarin quinone
National Category
Physiology Pathobiology Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:liu:diva-11051DOI: 10.1007/s11357-007-9045-9OAI: oai:DiVA.org:liu-11051DiVA: diva2:17508
Note

Note: Because of an embargo period with Springer journals, the full text will become available at LiU E-Press, January 2009. Original publication: Yuri Stroikin, Hanna Mild, Uno Johansson, Karin Roberg and Karin Öllinger, Lysosome-targeted stress reveals increased stability of lipofuscin-containing lysosomes, 2008, AGE http://dx.doi.org/10.1007/S11357-007-9045-9. Copyright: The original publication is available at http://www.springerlink.com

The previous status of this article was Manuscript and the working title was Lipofuscin preserves lysosome integrity under conditions of organelle-targeted stress.

Available from: 2009-01-12 Created: 2008-04-15 Last updated: 2017-08-30
In thesis
1. Ageing-associated changes of lysosomal compartment: implications on cellular functions
Open this publication in new window or tab >>Ageing-associated changes of lysosomal compartment: implications on cellular functions
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The lysosomal compartment is a major site for intracellular degradation. Lysosomal degradation of the cell’s own constituents, so-called autophagy, not only provides a cell with nutrients, but also removes damaged and potentially dangerous endogenous structures, thus securing intracellular homeostasis. On the other hand, lysosomes have been shown to be involved in the initial stages of apoptosis, and the protective effect of autophagy has been suggested to switch to cell death when excessive.

Ageing-related changes of cellular structures result from damage caused by eactive oxygen species (ROS), which are an inevitable by-product of aerobic life. Intracellular turnover of compromised organelles and macromolecules, to which lysosomal degradation is a major contributor, does not function perfectly, even under favourable conditions. This inherent incompleteness of lysosomal degradation is responsible for the accumulation of a variety of nondegraded and functionally inefficient structures, which can be considered biological “garbage”. Biological “garbage” includes damaged non-degraded macromolecules and organelles, as well as intralysosomal non-degradable polymer-like structure called lipofuscin, or age pigment. Although accumulation of biological “garbage” has been suggested harmful, little is known about the mechanisms of its deleterious effects.

To gain a better understanding of ageing-related changes of the lysosomal compartment and their influence on cell functions, we focused on studying: (1) the role of macroautophagy in the turnover of organelles and lipofuscin formation; (2) the role of biological “garbage” accumulation in the development of ageing-related changes and eventual death of growth-arrested, postmitotic-like cells; (3) the possible cell-protective effect of mitosis; (4) the influence of lipofuscin on cell survival during complete starvation; and (5) the effects of lipofuscin on lysosomal stability.

As a model of induced biological “garbage” accumulation we used confluent human fibroblasts treated with the autophagy inhibitor 3-methyladenine (3MA). Alternatively, lysosomal degradation was suppressed by using the cysteine protease inhibitor leupeptin, or the cathepsin D inhibitor pepstatin A. As a cellular model of aged cells, we used lipofucsin-loaded human fibroblasts. Lipofuscin-loading was achieved by culturing confluent fibroblasts under hyperoxic conditions for 2-4 months. Using these in vitro models, the present study shows that: (1) inhibition of autophagy results in accumulation of lysosome-associated autofluorescent material and mitochondria with low membrane potential; (2) detrimental effect of biological “garbage” accumulation following inhibition of autophagy is prevented by continuous cell division; (3) lipofuscin-loaded cells are more resistant to starvation-induced cell death than control cells; (4) lysosomes of lipofuscinloaded fibroblasts are more resistant to the organelle-targeted stress then lysosomes of control cells.

Based on the results of the present study we conclude that properly operating autophagic machinery plays a crucial role in preventing age-related changes associated with accumulation of biological “garbage”. We also suggest that continual proliferation is the natural mechanism by which cells cope with the accumulation of non-degradable material, employing mechanical dilution during the cell division. Finally, we introduce an idea of lipofuscin being a hormetic agent, and possibly possessing some lysosome-stabilising properties. Better understanding of the influence of the age-related accumulation of biological “garbage” on cellular functions may be helpful for future development of anti-ageing therapy and management of age-associated pathologies.

Place, publisher, year, edition, pages
Institutionen för nervsystem och rörelseorgan, 2007. 68 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 978
Keyword
Ageing, Apoptosis, Biological gabarge, Hormesis, Lipofuscin, Lysosome
National Category
Pathobiology
Identifiers
urn:nbn:se:liu:diva-8012 (URN)91-85643-13-0 (ISBN)
Public defence
2007-02-02, Berzeliussalen, Campus US, Linköping, 09:00 (English)
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Supervisors
Available from: 2007-01-09 Created: 2007-01-09 Last updated: 2017-08-30

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Stroikin, YuriMild, HannaJohansson, UnoRoberg, KarinÖllinger, Karin

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Experimental PathologyFaculty of Health SciencesOto-Rhiono-Laryngology and Head & Neck SurgeryDepartment of ENT - Head and Neck Surgery UHLDepartment of Clinical Pathology and Clinical Genetics
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