Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content

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Appelqvist, HannaLinköpings universitet,Experimentell patologi,Hälsouniversitetet (author)

Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content

Article/chapterEnglish2012

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2012-11-16
Public Library of Science,2012
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LIBRIS-ID:oai:DiVA.org:liu-85004
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-85004URI
https://doi.org/10.1371/journal.pone.0050262DOI

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Language:English
Summary in:English

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Funding Agencies|Swedish Research Council|2010-3463|Deutsche Forschungsgemeinschaft||foundation of Olle Engqvist||foundation of Ake Wiberg||
Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2), which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determined the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

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MEDICINE
MEDICIN

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Sandin, LinneaLinköpings universitet,Cellbiologi,Hälsouniversitetet(Swepub:liu)linsa35 (author)
Björnström, KarinÖstergötlands Läns Landsting,Linköpings universitet,Anestesiologi med intensivvård,Hälsouniversitetet,Intensivvårdskliniken US(Swepub:liu)karbj69 (author)
Saftig, PaulBiochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany (author)
Garner, BrettIllawarra Health and Medical Research Institute, University of Wollongong, Australia (author)
Öllinger, KarinÖstergötlands Läns Landsting,Linköpings universitet,Experimentell patologi,Hälsouniversitetet,Klinisk patologi och klinisk genetik(Swepub:liu)karol56 (author)
Kågedal, KatarinaLinköpings universitet,Patologi,Hälsouniversitetet(Swepub:liu)katka10 (author)
Linköpings universitetExperimentell patologi (creator_code:org_t)

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In:PLOS ONE: Public Library of Science7:111932-6203

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