Sensitivity to Lysosome-Dependent Cell Death Is Directly Regulated by Lysosomal Cholesterol Content
Open accessAbstract
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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Under physiological conditions, lysosomal membranes can be stabilized by altering lysosomal cholesterol content or boosting endogenous HSP70 activity.
“Moreover, under physiological conditions, lysosomal membranes can be stabilized by altering lysosomal cholesterol content [788] or by boosting endogenous activity of heat shock protein family A (Hsp70) member 1A (HSPA1A; best known as HSP70) [789, 790].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [788]
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“demonstrated that Npc1 null cells or U18666A-treated cells significantly attenuated cell injury induced by O-methyl-serine dodecylamide hydrochloride, an apoptosis inducer, and hydrogen peroxide, an oxidative stress inducer, and suggested that the Npc1 mutation and inhibition can modulate lysosomal function through an…”
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“Our results with lowered lysosomal cholesterol by DOPGmake sense in the context of previous studies that showed U18666A-induced lysosomal cholesterol accumulation caused a decrease in susceptibility to LMP caused by various agents (Appelqvist et al., 2011; Reiners et al., 2011; Appelqvist et al., 2012).”
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- Authors
- Appelqvist, H., Sandin, L., Björnström, K., Saftig, P., Garner, B., Öllinger, K., & Kågedal, K.
- Affiliations
- Linköping University (SE)
- University of Wollongong (AU)
- Corresponding author
- Appelqvist, Hanna
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-11-16
- Volume
- 7
- Issue
- 11
- Pages
- e50262
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3500374
- OpenAlex
- W2033615443
- Cited by
- 108
- References
- 46
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 13 · 2022: 5 · 2021: 13 · 2020: 14 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 7 · 2013: 9
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Figshare (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Vetenskapsrådet (2010-03463)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- lysosomal cholesterol, lysosome-dependent cell death, apoptosis, lysosomal membrane stability, lysosomal membrane permeabilization, Niemann-Pick disease type C1, NPC1 protein, cholesterol accumulation, lipid homeostasis, neurodegenerative diseases, oxidative stress, myriocin, methyl-β-cyclodextrin, 25-hydroxycholesterol, LAMP2, neurons, fibroblasts
- MeSH terms
- Niemann-Pick C1 Protein, Androstenes, Carrier Proteins, Cholesterol, Fibroblasts, Flow Cytometry, Humans, Hydroxycholesterols, Immunohistochemistry, Lysosomes, Membrane Glycoproteins, Microscopy, Phase-Contrast, Mutation, Neurons, Quinacrine, Blotting, Western, Cell Death, Statistics, Nonparametric, beta-Cyclodextrins, Intracellular Signaling Peptides and Proteins, Lysosomal Membrane Proteins
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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