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Induction of cell death by the lysosomotropic detergent MSDH
W Li1, X Yuan, G Nordgren
1Division of Pathology II, Faculty of Health Sciences, University of Linköping, S-581 85, Linköping, Sweden.
Abstract:
Controlled lysosomal rupture was initiated in lysosome-rich, macrophage-like cells by the synthetic lysosomotropic detergent, O-methyl-serine dodecylamide hydrochloride (MSDH). When MSDH was applied at low concentrations, resulting in partial lysosomal rupture, activation of pro-caspase-3-like proteases and apoptosis followed after some hours. Early during apoptosis, but clearly secondary to lysosomal destabilization, the mitochondrial transmembrane potential declined. At high concentrations, MSDH caused extensive lysosomal rupture and necrosis. It is suggested that lysosomal proteases, if released to the cytosol, may cause apoptosis directly by pro-caspase activation and/or indirectly by mitochondrial attack with ensuing discharge of pro-apoptotic factors.
Insights
Lysosomal rupture induced by O-methyl-serine dodecylamide hydrochloride (MSDH) triggers apoptosis via caspase activation or necrosis. This suggests lysosomal proteases can directly cause cell death.
Area of Science:
- Cell Biology
- Biochemistry
- Toxicology
Background:
- Lysosomes are crucial cellular organelles involved in degradation.
- Lysosomal membrane integrity is vital for cell homeostasis.
- Dysfunctional lysosomes are implicated in various pathologies.
Purpose of the Study:
- To investigate the role of lysosomal rupture in programmed cell death.
- To explore the mechanism by which lysosomal damage induces apoptosis and necrosis.
- To characterize the effects of O-methyl-serine dodecylamide hydrochloride (MSDH) on lysosomal stability and cell fate.
Main Methods:
- Utilized macrophage-like cells rich in lysosomes.
- Applied varying concentrations of the synthetic detergent O-methyl-serine dodecylamide hydrochloride (MSDH).
- Monitored for lysosomal rupture, pro-caspase-3 activation, apoptosis, mitochondrial potential changes, and necrosis.
Main Results:
- Low MSDH concentrations caused partial lysosomal rupture, leading to delayed pro-caspase activation and apoptosis.
- Mitochondrial transmembrane potential declined early in apoptosis, secondary to lysosomal destabilization.
- High MSDH concentrations induced extensive lysosomal rupture, resulting in necrosis.
Conclusions:
- Controlled lysosomal rupture can initiate apoptosis through caspase activation.
- Released lysosomal proteases may directly trigger apoptosis or indirectly cause cell death via mitochondrial damage.
- MSDH serves as a tool to study lysosomal function and its role in cell death pathways.