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Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages

Moumita Ghosh1, Fredrik Carlsson, Amit Laskar

  • 1Division of Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, Linköping, Sweden.

FEBS Letters
|January 12, 2011
PubMed

Insights

Lysosomal membrane permeabilization (LMP) triggers cell death via oxidative stress and ferritin changes. Inhibiting cysteine cathepsins offers protection, suggesting therapeutic targets for lysosomotropic substance-induced disorders.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Toxicology

Background:

  • Lysosomal membrane permeabilization (LMP) is a known inducer of apoptosis.
  • Macrophages, crucial in immune responses, possess abundant hydrolytic enzymes and iron, making them susceptible to lysosomal damage.
  • Lysosomotropic substances can disrupt lysosomal integrity, leading to cellular dysfunction.

Purpose of the Study:

  • To investigate the molecular mechanisms linking lysosomal membrane permeabilization (LMP) to apoptosis in macrophages.
  • To explore the role of oxidative stress and ferritin in LMP-induced cell death.
  • To evaluate the protective effects of specific inhibitors against LMP-induced cellular damage.

Main Methods:

  • Induction of LMP using the lysosomotropic detergent MSDH in macrophage models.
  • Treatment with lysosomotropic base NH(4)Cl and cysteine cathepsin inhibitors.
  • Assessment of cathepsin activity, oxidative stress markers, ferritin levels, and cell viability.

Main Results:

  • MSDH-induced LMP led to early cathepsin up-regulation, increased oxidative stress, ferritin accumulation, and cell death.
  • NH(4)Cl treatment attenuated ferritin induction and oxidative stress.
  • Cysteine cathepsin inhibitors significantly reduced cell death and oxidative stress, with a lesser impact on ferritin induction.

Conclusions:

  • Oxidative stress resulting from lysosomal rupture is a key driver of ferritin induction and subsequent mitochondrial damage.
  • Targeting oxidative stress and ferritin pathways presents a potential therapeutic strategy for disorders involving lysosomotropic substances.
  • Cysteine cathepsins play a significant role in LMP-induced apoptosis, but ferritin induction is partially independent of their direct inhibition.

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