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Interplay between lysosomal, mitochondrial and death receptor pathways during manganese-induced apoptosis in glial

R M Gorojod1, A Alaimo1, S Porte Alcon1

  • 1CONICET- Universidad de Buenos Aires, Instituto de Química Biológica Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Laboratorio de Disfunción Celular en Enfermedades Neurodegenerativas y Nanomedicina, Buenos Aires, Argentina.

Archives of Toxicology
|April 6, 2017
PubMed

Insights

Manganese (Mn) overexposure triggers cell death by damaging lysosomes and releasing cathepsins, key players in apoptosis. Targeting this lysosomal pathway offers a potential therapeutic strategy for Manganism, a Parkinsonism linked to Mn toxicity.

Area of Science:

  • Neuroscience
  • Toxicology
  • Cell Biology

Background:

  • Manganese (Mn) is vital for brain function but toxic in excess, causing Manganism, a Parkinsonian syndrome.
  • Previous studies indicated Mn induces oxidative stress-mediated apoptosis in C6 astrocytoma cells.

Purpose of the Study:

  • To investigate the role of cathepsins in manganese-induced apoptosis.
  • To elucidate the impact of lysosomal membrane permeabilization (LMP) and cathepsin release in Mn toxicity.

Main Methods:

  • Utilized cathepsin B and D inhibitors (Ca-074 Me, Pepstatin A) and Bafilomycin A1 in cell culture models.
  • Administered intrastriatal Mn injections in vivo to assess cathepsin D levels in specific brain regions.

Main Results:

  • Manganese exposure caused lysosomal membrane permeabilization (LMP) and subsequent cathepsin release.
  • Inhibitors of cathepsins B and D, and Bafilomycin A1, blocked Mn-induced caspase activation, FasL upregulation, Bid cleavage, mitochondrial membrane potential disruption, and cytochrome c release.
  • In vivo studies confirmed increased cathepsin D levels in the corpus striatum and substantia nigra pars compacta following Mn injection.

Conclusions:

  • Lysosomal membrane permeabilization and cathepsin release are critical mediators of manganese-induced apoptosis.
  • Targeting the lysosomal pathway presents a promising therapeutic avenue for Manganism.
Keywords:
ApoptosisCathepsinsGliaLysosomesManganeseParkinsonism

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