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Calcium influx through receptor-operated channel induces mitochondria-triggered paraptotic cell death

Enrique Jambrina1, Roberto Alonso, Marta Alcalde

  • 1Instituto de Biologia y Genética Molecular, CSIC-Universidad de Valladolid, Facultad de Medicina, Ramón y Cajal 7, Spain.

The Journal of Biological Chemistry
|February 7, 2003
PubMed

Insights

Cytoplasmic calcium (Ca2+) overload via the vanilloid receptor subtype 1 (VR1) channel triggers a unique cell death pathway. This process involves mitochondrial damage and oxidative stress, distinct from apoptosis or necrosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cytoplasmic Ca(2+) overload is implicated in cell death.
  • The specific mechanisms and pathways remain incompletely understood.

Purpose of the Study:

  • To investigate the role of cytoplasmic Ca(2+) overload as a cell death trigger.
  • To elucidate the specific Ca(2+) influx pathway involved in cell death.

Main Methods:

  • Expression of vanilloid receptor subtype 1 (VR1) in Jurkat cells.
  • Measurement of intracellular Ca(2+) levels.
  • Assessment of phosphatidylserine exposure and mitochondrial damage.
  • Analysis of caspase activation, DNA cleavage, and cytochrome c release.

Main Results:

  • Ca(2+) uptake through VR1 channels induced sustained intracellular [Ca(2+)] rises, phosphatidylserine exposure, and cell death.
  • This Ca(2+) influx triggered mitochondrial damage, including permeability transition pore opening and collapse of mitochondrial membrane potential.
  • Ca(2+)-induced cell death required mitochondrial calcium uptake and was associated with oxidative/nitrative stress, but not caspase activation or DNA fragmentation.

Conclusions:

  • Cytoplasmic Ca(2+) overload via VR1 channels initiates a distinct cell death program.
  • This pathway, termed paraptosis, involves mitochondrial dysfunction and oxidative stress, differentiating it from apoptosis and necrosis.

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