J Biol Chem. 2003 Apr; 278 (16):14134-14145.

Jambrina E, Alonso R, Alcalde M, del Carmen Rodríguez M, Serrano A, Martínez-A C, García-Sancho J, Izquierdo M.

We address the specific role of cytoplasmic Ca²⁺ overload as a cell death trigger by expressing a receptor-operated specific Ca²⁺ channel, vanilloid receptor subtype 1 (VR1), in Jurkat cells. Ca²⁺ uptake through the VR1 channel, but not capacitative Ca²⁺ influx stimulated by the muscarinic type 1 receptor, induced sustained intracellular [Ca²⁺] rises, exposure of phosphatidylserine, and cell death.

Ca²⁺ influx was necessary and sufficient to induce mitochondrial damage, as assessed by opening of the permeability transition pore and collapse of the mitochondrial membrane potential. Ca²⁺-induced cell death was inhibited by ruthenium red, protonophore carbonyl cyanidem-chlorophenylhydrazone, or cyclosporin A treatment, as well as by Bcl-2 expression, indicating that this process requires mitochondrial calcium uptake and permeability transition pore opening. Cell death occurred without caspase activation, oligonucleosomal/50-kilobase pair DNA cleavage, or release of cytochrome c or apoptosis inducer factor from mitochondria, but it required oxidative/nitrative stress.

Thus, Ca²⁺influx triggers a distinct program of mitochondrial dysfunction leading to paraptotic cell death, which does not fulfill the criteria for either apoptosis or necrosis.