Menadione-induced apoptosis: roles of cytosolic Ca(2+) elevations and the mitochondrial permeability transition pore

Area of Science:

• Cell Biology
• Mitochondrial Function
• Apoptosis Signaling

Background:

• Pancreatic acinar cells exhibit cytosolic Ca(2+) spikes upon stimulation by physiological agonists like acetylcholine.
• Oxidative stress, induced by menadione, triggers Ca(2+) spikes, mitochondrial depolarization, and apoptosis in these cells.

Purpose of the Study:

• To elucidate the mechanisms by which menadione induces apoptosis in pancreatic acinar cells.
• To investigate the roles of cytosolic Ca(2+) and mitochondrial function in menadione-induced cell death.

Main Methods:

• Utilized menadione and physiological agonists (acetylcholine, cholecystokinin) to stimulate pancreatic acinar cells.
• Monitored cytosolic Ca(2+) levels, mitochondrial membrane potential, and cytochrome c release.
• Employed bongkrekic acid and BAPTA to block the mitochondrial permeability transition pore and Ca(2+) buffering, respectively.

Main Results:

• Menadione induced Ca(2+) spikes, mitochondrial depolarization, and apoptosis, unlike physiological agonists.
• Menadione-induced depolarization involved the mitochondrial permeability transition pore, which, when blocked, prevented caspase activation and apoptosis.
• Enhanced Ca(2+) buffering prevented menadione-induced depolarization and apoptosis, while antimycin A + acetylcholine caused depolarization without apoptosis.

Conclusions:

• Apoptosis initiation in pancreatic acinar cells requires a dual mechanism: intracellular Ca(2+) release and induction of the mitochondrial permeability transition pore.
• Mitochondrial Ca(2+) uptake and buffering play critical roles in preventing oxidative stress-induced cell death.