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Menadione-induced apoptosis: roles of cytosolic Ca²⁺ elevations and the mitochondrial permeability transition pore

¹ Medical Research Council Secretory Control Research Group, Physiological Laboratory, University of Liverpool L69 3BX, UK
² Department of Medicine, University of Liverpool L69 3BA, UK

^* Author for correspondence (e-mail: alastair.watson{at}liv.ac.uk)

Accepted 1 November 2001

In normal pancreatic acinar cells, the oxidant menadione evokes repetitive cytosolic Ca²⁺ spikes, partial mitochondrial depolarisation, cytochrome c release and apoptosis. The physiological agonists acetylcholine and cholecystokinin also evoke cytosolic Ca²⁺ spikes but do not depolarise mitochondria and fail to induce apoptosis. Ca²⁺ spikes induced by low agonist concentrations are confined to the apical secretory pole of the cell by the buffering action of perigranular mitochondria. Menadione prevents mitochondrial Ca²⁺ uptake, which permits rapid spread of Ca²⁺ throughout the cell. Menadione-induced mitochondrial depolarisation is due to induction of the permeability transition pore. Blockade of the permeability transition pore with bongkrekic acid prevents activation of caspase 9 and 3. In contrast, the combination of antimycin A and acetylcholine does not cause apoptosis but elicits a global cytosolic Ca²⁺ rise and mitochondrial depolarisation without induction of the permeability transition pore. Increasing the cytosolic Ca²⁺ buffering power by BAPTA prevents cytosolic Ca²⁺ spiking, blocks the menadione-elicited mitochondrial depolarisation and blocks menadione-induced apoptosis. These results suggest a twin-track model in which both intracellular release of Ca²⁺ and induction of the permeability transition pore are required for initiation of apoptosis.

Key words: Calcium, Apoptosis, Menadione, Mitochondria, Permeability transition pore

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