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

Gerasimenko, Julia Vladimirovna, Gerasimenko, Oleg Vsevolodovich, Palejwala, Altaf, Tepikin, Alexei, Petersen, Ole Holger and Watson, Alistair J. M. 2002. Menadione-induced apoptosis: Roles of cytosolic Ca2+ elevations and the mitochondrial permeability transition pore. Journal of Cell Science 115 , pp. 485-497.

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Abstract

In normal pancreatic acinar cells, the oxidant menadione evokes repetitive cytosolic Ca(2+) spikes, partial mitochondrial depolarisation, cytochrome c release and apoptosis. The physiological agonists acetylcholine and cholecystokinin also evoke cytosolic Ca(2+) spikes but do not depolarise mitochondria and fail to induce apoptosis. Ca(2+) 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 Ca(2+) uptake, which permits rapid spread of Ca(2+) 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 Ca(2+) rise and mitochondrial depolarisation without induction of the permeability transition pore. Increasing the cytosolic Ca(2+) buffering power by BAPTA prevents cytosolic Ca(2+) 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 Ca(2+) and induction of the permeability transition pore are required for initiation of apoptosis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology
Publisher: The Company of Biologists Ltd
ISSN: 0021-9533
Last Modified: 19 May 2019 23:16
URI: http://orca.cf.ac.uk/id/eprint/71001

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