Menadione-induced apoptosis: roles of cytosolic Ca(2+) elevations and the mitochondrial permeability transition pore.
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.
Gerasimenko
Julia V
JV
Medical Research Council Secretory Control Research Group, Physiological Laboratory, University of Liverpool L69 3BX, UK.
Gerasimenko
Oleg V
OV
Palejwala
Altaf
A
Tepikin
Alexei V
AV
Petersen
Ole H
OH
Watson
Alastair J M
AJ
D000109:Acetylcholine / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001865:Bongkrekic Acid / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005452:Fluoresceins / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D024483:Vitamin K 3 / Q000494:pharmacology*
D000590:Amino Acid Chloromethyl Ketones; D000900:Anti-Bacterial Agents; D000933:Antifibrinolytic Agents; D002614:Chelating Agents; D015853:Cysteine Proteinase Inhibitors; D005452:Fluoresceins; D005456:Fluorescent Dyes; D014665:Vasodilator Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D001865:Bongkrekic Acid; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D000968:Antimycin A; D024483:Vitamin K 3; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D000109:Acetylcholine; D002118:Calcium; C007740:fluorexon