Purinergic Receptor-Mediated Cytotoxicity
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Mitochondria are vitally important for maintaining cellular integrity. Calcium is considered a mediator of necrosis as well as a main cause of damage in isolated mitochondria. Our results show that mitochondrial Ca2+ regulation in hepatocytes is affected when [Ca2+]i is increased; this is followed by mitochondrial dysfunction and irreversible cell injury. Mitochondrial free [Ca2+] is indicated as a key parameter in this process, and phosphate is indicated as a possible important regulator of [Ca2+]mito. In addition, we suggest a role for mitochondrial Ca2+ deposits, which present only in cells killed by high [Ca2+]i.
The mechanisms underlying Ca2+-induced mitochondrial damage are rapidly elucidated; it remains to be seen whether, in intact cells, opening of a large membranous pore, opening of small ion channels, or nonspecific mitochondrial membrane destruction is involved. Our results suggest at least a small permeability change of the mitochondrial inner membrane, allowing, for example, K+ fluxes.
Future issues include the question of what happens after mitochondrial failure. Several processes, such as extreme mitochondrial swelling, mitochondrial NAD(P)H depletion, and release of mitochondrial components must be considered as critical consequences of mitochondrial dysfunction.
KeywordsCell Injury Mitochondrial Permeability Transition Mitochondrial Damage Mitochondrial Accumulation Lethal Injury
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