Distinct Ca2+ thresholds determine cytochrome c release or permeability transition pore opening in brain mitochondria.
In diseases associated with neuronal degeneration, such as Alzheimer's or cerebral ischemia, the cytosolic Ca2+ concentration ([Ca2+]cyt) is pathologically elevated. It is still unclear, however, under which conditions Ca2+ induces either apoptotic or necrotic neuronal cell death. Studying respiration and morphology of rat brain mitochondria, we found that extramitochondrial [Ca2+] above 1 M causes reversible release of cytochrome c, a key trigger of apoptosis. This event was NO-independent but required Ca2+ influx into the mitochondrial matrix. The mitochondrial permeability transition pore (PTP), widely thought to underlie cytochrome c release, was not involved. In contrast to noncerebral tissue, only relatively high [Ca2+] (is approximately equal to 200 M) opened PTP and ruptured mitochondria. Our findings might reflect a fundamental mechanism to protect postmitotic neuronal tissue against necrotic devastation and inflammation.
Institute of Clinical Chemistry, Department of Pathological Biochemistry, Institute of Medical Neurobiology, Institute of Neurobiochemistry, Medical Faculty, Otto-von-Guericke-University, Magdeburg, Germany. lorenz.schild@medizin.uni-magdeburg.de
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Schild
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Keilhoff
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Augustin
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Reiser
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Striggow
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D019069:Cell Respiration / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D003911:Dextrans / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D018272:Porins / Q000378:metabolism; D051381:Rats; D050994:Voltage-Dependent Anion Channels
D003574:Cytochrome c Group; D003911:Dextrans; D004791:Enzyme Inhibitors; D018272:Porins; D050994:Voltage-Dependent Anion Channels; D009569:Nitric Oxide; D016572:Cyclosporine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester