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The Journal of Neuroscience, July 1, 2001, 21(13):4551-4563

Dissipation of Potassium and Proton Gradients Inhibits Mitochondrial Hyperpolarization and Cytochrome c Release during Neural Apoptosis

Monika Poppe¹, Claus Reimertz¹, Heiko Düßmann¹, Aaron J. Krohn¹, C. Marc Luetjens¹, Doris Böckelmann¹, Anna-Liisa Nieminen³, Donat Kögel¹, and Jochen H. M. Prehn^{1, 2}

¹ Interdisciplinary Center for Clinical Research, Research Group "Apoptosis and Cell Death" and ² Department of Pharmacology and Toxicology, Westphalian Wilhelms-University, D-48149 Münster, Germany, and ³ Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

Exposure of rat hippocampal neurons or human D283 medulloblastoma cells to the apoptosis-inducing kinase inhibitor staurosporine induced rapid cytochrome c release from mitochondria and activation of the executioner caspase-3. Measurements of cellular tetramethylrhodamine ethyl ester fluorescence and subsequent simulation of fluorescence changes based on Nernst calculations of fluorescence in the extracellular, cytoplasmic, and mitochondrial compartments revealed that the release of cytochrome c was preceded by mitochondrial hyperpolarization. Overexpression of the anti-apoptotic protein Bcl-xL, but not pharmacological blockade of outward potassium currents, inhibited staurosporine-induced hyperpolarization and apoptosis. Dissipation of mitochondrial potassium and proton gradients by valinomycin or carbonyl cyanide p-trifluoromethoxy-phenylhydrazone also potently inhibited staurosporine-induced hyperpolarization, cytochrome c release, and caspase activation. This effect was not attributable to changes in cellular ATP levels. Prolonged exposure to valinomycin induced significant matrix swelling, and per se also caused release of cytochrome c from mitochondria. In contrast to staurosporine, however, valinomycin-induced cytochrome c release and cell death were not associated with caspase-3 activation and insensitive to Bcl-xL overexpression. Our data suggest two distinct mechanisms for mitochondrial cytochrome c release: (1) active cytochrome c release associated with early mitochondrial hyperpolarization, leading to neuronal apoptosis, and (2) passive cytochrome c release secondary to mitochondrial depolarization and matrix swelling.

Key words: mitochondrial membrane potential; staurosporine; valinomycin; potassium ionophore; proton ionophore; Bcl-2; necrosis; hippocampal neurons; medulloblastoma cells

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21134551-13$05.00/0

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