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Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis.

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posted on 2022-03-15, 14:59 authored by Monika Poppe, Claus Reimertz, Heiko DuessmannHeiko Duessmann, Aaron J. Krohn, C Marc Luetjens, Doris Böckelmann, Anna-Liisa Nieminen, Donat Kögel, Jochen PrehnJochen Prehn

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.


Deutsche Forschungsgemeinschaft (Pr338/9–1), the Interdisciplinary Center for Clinical Research, University of Münster (Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie Grant 01 KS 9604/0), and Stiftung VerUm.



This article is also available at http://www.jneurosci.org/content/21/13/4551.full.pdf+html

Published Citation

Poppe M1, Reimertz C, Düssmann H, Krohn AJ, Luetjens CM, Böckelmann D, Nieminen AL, Kögel D, Prehn JH. Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis. Journal of Neuroscience. 2001;31(13):4551-63.

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