Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis
| Autor: | A L Nieminen, D Böckelmann, Monika Poppe, C M Luetjens, Heiko Düssmann, Aaron J. Krohn, Jochen H. M. Prehn, Claus Reimertz, D Kögel |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
bcl-X Protein
Apoptosis Cytochrome c Group Mitochondrion Transfection Mitochondrial apoptosis-induced channel Hippocampus Valinomycin chemistry.chemical_compound medicine Staurosporine Cytochrome c oxidase Animals Enzyme Inhibitors ARTICLE Cells Cultured Fluorescent Dyes Neurons biology Ionophores Caspase 3 General Neuroscience Cytochrome c Hyperpolarization (biology) Immunohistochemistry Rats Inbred F344 Cell biology Mitochondria Rats chemistry Proto-Oncogene Proteins c-bcl-2 Caspases biology.protein Potassium Apoptosome Protons medicine.drug Medulloblastoma |
| Zdroj: | ResearcherID Scopus-Elsevier |
| ISSN: | 1529-2401 |
| Popis: | 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 cyanidep-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. |
| Databáze: | OpenAIRE |
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