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

• DOI: 10.1523/jneurosci.21-13-04551.2001
• Publication Date: 2018-04-05T14:20:19Z
• Authors: Monika Poppe; Claus Reimertz; Heiko Düßmann; Aaron J. Krohn; C. Marc Luetjens; Doris Böckelmann; Anna-Liisa Nieminen; Donat Kögel; Jochen H. M. Prehn
• Keywords: Staurosporine; Hyperpolarization; Valinomycin; Mitochondrial apoptosis-induced channel

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