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First published online 11 December 2002
doi: 10.1242/jcs.00236

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Outer mitochondrial membrane permeabilization during apoptosis triggers caspase-independent mitochondrial and caspase-dependent plasma membrane potential depolarization: a single-cell analysis

¹ Interdisciplinary Center for Clinical Research (IZKF), Westphalian Wilhelms-University, D-48149 Münster, Germany
² Department of Pharmacology and Toxicology, Westphalian Wilhelms-University, D-48149 Münster, Germany

^* Author for correspondence (e-mail: prehn{at}uni-muenster.de)

Accepted 24 October 2002

Little is known about the temporal relationship between mitochondrial and plasma membrane potential changes and outer mitochondrial membrane permeabilization during apoptosis. Confocal imaging of breast carcinoma and HeLa cells stably transfected with cytochrome-C-GFP demonstrated that mitochondria rapidly depolarized after the release of the fusion protein into the cytosol. Of note, mitochondria did not completely depolarize but established a new steady-state level that could be further dissipated by treatment with the protonophore carbonyl cyanide p-trifluoromethoxy-phenylhydrazone. Treatment with the F_OF₁-ATP-synthase inhibitor oligomycin likewise induced a collapse of this steady-state level, suggesting that F_OF₁-ATP-synthase reversal maintained mitochondrial potential after outer mitochondrial membrane permeabilization. Treatment with a broad spectrum caspase inhibitor failed to inhibit the partial depolarization of mitochondria during apoptosis, yet potently abolished the activation of effector caspases detected by fluorescence resonance energy transfer analysis in the same experiment. Interestingly, the onset of mitochondrial depolarization was always coupled with a depolarization of the plasma membrane potential. This was associated with the degradation of the regulatory Na⁺/K⁺-ATPase ß-subunit, and both events were blocked by caspase inhibition. Our results demonstrate that outer mitochondrial membrane permeabilization coordinates the depolarization of both membrane potentials during apoptosis.

Key words: Apoptosis, Mitochondrial membrane potential, Plasma membrane potential, Confocal imaging, Mitochondrial respiration

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