Abstract
During apoptosis, the mitochondrial membrane potential (MMP) decreases, but it is not known how this relates to the apoptotic process. It was recently suggested that cytochrome c is compartmentalized in closed cristal regions and therefore, matrix remodeling is required to attain complete cytochrome c release from the mitochondria. In this work we show that, at the onset of apoptosis, changes in MMP control matrix remodeling prior to cytochrome c release. Early after growth factor withdrawal the MMP declines and the matrix condenses. Both phenomena are reversed by adding oxidizable substrates. In mitochondria isolated from healthy cells, matrix condensation can be induced by either denying oxidizable substrates or by protonophores that dissipate the membrane potential. Matrix remodeling to the condensed state results in cristal unfolding and exposes cytochrome c to the intermembrane space facilitating its release from the mitochondria during apoptosis. In contrast, when a transmembrane potential is generated due to either electron transport or a pH gradient formed by acidifying the medium, mitochondria maintain an orthodox configuration in which most cytochrome c is sequestered in the cristae and is resistant to release by agents that disrupt the mitochondrial outer membrane.
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Abbreviations
- MMP:
-
mitochondrial membrane potential
- EM:
-
electron microscopy
- TMRE:
-
tetramethyl-rhodamine ethyl ester
- CCCP:
-
carbonylcyanide m-chlorophenylhydrazone
- BH3:
-
Bcl–2 homology region-3
- MIB:
-
mitochondrial isolation buffer
- MRB:
-
mitochondrial reaction buffer
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Acknowledgements
We thank the Biomedical Imaging Core Facility at the University of Pennsylvania for excellent performance with EM analysis and Ayala King and Mary Selak for fruitful discussions and editorial advice. BH3 peptides were a gift of Kevin Tomaselli of Idun Pharmaceuticals. Eyal Gottlieb is supported by a special fellowship from the Leukemia and Lymphoma Society.
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Gottlieb, E., Armour, S., Harris, M. et al. Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis. Cell Death Differ 10, 709–717 (2003). https://doi.org/10.1038/sj.cdd.4401231
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DOI: https://doi.org/10.1038/sj.cdd.4401231
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