Abstract
Proapoptotic Bcl-2 family members alter mitochondrial permeability resulting in the release of apoptogenic factors that initiate a caspase cascade. These changes are well described; however, the effects of caspases on mitochondrial function are less well characterized. Here we describe the consequence of caspase-9 and effector caspase inhibition on mitochondrial physiology during intrinsic cell death. Caspase inhibition prevents the complete loss of mitochondrial membrane potential without affecting cytochrome c release. When effector caspases are inhibited, mitochondria become uncoupled and produce reactive oxygen species. Interestingly, the effector caspase-mediated depolarization of the mitochondria occurs independent of the activity of complexes I–IV of the electron transport chain. In contrast, caspase-9 inhibition prevents mitochondrial uncoupling and ROS production and allows for continued electron transport despite the release of cytochrome c. Taken together, these data suggest that activated caspase-9 prevents the accessibility of cytochrome c to complex III, resulting in the production of reactive oxygen species, and that effector caspases may depolarize mitochondria to terminate ROS production and preserve an apoptotic phenotype.
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Acknowledgements
We would like to thank Carlos Moraes, Yuri Lazebnik, Colin Duckett, Bryan Johnson, Esther Obeng, Robert Levy, Jennifer McCafferty and Kelvin Lee for reagents, advice and a critical review of the manuscript. This work was supported by F31 GM20435 (EC) and R01 GM65813 (LHB).
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Cepero, E., King, A., Coffey, L. et al. Caspase-9 and effector caspases have sequential and distinct effects on mitochondria. Oncogene 24, 6354–6366 (2005). https://doi.org/10.1038/sj.onc.1208793
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DOI: https://doi.org/10.1038/sj.onc.1208793
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