During apoptosis, the permeabilization of the mitochondrial outer membrane allows the release of cytochrome c, which induces caspase activation to orchestrate the death of the cell. Mitochondria rapidly lose their transmembrane potential (ΔΨm) and generate reactive oxygen species (ROS), both of which are likely to contribute to the dismantling of the cell. Here we show that both the rapid loss of ΔΨm and the generation of ROS are due to the effects of activated caspases on mitochondrial electron transport complexes I and II. Caspase-3 disrupts oxygen consumption induced by complex I and II substrates but not that induced by electron transfer to complex IV. Similarly, ΔΨm generated in the presence of complex I or II substrates is disrupted by caspase-3, and ROS are produced. Complex III activity measured by cytochrome c reduction remains intact after caspase-3 treatment. In apoptotic cells, electron transport and oxygen consumption that depends on complex I or II was disrupted in a caspase-dependent manner. Our results indicate that after cytochrome c release the activation of caspases feeds back on the permeabilized mitochondria to damage mitochondrial function (loss of ΔΨm) and generate ROS through effects of caspases on complex I and II in the electron transport chain. apoptosis; mitochondria; caspases; transmembrane potential; ROS Footnotes ↵ * Abbreviations used in this paper: ΔΨm, mitochondrial transmembrane potential; ActD, actinomycin D; 2-HE, dihydroethidium; KCN, potassium cyanide; FCCP, carbonyl cyanide p -(trifluoromethoxy) phenylhydrazone; PI, propidium iodide; ROS, reactive oxygen species; tBid, truncated Bid; TMRE, tetramethylrhodamine ethyl ester; TMPD, tetrametyl- p -phenylenediamine; zVAD-fmk, N -benzoylcarbanyl-Val-Ala-Asp-fluoro methylketone. Submitted: 15 August 2002 Accepted: 2 December 2002 Revision received 25 November 2002
The Journal of Cell Biology – Rockefeller University Press
Published: Jan 6, 2003
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