Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis.
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 (Delta Psi m) 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 Delta Psi m 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, Delta Psi m 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 Delta Psi m) and generate ROS through effects of caspases on complex I and II in the electron transport chain.
Ricci
Jean-Ehrland
JE
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Gottlieb
Roberta A
RA
Green
Douglas R
DR
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport; D006367:HeLa Cells; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins / Q000378:metabolism; D014466:Ultraviolet Rays
D000590:Amino Acid Chloromethyl Ketones; D003574:Cytochrome c Group; D011500:Protein Synthesis Inhibitors; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D003609:Dactinomycin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D010100:Oxygen