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Published 6 January 2003. doi:10.1083/jcb.200208089
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© The Rockefeller University Press, 0021-9525/2003/1/65 $5.00
The Journal of Cell Biology, Volume 160, Number 1, 65-75

Article

Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis



Jean-Ehrland Ricci1, Roberta A. Gottlieb2 and Douglas R. Green1

1 Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
2 Division of Hematology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM220, La Jolla, CA 92037

Address correspondence to Douglas R. Green, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Tel.: (858) 678-4675. Fax: (858) 558-3526. E-mail: doug{at}liai.org

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.

Key Words: apoptosis; mitochondria; caspases; transmembrane potential; ROS


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