Caspase-9 and effector caspases have sequential and distinct effects on mitochondria.
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.
Cepero
Enrique
E
Department of Microbiology and Immunology, University of Miami School of Medicine, PO Box 016960 (R-138), Miami, FL 33101, USA.
King
Anne M
AM
Coffey
Lane M
LM
Perez
Rebeka G
RG
Boise
Lawrence H
LH
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004579:Electron Transport; D007377:Interleukin-3 / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D061945:Caspase Inhibitors; D007377:Interleukin-3; D017382:Reactive Oxygen Species; D045304:Cytochromes c; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases