Interplay between bax, reactive oxygen species production, and cardiolipin oxidation during apoptosis.
Bax/Bak activation and cardiolipin peroxidation are essential for cytochrome c release during apoptosis, yet, the link between them remains elusive. We report that sequence of events after exposure of mouse embryonic fibroblast (MEF) cells to actinomycin D followed the order: Bax translocation-->superoxide production-->cardiolipin peroxidation. Genetic ablation of Bax/Bak inhibited actinomycin D induced superoxide production and cardiolipin peroxidation. Rotenone caused robust superoxide generation but did not trigger cardiolipin peroxidation in Bax/Bak double knockout MEF cells. This suggests that, in addition to participating in ROS generation, Bax/Bak play another specific role in cardiolipin oxidation. In isolated mitochondria, recombinant Bax enhanced succinate induced cardiolipin oxidation and cytochrome c release. Mitochondrial peroxidase activity, likely involved in cardiolipin peroxidation, was enhanced upon incubation with recombinant Bax. Thus, cardiolipin peroxidation may be causatively and time-dependently related to Bax/Bak effects on ROS generation and peroxidase activation of cytochrome c.
Jiang
Jianfei
J
Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Bridgeside Point, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219, USA.
Huang
Zhentai
Z
Zhao
Qing
Q
Feng
Weihong
W
Belikova
Natalia A
NA
Kagan
Valerian E
VE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002308:Cardiolipins / Q000378:metabolism*; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D005347:Fibroblasts; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010544:Peroxidases / Q000378:metabolism; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D002308:Cardiolipins; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D012402:Rotenone; D003609:Dactinomycin; D045304:Cytochromes c; D010544:Peroxidases