A Bax-induced pro-oxidant state is critical for cytochrome c release during programmed neuronal death.
Bax is required for the apoptotic death of sympathetic neurons deprived of nerve growth factor (NGF). After NGF withdrawal, Bax translocates from the cytoplasm to the mitochondria of these cells and induces release of the proapoptotic protein cytochrome c. Here, we report that withdrawing NGF from mouse sympathetic neurons caused an increase of mitochondria-derived reactive oxygen species (ROS). Suppressing these ROS inhibited apoptosis. Bax deletion blocked death and prevented the ROS burst. Inducing a pro-oxidant state similar to that in NGF-deprived, wild-type cells caused cytochrome c release even in neurons lacking Bax. A similar ROS burst in cerebellar granule neurons undergoing apoptosis was also blocked by Bax deletion. These findings indicate that Bax lies upstream from increased ROS in NGF-deprived neurons and suggest that the Bax-induced ROS burst is both necessary and sufficient for cytochrome c redistribution in these cells.
Kirkland
Rebecca A
RA
Department of Neurological Surgery, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
Windelborn
James A
JA
Kasprzak
Julia M
JM
Franklin
James L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003574:Cytochrome c Group / Q000378:metabolism*; D004579:Electron Transport / Q000187:drug effects; D005456:Fluorescent Dyes; D006579:Heterozygote; D006720:Homozygote; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000172:deficiency / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species / Q000378:metabolism; D017783:Superior Cervical Ganglion / Q000166:cytology; D014475:Uncoupling Agents / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D003574:Cytochrome c Group; D005456:Fluorescent Dyes; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D051028:bcl-2-Associated X Protein; D020932:Nerve Growth Factor; D006861:Hydrogen Peroxide