Alternating metabolic pathways in NGF-deprived sympathetic neurons affect caspase-independent death.
Mitochondrial release of cytochrome c in apoptotic cells activates caspases, which execute apoptotic cell death. However, the events themselves that culminate in caspase activation can have deleterious effects because caspase inhibitor-saved cells ultimately die in a caspase-independent manner. To determine what events may underlie this form of cell death, we examined bioenergetic changes in sympathetic neurons deprived of NGF in the presence of a broad-spectrum caspase inhibitor, boc-aspartyl-(OMe)-fluoromethylketone. Here, we report that NGF-deprived, boc-aspartyl-(OMe)-fluoromethylketone-saved neurons rely heavily on glycolysis for ATP generation and for survival. Second, the activity of F0F1 contributes to caspase-independent death, but has only a minor role in the maintenance of mitochondrial membrane potential, which is maintained primarily by electron transport. Third, permeability transition pore inhibition by cyclosporin A attenuates NGF deprivation-induced loss of mitochondrial proteins, suggesting that permeability transition pore opening may have a function in regulating the degradation of mitochondria after cytochrome c release. Identification of changes in caspase inhibitor-saved cells may provide the basis for rational strategies to augment the effectiveness of the therapeutic use of postmitochondrial interventions.
Chang
Louis K
LK
Washington University School of Medicine, Saint Louis, MO 63110, USA.
Schmidt
Robert E
RE
Johnson
Eugene M
EM
D000255:Adenosine Triphosphate / Q000032:analysis; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D020932:Nerve Growth Factor / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010085:Oxidative Phosphorylation / Q000187:drug effects; D006180:Proton-Translocating ATPases / Q000187:drug effects; D051381:Rats
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D003574:Cytochrome c Group; C103192:butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone; D000255:Adenosine Triphosphate; D020932:Nerve Growth Factor; D006180:Proton-Translocating ATPases