期刊
JOURNAL OF CELL BIOLOGY
卷 162, 期 2, 页码 245-256出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200302109
关键词
apoptosis; cytochrome c; mitochondria; permeability transition pore; programmed cell death
类别
资金
- NIA NIH HHS [AG 12957] Funding Source: Medline
- NINDS NIH HHS [NS 38651] Funding Source: Medline
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)-fluoromethyl ketone. Here, we report that NGF-deprived, boc-aspartyl-(OMe)-fluoromethyl ketone-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.
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