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Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis.
- Source :
-
Nature cell biology [Nat Cell Biol] 2000 Jun; Vol. 2 (6), pp. 318-25. - Publication Year :
- 2000
-
Abstract
- Mitochondria trigger apoptosis by releasing caspase activators, including cytochrome c (cytC). Here we show, using a pH-sensitive green fluorescent protein (GFP), that mitochondria-dependent apoptotic stimuli (such as Bax, staurosporine and ultraviolet irradiation) induce rapid, Bcl-2-inhibitable mitochondrial alkalinization and cytosol acidification, followed by cytC release, caspase activation and mitochondrial swelling and depolarization. These events are not induced by mitochondria-independent apoptotic stimuli, such as Fas. Activation of cytosolic caspases by cytC in vitro is minimal at neutral pH, but maximal at acidic pH, indicating that mitochondria-induced acidification of the cytosol may be important for caspase activation; this finding is supported by results obtained from cells using protonophores. Cytosol acidification and cytC release are suppressed by oligomycin, a FoF1-ATPase/H +-pump inhibitor, but not by caspase inhibitors. Ectopic expression of Bax in wild-type, but not FoF1/H+-pump-deficient, yeast cells similarly results in mitochondrial matrix alkalinization, cytosol acidification and cell death. These findings indicate that mitochondria-mediated alteration of intracellular pH may be an early event that regulates caspase activation in the mitochondrial pathway for apoptosis.
- Subjects :
- Animals
Carbonyl Cyanide m-Chlorophenyl Hydrazone pharmacology
Caspase Inhibitors
Cell Line
Cytochrome c Group metabolism
Cytosol drug effects
Cytosol enzymology
Cytosol radiation effects
Deoxyadenine Nucleotides pharmacology
Enzyme Activation drug effects
Enzyme Activation radiation effects
Green Fluorescent Proteins
Humans
Luminescent Proteins genetics
Luminescent Proteins metabolism
Mitochondria drug effects
Mitochondria enzymology
Mitochondria radiation effects
Mitochondrial Swelling drug effects
Mitochondrial Swelling radiation effects
Mutation
Oligomycins pharmacology
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 genetics
Proto-Oncogene Proteins c-bcl-2 metabolism
Proton-Translocating ATPases antagonists & inhibitors
Proton-Translocating ATPases genetics
Proton-Translocating ATPases metabolism
Saccharomyces cerevisiae cytology
Saccharomyces cerevisiae enzymology
Saccharomyces cerevisiae genetics
Saccharomyces cerevisiae metabolism
Staurosporine antagonists & inhibitors
Staurosporine pharmacology
Ultraviolet Rays
bcl-2-Associated X Protein
fas Receptor physiology
Apoptosis drug effects
Apoptosis radiation effects
Caspases metabolism
Cytosol metabolism
Mitochondria metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1465-7392
- Volume :
- 2
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Nature cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 10854321
- Full Text :
- https://doi.org/10.1038/35014006