Calphostin C-mediated translocation and integration of Bax into mitochondria induces cytochrome c release before mitochondrial dysfunction.

Abstract

Calphostin C-mediated apoptosis in glioma cells was reported previously to be associated with down-regulation of Bcl-2 and Bcl-xL. In this study, we report that 100 nM calphostin C also induces translocation and integration of monomeric Bax into mitochondrial membrane, followed by cytochrome c release into cytosol and subsequent decrease of mitochondrial inner membrane potential (DeltaPsim) before activation of caspase-3. The integration of monomeric Bax was associated with acquirement of alkali-resistance. The translocated monomeric Bax was partly homodimerized after cytochrome c release and decrease of DeltaPsim. The translocation and homodimerization of Bax, cytochrome c release, and decrease of DeltaPsim were not blocked by 100 microM z-VAD.fmk, a pan-caspase inhibitor, but the homodimerization of Bax and decrease of DeltaPsim were inhibited by 10 microM oligomycin, a mitochondrial F0F1-ATPase inhibitor. Therefore, it would be assumed that mitochondrial release of cytochrome c results from translocation and integration of Bax and is independent of permeability transition of mitochondria and caspase activation, representing a critical step in calphostin C-induced cell death.

• Authors: H Ikemoto, E Tani, I Ozaki, H Kitagawa, N Arita
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 7 Issue 6 Pg. 511-20 (Jun 2000) ISSN: 1350-9047 [Print] England
• PMID: 10822274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BAX protein, human
• Cytochrome c Group
• Enzyme Inhibitors
• Naphthalenes
• Oligomycins
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• Protein Kinase C
• CASP3 protein, human
• Caspase 3
• Caspases
• calphostin C

Topics

• Apoptosis (drug effects)
• Caspase 3
• Caspases (metabolism)
• Cytochrome c Group (metabolism)
• Dimerization
• Enzyme Activation
• Enzyme Inhibitors (metabolism, pharmacology)
• Humans
• Mitochondria (drug effects, metabolism, physiology)
• Naphthalenes (metabolism, pharmacology)
• Oligomycins
• Protein Kinase C (antagonists & inhibitors)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-bcl-2
• Tumor Cells, Cultured
• bcl-2-Associated X Protein