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PMID: 9427739 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization.

The EMBO journal ·Vol. 17 ·No. 1 ·1998-01-02 ·Pages 37-49

Bossy-Wetzel E, Newmeyer DD, Green DR

Abstract

Mitochondrial cytochrome c, which functions as an electron carrier in the respiratory chain, translocates to the cytosol in cells undergoing apoptosis, where it participates in the activation of DEVD-specific caspases. The apoptosis inhibitors Bcl-2 or Bcl-xL prevent the efflux of cytochrome c from mitochondria. The mechanism responsible for the release of cytochrome c from mitochondria during apoptosis is unknown. Here, we report that cytochrome c release from mitochondria is an early event in the apoptotic process induced by UVB irradiation or staurosporine treatment in CEM or HeLa cells, preceding or at the time of DEVD-specific caspase activation and substrate cleavage. A reduction in mitochondrial transmembrane potential (Deltapsim) occurred considerably later than cytochrome c translocation and caspase activation, and was not necessary for DNA fragmentation. Although zVAD-fmk substantially blocked caspase activity, a reduction in Deltapsim and cell death, it failed to prevent the passage of cytochrome c from mitochondria to the cytosol. Thus the translocation of cytochrome c from mitochondria to cytosol does not require a mitochondrial transmembrane depolarization.

MeSH Terms
Amino Acid Chloromethyl Ketones/pharmacology Apoptosis/drug effects Biological Transport Cell Line Cysteine Endopeptidases/metabolism Cysteine Proteinase Inhibitors/pharmacology Cytochrome c Group/metabolism Cytosol/enzymology DNA Fragmentation Enzyme Activation Humans Membrane Potentials Mitochondria/enzymology,physiology Oligopeptides/metabolism Staurosporine/pharmacology Tumor Cells, Cultured Ultraviolet Rays
Chemicals
Amino Acid Chloromethyl Ketones Cysteine Proteinase Inhibitors Cytochrome c Group Oligopeptides benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone Cysteine Endopeptidases Staurosporine
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Bossy-Wetzel E
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121 USA.
Newmeyer D D
Green D R
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/17.1.37
Published
1998-01-02
Pages
37-49
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1170356
Subset
IM
Grants
NCI NIH HHS · CA69381 · United States
NIGMS NIH HHS · GM50284 · United States
NIGMS NIH HHS · GM52735 · United States
External Links
PubMed source DOI: 10.1093/emboj/17.1.37 PMC Full Text View journal details
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