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

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  • Author(s): Bossy-Wetzel E;Bossy-Wetzel E; Newmeyer DD; Green DR
  • Source:
    The EMBO journal [EMBO J] 1998 Jan 02; Vol. 17 (1), pp. 37-49.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print Cited Medium: Print ISSN: 0261-4189 (Print) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE
    • Publication Information:
      Publication: 2024- : [London] : Nature Publishing Group
      Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-
    • Subject Terms:
      Apoptosis*/drug effects; Cysteine Endopeptidases/*metabolism ; Cytochrome c Group/*metabolism ; Mitochondria/*enzymology ; Oligopeptides/*metabolism; Amino Acid Chloromethyl Ketones/pharmacology ; Biological Transport ; Cell Line ; Cysteine Proteinase Inhibitors/pharmacology ; Cytosol/enzymology ; DNA Fragmentation ; Enzyme Activation ; Humans ; Membrane Potentials ; Mitochondria/physiology ; Staurosporine/pharmacology ; Tumor Cells, Cultured ; Ultraviolet Rays
    • 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.
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    • Grant Information:
      CA69381 United States CA NCI NIH HHS; GM50284 United States GM NIGMS NIH HHS; GM52735 United States GM NIGMS NIH HHS
    • Accession Number:
      0 (Amino Acid Chloromethyl Ketones)
      0 (Cysteine Proteinase Inhibitors)
      0 (Cytochrome c Group)
      0 (Oligopeptides)
      0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
      EC 3.4.22.- (Cysteine Endopeptidases)
      H88EPA0A3N (Staurosporine)
    • Publication Date:
      Date Created: 19980228 Date Completed: 19980226 Latest Revision: 20220331
    • Publication Date:
      20250114
    • Accession Number:
      PMC1170356
    • Accession Number:
      10.1093/emboj/17.1.37
    • Accession Number:
      9427739