Reduction in mitochondrial membrane potential is an early event in Fas-independent CTL-mediated apoptosis

Cell Immunol. 1999 Jul 10;195(1):43-52. doi: 10.1006/cimm.1999.1513.


Cytotoxic T lymphocytes (CTL) can destroy target cells via the Fas-mediated pathway or the granule-mediated pathway. We used Fas-negative target cells to examine for target-cell reduction in mitochondrial membrane potential (DeltaPsi(m)) induced by intact CTL via the granule-mediated pathway. We find that reduction in DeltaPsi(m) is an early step in Fas-independent CTL killing of target cells that precedes phosphatidyl serine translocation, cytosolic protein release, or loss of plasma membrane integrity. Target-cell reduction in DeltaPsi(m) and cytoplasmic protein release in Fas-independent CTL killing were inhibited by N-carbobenzoxy-Ala-Pro-Phe chloromethyl ketone, but not by caspase inhibitors N-carbobenzoxy-Val-Ala-Asp fluoromethyl ketone (z-VAD-fmk) or N-carbobenzoxy-Asp-Glu-Val-Asp fluoromethyl ketone (z-DEVD-fmk). This contrasts with Fas-mediated apoptosis, in which the reduction in DeltaPsi(m) can be inhibited by z-VAD-fmk or z-DEVD-fmk. Assessing the changes in target-cell DeltaPsi(m) can provide for a sensitive and rapid means with which to monitor CTL activity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis*
  • Biological Transport
  • Cell Membrane Permeability
  • Cysteine Proteinase Inhibitors / pharmacology
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / physiology*
  • Membrane Potentials
  • Mice
  • Mice, Inbred CBA
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • Oligopeptides / pharmacology
  • Peptides / pharmacology
  • Phosphatidylserines / metabolism
  • Protease Inhibitors / pharmacology
  • Proteins / metabolism
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / physiology*
  • fas Receptor / physiology*


  • Amino Acid Chloromethyl Ketones
  • Cysteine Proteinase Inhibitors
  • Oligopeptides
  • Peptides
  • Phosphatidylserines
  • Protease Inhibitors
  • Proteins
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • fas Receptor