Apoptosis, in human monocytic THP.1 cells, results in the release of cytochrome c from mitochondria prior to their ultracondensation, formation of outer membrane discontinuities and reduction in inner membrane potential

Cell Death Differ. 1998 Nov;5(11):953-62. doi: 10.1038/sj.cdd.4400440.

Abstract

Induction of apoptosis in human monocytic THP.1 cells by etoposide or N-tosyl-L-phenylalanyl chloromethyl ketone resulted in release of mitochondrial cytochrome c, formation of ultracondensed mitochondria, development of outer mitochondrial membrane discontinuities and a reduction in mitochondrial membrane potential (delta psi m), as well as externalisation of phosphatidylserine, caspase-3 and -7 activation, proteolysis of poly(ADP-ribose) polymerase and lamin B1. The caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone inhibited all these ultrastructural and biochemical characteristics of apoptosis except for the release of cytochrome c. Release of mitochondrial cytochrome c was a late event in non-apoptotic cell death occurring after commitment to cell death and without caspase activation. Thus apoptosis is characterised by release of mitochondrial cytochrome c prior to formation of ultracondensed mitochondria and a reduction in delta psi m and by a mechanism independent of rupture of the outer mitochondrial membrane.

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 3
  • Caspase 7
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Line
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytochrome c Group / metabolism*
  • Enzyme Activation / drug effects
  • Etoposide / pharmacology
  • Humans
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / ultrastructure
  • Lamin Type B*
  • Lamins
  • Membrane Potentials / drug effects
  • Microscopy, Electron
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Nuclear Proteins / metabolism
  • Phosphatidylserines / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Tosylphenylalanyl Chloromethyl Ketone / pharmacology
  • Zinc / pharmacology

Substances

  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Cytochrome c Group
  • Lamin Type B
  • Lamins
  • Nuclear Proteins
  • Phosphatidylserines
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • lamin B1
  • Tosylphenylalanyl Chloromethyl Ketone
  • Etoposide
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • CASP7 protein, human
  • Caspase 3
  • Caspase 7
  • Caspases
  • Zinc