title: 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.
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.
authors.affiliation: MRC Toxicology Unit, University of Leicester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Zhuang
authors.forename: D
authors.initials: D
authors.lastname: Dinsdale
authors.forename: G M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D053179:Caspase 7; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000648:ultrastructure; D034921:Lamin Type B; D034882:Lamins; D008564:Membrane Potentials / Q000187:drug effects; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D034921:Lamin Type B; D034882:Lamins; D009687:Nuclear Proteins; D010718:Phosphatidylserines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D014108:Tosylphenylalanyl Chloromethyl Ketone; D005047:Etoposide; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D015032:Zinc