The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis.
In a cell-free apoptosis system, mitochondria spontaneously released cytochrome c, which activated DEVD-specific caspases, leading to fodrin cleavage and apoptotic nuclear morphology. Bcl-2 acted in situ on mitochondria to prevent the release of cytochrome c and thus caspase activation. During apoptosis in intact cells, cytochrome c translocation was similarly blocked by Bcl-2 but not by a caspase inhibitor, zVAD-fmk. In vitro, exogenous cytochrome c bypassed the inhibitory effect of Bcl-2. Cytochrome c release was unaccompanied by changes in mitochondrial membrane potential. Thus, Bcl-2 acts to inhibit cytochrome c translocation, thereby blocking caspase activation and the apoptotic process.
Kluck
R M
RM
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Bossy-Wetzel
E
E
Green
D R
DR
Newmeyer
D D
DD
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D002457:Cell Extracts; D002474:Cell-Free System; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D008564:Membrane Potentials; D008840:Microfilament Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D010063:Ovum; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins; D014981:Xenopus; D013049:Spectrin
D000590:Amino Acid Chloromethyl Ketones; D002352:Carrier Proteins; D002457:Cell Extracts; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D008840:Microfilament Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D013049:Spectrin; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone