Mitochondrial Release of Caspase-2 and -9 during the Apoptotic Process
Susin, Santos A. ; Lorenzo, Hans K. ; Zamzami, Naoufal ; Marzo, Isabel ; Brenner, Catherine ; Larochette, Nathanael ; Prévost, Marie-Christine ; Alzari, Pedro M. ; Kroemer, Guido
Resumen: The barrier function of mitochondrial membranes is perturbed early during the apoptotic process. Here we show that the mitochondria contain a caspase-like enzymatic activity cleaving the caspase substrate Z-VAD.afc, in addition to three biological activities previously suggested to participate in the apoptotic process: (a) cytochrome c; (b) an apoptosis-inducing factor (AIF) which causes isolated nuclei to undergo apoptosis in vitro; and (c) a DNAse activity. All of these factors, which are biochemically distinct, are released upon opening of the permeability transition (PT) pore in a coordinate, Bcl-2-inhibitable fashion. Caspase inhibitors fully neutralize the Z-VAD.afc-cleaving activity, have a limited effect on the AIF activity, and have no effect at all on the DNase activities. Purification of proteins reacting with the biotinylated caspase substrate Z-VAD, immunodetection, and immunodepletion experiments reveal the presence of procaspase-2 and -9 in mitochondria. Upon induction of PT pore opening, these procaspases are released from purified mitochondria and become activated. Similarly, upon induction of apoptosis, both procaspases redistribute from the mitochondrion to the cytosol and are processed to generate enzymatically active caspases. This redistribution is inhibited by Bcl-2. Recombinant caspase-2 and -9 suffice to provoke full-blown apoptosis upon microinjection into cells. Altogether, these data suggest that caspase-2 and -9 zymogens are essentially localized in mitochondria and that the disruption of the outer mitochondrial membrane occurring early during apoptosis may be critical for their subcellular redistribution and activation.
Idioma: Inglés
DOI: 10.1084/jem.189.2.381
Año: 1999
Publicado en: JOURNAL OF EXPERIMENTAL MEDICINE 189, 2 (1999), 381-394
ISSN: 0022-1007
Factor impacto JCR: 15.651 (1999)
Categ. JCR: MEDICINE, RESEARCH & EXPERIMENTAL rank: 2 / 76 = 0.026 (1999) - Q1 - T1
Categ. JCR: IMMUNOLOGY rank: 4 / 115 = 0.035 (1999) - Q1 - T1
Tipo y forma: Article (Published version)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. If you remix, transform, or build upon the material, you must distribute your contributions under the same license as the original.
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Idioma: Inglés
DOI: 10.1084/jem.189.2.381
Año: 1999
Publicado en: JOURNAL OF EXPERIMENTAL MEDICINE 189, 2 (1999), 381-394
ISSN: 0022-1007
Factor impacto JCR: 15.651 (1999)
Categ. JCR: MEDICINE, RESEARCH & EXPERIMENTAL rank: 2 / 76 = 0.026 (1999) - Q1 - T1
Categ. JCR: IMMUNOLOGY rank: 4 / 115 = 0.035 (1999) - Q1 - T1
Tipo y forma: Article (Published version)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. If you remix, transform, or build upon the material, you must distribute your contributions under the same license as the original. Exportado de SIDERAL (2020-10-27-15:03:55)
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Record created 2020-10-27, last modified 2020-10-27