J. Exp. Med., Volume 189, Number 2, January 18, 1999 381-394

Mitochondrial Release of Caspase-2 and -9 during the Apoptotic Process

By Santos A. Susin,^* Hans K. Lorenzo, Naoufal Zamzami,^* Isabel Marzo,^* Catherine Brenner,^*§ Nathanael Larochette,^* Marie-Christine Prévost, Pedro M. Alzari, and Guido Kroemer^*

From ^* Centre National de la Recherche Scientifique, UPR 420, F-94801 Villejuif, France;  Unité de Biochimie Structurale, Institut Pasteur, F-75724 Paris Cedex 15, France; ^§ Centre National de la Recherche Scientifique, UPRES-A6022, Université de Technologie de Compiègne, F-60200 Compiègne, France; and  Unité d'Oncologie Virale, Institut Pasteur, F-75724 Paris Cedex 15, France

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.

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• RIPPO, M. R., MALISAN, F., RAVAGNAN, L., TOMASSINI, B., CONDO, I., COSTANTINI, P., SUSIN, S. A., RUFINI, A., TODARO, M., KROEMER, G., TESTI, R. (2000). GD3 ganglioside directly targets mitochondria in a bcl-2-controlled fashion. FASEB J. 14: 2047-2054 [Abstract] [Full Text]  
• Hennino, A., Berard, M., Casamayor-Palleja, M., Krammer, P. H., Defrance, T. (2000). Regulation of the Fas Death Pathway by FLICE-Inhibitory Protein in Primary Human B Cells. J. Immunol. 165: 3023-3030 [Abstract] [Full Text]  
• von Ahsen, O., Renken, C., Perkins, G., Kluck, R. M., Bossy-Wetzel, E., Newmeyer, D. D. (2000). Preservation of Mitochondrial Structure and Function after Bid- or Bax-mediated Cytochrome c Release. J. Cell Biol. 150: 1027-1036 [Abstract] [Full Text]  
• Watabe, M., Machida, K., Osada, H. (2000). MT-21 Is a Synthetic Apoptosis Inducer That Directly Induces Cytochrome c Release from Mitochondria. Cancer Res. 60: 5214-5222 [Abstract] [Full Text]  
• Torban, E., Eccles, M. R., Favor, J., Goodyer, P. R. (2000). PAX2 Suppresses Apoptosis in Renal Collecting Duct Cells. Am. J. Pathol. 157: 833-842 [Abstract] [Full Text]  
• Susin, S. A., Daugas, E., Ravagnan, L., Samejima, K., Zamzami, N., Loeffler, M., Costantini, P., Ferri, K. F., Irinopoulou, T., Prevost, M.-C., Brothers, G., Mak, T. W., Penninger, J., Earnshaw, W. C., Kroemer, G. (2000). Two Distinct Pathways Leading to Nuclear Apoptosis. J. Exp. Med. 192: 571-580 [Abstract] [Full Text]  
• Li, M., Beg, A. A. (2000). Induction of Necrotic-Like Cell Death by Tumor Necrosis Factor Alpha and Caspase Inhibitors: Novel Mechanism for Killing Virus-Infected Cells. J. Virol. 74: 7470-7477 [Abstract] [Full Text]  
• Danen-van Oorschot, A. A. A. M., van der Eb, A. J., Noteborn, M. H. M. (2000). The Chicken Anemia Virus-Derived Protein Apoptin Requires Activation of Caspases for Induction of Apoptosis in Human Tumor Cells. J. Virol. 74: 7072-7078 [Abstract] [Full Text]  
• Stegh, A. H., Herrmann, H., Lampel, S., Weisenberger, D., Andrä, K., Seper, M., Wiche, G., Krammer, P. H., Peter, M. E. (2000). Identification of the Cytolinker Plectin as a Major Early In Vivo Substrate for Caspase 8 during CD95- and Tumor Necrosis Factor Receptor-Mediated Apoptosis. Mol. Cell. Biol. 20: 5665-5679 [Abstract] [Full Text]  
• Kluza, J., Lansiaux, A., Wattez, N., Mahieu, C., Osheroff, N., Bailly, C. (2000). Apoptotic Response of HL-60 Human Leukemia Cells to the Antitumor Drug TAS-103. Cancer Res. 60: 4077-4084 [Abstract] [Full Text]  
• Schlottmann, K., Wachs, F.-P., Christian Krieg, R., Kullmann, F., Schölmerich, J., Rogler, G. (2000). Characterization of Bile Salt-induced Apoptosis in Colon Cancer Cell Lines. Cancer Res. 60: 4270-4276 [Abstract] [Full Text]  
• Blanc, C., Deveraux, Q. L., Krajewski, S., Jänicke, R. U., Porter, A. G., Reed, J. C., Jaggi, R., Marti, A. (2000). Caspase-3 Is Essential for Procaspase-9 Processing and Cisplatin-induced Apoptosis of MCF-7 Breast Cancer Cells. Cancer Res. 60: 4386-4390 [Abstract] [Full Text]  
• Dumont, C., Durrbach, A., Bidere, N., Rouleau, M., Kroemer, G., Bernard, G., Hirsch, F., Charpentier, B., Susin, S. A., Senik, A. (2000). Caspase-independent commitment phase to apoptosis in activated blood T lymphocytes: reversibility at low apoptotic insult. Blood 96: 1030-1038 [Abstract] [Full Text]  
• Costantini, P., Jacotot, E., Decaudin, D., Kroemer, G. (2000). Mitochondrion as a Novel Target of Anticancer Chemotherapy. JNCI J Natl Cancer Inst 92: 1042-1053 [Abstract] [Full Text]  
• Barry, M., Heibein, J. A., Pinkoski, M. J., Lee, S.-F., Moyer, R. W., Green, D. R., Bleackley, R. C. (2000). Granzyme B Short-Circuits the Need for Caspase 8 Activity during Granule-Mediated Cytotoxic T-Lymphocyte Killing by Directly Cleaving Bid. Mol. Cell. Biol. 20: 3781-3794 [Abstract] [Full Text]  

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