Bcl-2 inhibits the mitochondrial release of an apoptogenic protease

doi:10.1084/jem.184.4.1331

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Bcl-2 inhibits the mitochondrial release of an apoptogenic protease

SA Susin, N Zamzami, M Castedo, T Hirsch, P Marchetti, A Macho, E Daugas, M Geuskens and G Kroemer
Centre national de la Reccherche Scientifique-UPR420, F-94801 Villejuif, France.

Bcl-2 belongs to a family of apoptosis-regulatory proteins which incorporate into the outer mitochondrial as well as nuclear membranes. The mechanism by which the proto-oncogene product Bcl-2 inhibits apoptosis is thus far elusive. We and others have shown previously that the first biochemical alteration detectable in cells undergoing apoptosis, well before nuclear changes become manifest, is a collapse of the mitochondrial inner membrane potential (delta psi m), suggesting the involvement of mitochondrial products in the apoptotic cascade. Here we show that mitochondria contain a pre-formed approximately 50-kD protein which is released upon delta psi m disruption and which, in a cell-free in vitro system, causes isolated nuclei to undergo apoptotic changes such as chromatin condensation and internucleosomal DNA fragmentation. This apoptosis-inducing factor (AIF) is blocked by N- benzyloxycarbonyl-Val-Ala-Asp.fluoromethylketone (Z-VAD.fmk), an antagonist of interleukin-1 beta-converting enzyme (ICE)-like proteases that is also an efficient inhibitor of apoptosis in cells. We have tested the effect of Bcl-2 on the formation, release, and action of AIF. When preventing mitochondrial permeability transition (which accounts for the pre-apoptotic delta psi m disruption in cells), Bcl-2 hyperexpressed in the outer mitochondrial membrane also impedes the release of AIF from isolated mitochondria in vitro. In contrast, Bcl-2 does not affect the formation of AIF, which is contained in comparable quantities in control mitochondria and in mitochondria from Bcl-2- hyperexpressing cells. Furthermore, the presence of Bcl-2 in the nuclear membrane does not interfere with the action of AIF on the nucleus, nor does Bcl-2 hyperexpression protect cells against AIF. It thus appears that Bcl-2 prevents apoptosis by favoring the retention of an apoptogenic protease in mitochondria.
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Ng, S. S. W., Tsao, M.-S., Chow, S., Hedley, D. W. (2000). Inhibition of Phosphatidylinositide 3-Kinase Enhances Gemcitabine-induced Apoptosis in Human Pancreatic Cancer Cells. Cancer Res. 60: 5451-5455 [Abstract] [Full Text]
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Zhang, J., Mikecz, K., Finnegan, A., Glant, T. T. (2000). Spontaneous Thymocyte Apoptosis Is Regulated by a Mitochondrion-Mediated Signaling Pathway. J. Immunol. 165: 2970-2974 [Abstract] [Full Text]
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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]
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Behnia, M., Robertson, K. A., Martin, W. J. II (2000). Lung Infections : Role of Apoptosis in Host Defense and Pathogenesis of Disease. Chest 117: 1771-1777 [Abstract] [Full Text]
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Tatsuta, T., Shiraishi, A., Mountz, J. D. (2000). The Prodomain of Caspase-1 Enhances Fas-mediated Apoptosis through Facilitation of Caspase-8 Activation. J. Biol. Chem. 275: 14248-14254 [Abstract] [Full Text]
Gross, A., Pilcher, K., Blachly-Dyson, E., Basso, E., Jockel, J., Bassik, M. C., Korsmeyer, S. J., Forte, M. (2000). Biochemical and Genetic Analysis of the Mitochondrial Response of Yeast to BAX and BCL-XL. Mol. Cell. Biol. 20: 3125-3136 [Abstract] [Full Text]
DAUGAS, E., SUSIN, S. A., ZAMZAMI, N., FERRI, K. F., IRINOPOULOU, T., LAROCHETTE, N., PRÉVOST, M.-C., LEBER, B., ANDREWS, D., PENNINGER, J., KROEMER, G. (2000). Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J. 14: 729-739 [Abstract] [Full Text]
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Yaoita, H., Ogawa, K., Maehara, K., Maruyama, Y. (2000). Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction. Cardiovasc Res 45: 630-641 [Abstract] [Full Text]
Jacotot, E., Ravagnan, L., Loeffler, M., Ferri, K. F., Vieira, H. L.A., Zamzami, N., Costantini, P., Druillennec, S., Hoebeke, J., Briand, J. P., Irinopoulou, T., Daugas, E., Susin, S. A., Cointe, D., Xie, Z. H., Reed, J. C., Roques, B. P., Kroemer, G. (2000). The HIV-1 Viral Protein R Induces Apoptosis via a Direct Effect on the Mitochondrial Permeability Transition Pore. J. Exp. Med. 191: 33-46 [Abstract] [Full Text]