Molecular characterization of mitochondrial apoptosis-inducing factor (original) (raw)

• Letter
• Published: 04 February 1999
• Hans K. Lorenzo2,
• Naoufal Zamzami1,
• Isabel Marzo1,
• Bryan E. Snow3,
• Greg M. Brothers3,
• Joan Mangion3,
• Etienne Jacotot1,
• Paola Costantini1,
• Markus Loeffler1,
• Nathanael Larochette1,
• David R. Goodlett4,
• Ruedi Aebersold4,
• David P. Siderovski3,
• Josef M. Penninger3 &
• …
• Guido Kroemer1

Nature volume 397, pages 441–446 (1999)Cite this article

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Abstract

Mitochondria play a key part in the regulation of apoptosis (cell death)1,2. Their intermembrane space contains several proteins that are liberated through the outer membrane in order to participate in the degradation phase of apoptosis3,4,5,6,7,8,9. Here we report the identification and cloning of an apoptosis-inducing factor, AIF5, which is sufficient to induce apoptosis of isolated nuclei. AIF is a flavoprotein of relative molecular mass 57,000 which shares homology with the bacterial oxidoreductases; it is normally confined to mitochondria but translocates to the nucleus when apoptosis is induced. Recombinant AIF causes chromatin condensation in isolated nuclei and large-scale fragmentation of DNA. It induces purified mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Microinjection of AIF into the cytoplasm of intact cells induces condensation of chromatin, dissipation of the mitochondrial transmembrane potential, and exposure of phosphatidylserine in the plasma membrane. None of these effects is prevented by the wide-ranging caspase inhibitor known as Z-VAD.fmk. Overexpression of Bcl-2, which controls the opening of mitochondrial permeability transition pores, prevents the release of AIF from the mitochondrion but does not affect its apoptogenic activity. These results indicate that AIF is a mitochondrial effector of apoptotic cell death.

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Acknowledgements

We thank P. M. Alzari for suggestions, M. Geuskens for electron microscopy, G.Salvesen for caspase-8, D. Andrews for Rat-1 cells, and S. Arya and S. Chung for expression constructs. This work was supported by grants from ANRS, ARC, CNRS, FF, FRM, INSERM, LNC, and PRFMMIP (to G.K.), the NIH, the NSF Science and Technology Center for Molecular Biotechnology (to R.A.), and Amgen (to D.P.S. and J.M.P.). S.A.S. and I.M. hold postdoctoral fellowships from the European Commission and from the Spanish Ministry of Science, respectively.

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Authors and Affiliations

1. Centre National de la Recherche Scientifique, UPR 420, 19 rue Guy Mquet, F-94801, Villejuif, France
   Santos A. Susin, Naoufal Zamzami, Isabel Marzo, Etienne Jacotot, Paola Costantini, Markus Loeffler, Nathanael Larochette & Guido Kroemer
2. Unit de Biochimie Structurale, Institut Pasteur, 25 rue du Dr Roux, Paris, F-75724 Cedex 15, France
   Hans K. Lorenzo
3. Department of Medical Biophysics and Immunology, The Amgen Institute and Ontario Cancer Institute, University of Toronto, 620 University Avenue, Suite 706, Toronto, M5G 2C1, Ontario, Canada
   Bryan E. Snow, Greg M. Brothers, Joan Mangion, David P. Siderovski & Josef M. Penninger
4. Department of Molecular Biotechnology, University of Washington, Seattle, 98195, Washington, USA
   David R. Goodlett & Ruedi Aebersold

Authors

1. Santos A. Susin
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2. Hans K. Lorenzo
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3. Naoufal Zamzami
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4. Isabel Marzo
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5. Bryan E. Snow
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6. Greg M. Brothers
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7. Joan Mangion
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8. Etienne Jacotot
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9. Paola Costantini
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10. Markus Loeffler
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11. Nathanael Larochette
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12. David R. Goodlett
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13. Ruedi Aebersold
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14. David P. Siderovski
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15. Josef M. Penninger
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16. Guido Kroemer
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Correspondence toGuido Kroemer.

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Susin, S., Lorenzo, H., Zamzami, N. et al. Molecular characterization of mitochondrial apoptosis-inducing factor.Nature 397, 441–446 (1999). https://doi.org/10.1038/17135

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• Received: 04 November 1998
• Accepted: 21 December 1998
• Issue Date: 04 February 1999
• DOI: https://doi.org/10.1038/17135

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