Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death

Nicholas Joza, Santos A. Susin, Eric Daugas, William L. Stanford, Sarah K. Cho, Carol Y. J. Li, Takehiko Sasaki, Andrew J. Elia, H.-Y. Mary Cheng, Luigi Ravagnan, Karine F. Ferri, Naoufal Zamzami, Andrew Wakeham, Razqallah Hakem, Hiroki Yoshida, Young-Yun Kong, Tak W. Mak, Juan Carlos Zúñiga-Pflücker, Guido Kroemer and Josef M. Penninger ()
Additional contact information
Nicholas Joza: Amgen Institute
Santos A. Susin: Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy
Eric Daugas: Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy
William L. Stanford: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Sarah K. Cho: University of Toronto
Carol Y. J. Li: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Takehiko Sasaki: Amgen Institute
Andrew J. Elia: Amgen Institute
H.-Y. Mary Cheng: Amgen Institute
Luigi Ravagnan: Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy
Karine F. Ferri: Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy
Naoufal Zamzami: Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy
Andrew Wakeham: Amgen Institute
Razqallah Hakem: Amgen Institute
Hiroki Yoshida: Amgen Institute
Young-Yun Kong: Amgen Institute
Tak W. Mak: Amgen Institute
Juan Carlos Zúñiga-Pflücker: University of Toronto
Guido Kroemer: Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy
Josef M. Penninger: Amgen Institute

Nature, 2001, vol. 410, issue 6828, 549-554

Abstract: Abstract Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis and tissue homeostasis. In mammals, release of mitochondrial cytochrome c leads to the cytosolic assembly of the apoptosome—a caspase activation complex involving Apaf1 and caspase-9 that induces hallmarks of apoptosis. There are, however, mitochondrially regulated cell death pathways that are independent of Apaf1/caspase-9. We have previously cloned a molecule associated with programmed cell death called apoptosis-inducing factor (AIF). Like cytochrome c, AIF is localized to mitochondria and released in response to death stimuli. Here we show that genetic inactivation of AIF renders embryonic stem cells resistant to cell death after serum deprivation. Moreover, AIF is essential for programmed cell death during cavitation of embryoid bodies—the very first wave of cell death indispensable for mouse morphogenesis. AIF-dependent cell death displays structural features of apoptosis, and can be genetically uncoupled from Apaf1 and caspase-9 expression. Our data provide genetic evidence for a caspase-independent pathway of programmed cell death that controls early morphogenesis.

Date: 2001
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DOI: 10.1038/35069004

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