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* Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, F-94805 Villejuif, France;
Assistance Publique-Hôpitaux de Paris, Service de Néphrologie B, Hôpital Tenon, F-75020, France;
Case Western Reserve University, Department of Anatomy, School of Medicine, Cleveland, Ohio 44106, USA; and
The Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada
1Correspondence: CNRS-UMR 1599, Institut Gustave Roussy, Pavillon de Recherche I, 39, rue Camille-Desmoulins, F-94805 Villejuif, France. E-mail: kroemer{at}igr.fr
The complete AIF cDNA comprising the amino-terminal mitochondrial
localization sequence (MLS) and the oxidoreductase domain has been
fused in its carboxyl terminus to enhanced green fluorescent protein
(GFP), thereby engineering an AIF-GFP fusion protein that is
selectively targeted to the mitochondrial intermembrane space. Upon
induction of apoptosis, the AIF-GFP protein translocates together with
cytochrome c (Cyt-c) to the extramitochondrial
compartment. Microinjection of recombinant AIF leads to the release of
AIF-GFP and Cyt-c-GFP, indicating that ectopic AIF can favor
permeabilization of the outer mitochondrial membrane. These
mitochondrial effects of AIF are caspase independent, whereas the
Cyt-c-microinjection induced translocation of AIF-GFP and Cyt-c-GFP is
suppressed by the pan-caspase inhibitor Z-VAD.fmk. Upon prolonged
culture, transfection-enforced overexpression of AIF results in
spontaneous translocation of AIF-GFP from mitochondria, nuclear
chromatin condensation, and cell death. These effects are caspase
independent and do not rely on the oxidoreductase function of AIF.
Spontaneous AIF-GFP translocation and subsequent nuclear apoptosis can
be retarded by overexpression of a Bcl-2 protein selectively targeted
to mitochondria, but not by a Bcl-2 protein targeted to the endoplasmic
reticulum. Overexpression of a mutant AIF protein in which the MLS has
been deleted (AIF 
1–100) results in the primary cytosolic
accumulation of AIF. AIF 1–100-induced cell death is suppressed by
neither Z-VAD.fmk or by Bcl-2. Thus, extramitochondrially targeted AIF
is a dominant cell death inducer.—Loeffler, M., Daugas, E., Susin,
S. A., Zamzami, N., Métivier, D., Nieminen, A.-L., Brothers,
G., Penninger, J. M., Kroemer, G. Dominant cell death induction by
extramitochondrially targeted apoptosis-inducing factor.
Key Words: AIF • apoptosis • Bcl-2 • caspases • cytochrome c
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