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Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis
Author(s) -
Daugas Eric,
Susin Santos A.,
Zamzami Naoufal,
Ferri Karine F.,
Irinopoulou Theano,
Larochette Nathanael,
Prévost MarieChristine,
Leber Brian,
Andrews David,
Penninger Josef,
Kroemer Guido
Publication year - 2000
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.14.5.729
Subject(s) - apoptosis inducing factor , dna fragmentation , microbiology and biotechnology , chromatin , biology , intermembrane space , heat shock protein , fragmentation (computing) , mitochondrial apoptosis induced channel , prophase , apoptosis , programmed cell death , mitochondrion , inner mitochondrial membrane , caspase , biochemistry , bacterial outer membrane , dna , ecology , meiosis , escherichia coli , gene
Apoptosis inducing factor (AIF) is a novel apoptotic effector protein that induces chro‐matin condensation and large‐scale (—50 kbp) DNA fragmentation when added to purified nuclei in vitro. Confocal and electron microscopy reveal that, in normal cells, AIF is strictly confined to mitochondria and thus colocalizes with heat shock protein 60 (hsp60). On induction of apoptosis by staurosporin, c‐Myc, etoposide, or ceramide, AIF (but not hsp60) translocates to the nucleus. This suggests that only the outer mitochondrial membrane (which retains AIF in the intermembrane space) but not the inner membrane (which retains hsp60 in the matrix) becomes protein permeable. The mitochondrio‐nuclear redistribution of AIF is prevented by a Bcl‐2 protein specifically targeted to mitochondrial membranes. The pan‐caspase inhibitor Z‐VAD.fmk does not prevent the staurosporin‐induced translocation of AIF, although it does inhibit oligonucleosomal DNA fragmentation and arrests chromatin condensation at an early stage. ATP depletion is sufficient to cause AIF translocation to the nucleus, and this phenomenon is accelerated by the apoptosis inducer staurosporin. However, in conditions in which both glycolytic and respiratory ATP generation is inhibited, cells fail to manifest any sign of chromatin condensation and advanced DNA fragmentation, thus manifesting a ‘necrotic’ phenotype. Both in the presence of Z‐VAD.fmk and in conditions of ATP depletion, AIF translocation correlates with the appearance of large‐scale DNA fragmentation. Altogether, these data are compatible with the hypothesis that AIF is a caspase‐independent mitochondrial death effector responsible for partial chromatinolysis.—Daugas, E., Susin, S. A., Zamzami, N., Ferri, K., Irinopoulou, T., Larochette, N., Prévost, M.‐C, Leber, B., Andrews, D., Penninger, J., Kroemer, G. Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis. FASEB J. 14, 729–739 (2000)