Apoptosis inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death

Although much emphasis has been laid on the role of caspase in cell death, recent data indicate that, in many instances, mammalian cell death is caspa se-independent. Thus, in many examples of mammalian cell death the 'decisio n' between death and life is upstream or independent of caspase activation. Similarly, it is unclear whether PCD of plants and fungi involves the acti vation of caspase-like enzymes, and no caspase-like gene has thus far been cloned in these phyla, Apoptosis inducing factor (AIF) is a new mammalian, caspase-independent death effector which, upon apoptosis induction, translo cates from its normal localization, the mitochondrial intermembrane space, to the nucleus, Once in the nucleus, AIF causes chromatin condensation and large scale DNA fragmentation to fragments of similar to 50 kbp, The AIF cD NA from mouse and man codes for a protein which possesses three domains (i) an amino-terminal presequence which is removed upon import into the interm embrane space of mitochondria; (ii) a spacer sequence of approximately 27 a mino acids; and (iii) a carboxyterminal 484 amino acid oxidoreductase domai n with strong homology to oxidoreductases from other vertebrates (X. laevis ), non-vertebrate animals (C.elegans, D. melanogaster), plants, fungi, euba cteria, and archaebacteria, Functionally important amino acids involved in the interaction with the prosthetic groups flavin adenine nucleotide and ni cotinamide adenine nucleotide are strongly conserved between AIF and bacter ial oxidoreductase, Several eukaryotes possess a similar domain organisatio n in their AIF homologs, making them candidates to be mitochondrial oxidore ductases as well as caspase-independent death effecters. The phylogenetic i mplications of these findings are discussed.