1 Centre National de la Recherche Scientifique, UMR 1599, Institut Gustave
Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France
2 Department of Biology, University of Rome Tor Vergata, Roma, Italy
* Author for correspondence (e-mail: kroemer{at}igr.fr)
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Summary |
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Key words: Apoptosis, Caspases, Cell death
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Introduction |
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AIF: a phylogenetically old flavoprotein with a glutathione reductase-like fold |
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The mature form of AIF (57 kDa) is generated by cleaving of the MLS, after
import into the mitochondrial intermembrane space. Because it can stably bind
FAD, AIF falls in the category of flavoproteins. AIF displays NAD(P)H oxidase
as well as monodehydroascorbate reductase activities
(Miramar et al., 2001). The
overall crystal structure of mature mouse AIF has been recently resolved at
2.0 Å resolution. AIF displays a glutathione-reductase-like fold, with
an FAD-binding domain (aa 122-262 and 400-477), an NADH-binding domain
(263-399), and a C-terminal domain (478-610) that bears a small AIF-specific
insertion (509-559) not found in glutathione reductase
(Fig. 2a). The amino acids
interacting with FAD and NADH have been mapped precisely, and the mutants
E313A and K176A have been shown to reduce FAD binding
(Mate et al., 2002
). Human
mature AIF (which is 92% identical to mouse AIF) has a very similar crystal
structure, resembling that of oxidoreductases
(Ye et al., 2002
). Regardless
of the presence or the absence of NAD(P)H) and/or FAD (which is the essential
prosthetic group of the oxidoreductase), AIF can induce nuclear apoptosis
(Loeffler et al., 2001
;
Miramar et al., 2001
).
Similarly, the AIF-related protein AMID/PRG3 induces apoptosis even after
deletion of large parts of the protein that share homology with the
flavoprotein domain of AIF (Ohiro et al.,
2002
; Wu et al.,
2002
). Together, these data strongly suggest that the
oxidoreductase function of AIF is not required for its apoptogenic action.
|
The redox reaction catalyzed by AIF in mitochondria in the living cell
still remains elusive. Based on its similarity to prokaryotic oxidoreductases,
it has been speculated that AIF might interact with the cytochrome bc1
complex, which catalyzes the electron transfer from ubihydroquinone to
cytochrome c in the mitochondrial respiratory chain
(Mate et al., 2002). Thus, AIF
can catalyze the reduction of cytochrome c in the presence of NADH in
vitro, meaning that cytochrome c is a possible electron acceptor for
AIF (Miramar et al., 2001
).
Alternatively or in addition, AIF might fulfill some yet-to-be-characterized
antioxidant function at the mitochondrial level.
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AIF: a bifunctional protein attacking DNA |
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The crystal structure of human AIF revealed the presence of a strong
positive electrostatic potential at the AIF surface
(Fig. 2b), despite its having a
calculated neutral isoelectric point. Recombinant human and mouse AIF
interacts with DNA, both in vitro (in gel retention assays) and in vivo, in
dying cells, where endogenous AIF becomes co-localized with DNA at an early
stage of nuclear morphological changes, as indicated by immune electron
microscopy. The electrostatic interaction between AIF and DNA is independent
of the DNA sequence. Structure-based mutagenesis showed that
DNA-binding-defective mutants of AIF, which were obtained by replacing
positively charged residues by alanines, failed to induce cell death. The
potential DNA-binding site identified from mutagenesis coincided remarkably
well with computational docking of a DNA duplex to the AIF protein
(Ye et al., 2002). Together,
these findings suggest that DNA binding by AIF is required for its apoptogenic
function, at least at the nuclear level. Two of the mutations that completely
blocked the capacity of AIF to interact with DNA and to induce chromatin
condensation (K255A, R265A and K510A,K518A), conserved NADH oxidase activity
(Ye et al., 2002
), thus
confirming that the oxidoreductase and apoptosis-inducing activities of AIF
can be fully dissociated. Note that one mutation that effectively abolished
DNA binding (K510A,K518A) affects the C-terminal insertion in AIF (residues
509-559) not found in glutathione reductase
(Fig. 2b), thus underscoring
the probable relevance of this protein to apoptosis.
How AIF induces chromatin condensation and DNA fragmentation remains, however, an conundrum. Three possibilities can be envisaged. First, AIF could itself have some cryptic nuclease activity. Second, the interaction of AIF with DNA may increase the susceptibility of DNA to latent nucleases. Third, AIF might recruit downstream nucleases to induce partial chromatinolysis.
AIF: its complex relationship to caspases
The idea that AIF can induce caspase-independent death is based on several
pieces of evidence. The mitochondrio-nuclear translocation of AIF is in a
caspase independent fashion, at least in some examples of apoptosis [e.g. when
cell death is induced by staurosporin
(Susin et al., 1999) or by HIV
infection (Ferri et al., 2000
)
and caspase activation is suppressed by the addition of chemical caspase
inhibitors]. Similarly, the translocation of AIF can be observed in vitro in
cells in which there is no caspase activation, owing to knockout of Apaf-1,
caspase-9 or caspase-3 (Susin et al.,
2000
). This AIF translocation also occurs in vivo in mice lacking
Apaf-1, which fail to activate caspases
(Cecconi et al., 1998
;
Yoshida et al., 1998
). In such
mice, the interdigital web persists transiently during embryonic development,
although interdigital cells eventually die without caspase activation, which
allows generation of correctly formed toes
(Cecconi et al., 1998
;
Yoshida et al., 1998
).
Additional evidence in favor of the caspase independency of interdigital cell
death is that addition of a chemical caspase inhibitor to explanted embryonic
limbs fails to inhibit cell death in vitro, although it does inhibit
(caspase-dependent) chromatin condensation in inderdigital cells
(Chautan et al., 1999
).
Importantly, it appears that, in dying interdigital
Apaf-1-/- cells, AIF is overexpressed and translocates to
the nucleus (Fig. 3). Similar
observations have been obtained in Apaf-1-/-,
caspase-9-/- or caspase-3-/- embryoid
bodies, in which AIF translocates from mitochondria to the nucleus when inner
mass cells die during cavitation (Joza et
al., 2001
).
|
Microinjection or transfection of Apaf-1-/-,
caspase-9-/- or caspase-3-/- cells
with AIF protein or AIF1-100 cDNA, respectively, also induces cell
death without caspase activation, but with some features of apoptosis, such as
phosphatidylserine exposure, partial chromatin condensation and cellular
shrinkage (Loeffler et al.,
2001
; Susin et al.,
2000
). In vitro, both purified natural AIF and recombinant AIF
protein affect the structure of chromatin and cause large-scale DNA
fragmentation in purified nuclei, in a fashion that is not influenced by
chemical caspase inhibitors (Susin et al.,
2000
).
Together, these data indicate that AIF can act as a caspase-independent
death effector. However, there is crosstalk between AIF and the caspase
cascade at several levels. When caspase activation occurs early during
apoptosis, for instance in CD95-triggered cell death, the release of AIF is
secondary to activation of caspase-8
(Susin et al., 1997).
Similarly, in etoposide-induced apoptosis, the activation of caspase-2 occurs
upstream of MMP and presumably upstream of the release of AIF
(Lassus et al., 2002
;
Robertson et al., 2002
).
Activated caspases and the caspase-activated protein t-Bid can
trigger the release of AIF from purified mitochondria
(Zamzami et al., 2000
).
Conversely, AIF can trigger the release of cytochrome c from isolated
mitochondria in vitro (Susin et al.,
1999
). In several paradigms of cell death induction, AIF is
released from mitochondria before cytochrome c
(Daugas et al., 2000
;
Susin et al., 1999
;
Yu et al., 2002
), and
neutralization of AIF (by microinjection of an antibody or by knockout)
(Ferri et al., 2000
;
Joza et al., 2001
;
Yu et al., 2002
) can prevent
cell death, as well as the mitochondrial release of cytochrome c.
This suggests that, at least in some cases, AIF can be required for the
cytochrome-c-dependent caspase activation cascade. However, in other
examples of cell death, mitochondria release AIF well after cytochrome
c (Cregan et al.,
2002
), which underlines the idea that different modes of MMP can
operate in apoptosis. Another level of crosstalk between AIF and caspases may
exist at the level of Hsp70. AIF interacts with Hsp70, an inhibitor of
Apaf-1-dependent caspase activation
(Ravagnan et al., 2001
).
Theoretically, AIF thus could indirectly (via Hsp70) de-inhibit the caspase
cascade.
AIF and caspases may thus cooperate in the cell death cascade, and their
contribution may depend on the specific apoptosis-inducing stimulus and
perhaps the cell type. In several cases, it appears that the simultaneous
neutralization of caspases and AIF is required to prevent hallmarks of
apoptosis such as chromatin condensation. This applies for instance to
staurosporin-induced death of mouse embryonic fibroblasts
(Susin et al., 2000), to
menadione-induced death of embryonic stem cells
(Joza et al., 2001
) or to
p53-dependent death of cortical neurons
(Cregan et al., 2002
).
![]() |
AIF: ontogeny recapitulates phylogeny? |
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The genetic inactivation of mitochondrial apoptogenic factors has been
employed to assess their relative contributions to apoptosis in mice. Thus,
inactivation of Smac/DIABLO (an inhibitor of inhibitors of apoptosis (IAPs),
which inhibit caspases) has no detectable phenotype; lack of caspase-9 causes
brain hyperplasia with perinatal lethality; lack of cytochrome c
results in a severe mitochondriopathy with deficient apoptosis and embryonic
death on day 10. These phenotypes are relatively weak compared with that of
the double knockout of the two pro-apoptotic Bcl-2 family proteins Bax and
Bak, which participate in the apoptotic permeabilization of mitochondrial
membranes (Table 1). The most
severe phenotype results from the inactivation of AIF, which abolishes
cavitation, an apoptosis-mediated process indispensable for early embryonic
morphogenesis, before gastrulation. Note that cavitation-associated apoptosis
does not appear to require caspase activation, since it occurs normally in the
presence of the caspase inhibitor Z-VAD.fmk, as well as in embryos lacking
Apaf-1, caspase-9 or caspase-3 (Joza et
al., 2001). Thus, the absence of AIF is embryonically lethal, at a
very early stage, and abrogates the first wave of caspase-independent
programmed cell death occurring during mammalian development, shortly after
formation of the pluricellular embryo. Whether the phenotype of the AIF
knockout is a consequence of some sort of mitochondriopathy (assuming that AIF
has a normal, presumably redox-related mitochondrial function) is currently
unknown. An indirect argument against this possibility is furnished by the
observation that AIF-deficient embryonic stem cells can differentiate into
cells from all three germ layers both in vitro and in vivo. Thus ES cells
injected into immunodeficient mice develop histologically undistinguishable
teratocarcinomas, irrespective of the status of the AIF gene, which
suggests that AIF is not generally required for proliferation and
differentiation in vivo (Joza et al.,
2001
). To resolve definitively the question of whether the redox
activity of AIF influences cell death control, it will be important to perform
knock-in mutations in the AIF gene that affect either its redox
activity or its DNA binding.
|
AIF thus appears to be involved in programmed cell death at early stages of ontogeny and phylogeny. However, this hypothesis requires further experimental evidence.
![]() |
Involvement of AIF in pathological apoptosis |
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In several instances, microinjection of an antibody recognizing a
surface-exposed domain of AIF (residues 151-200,
Fig. 2b) prevents cell death
but caspase inhibition alone has no beneficial effect on neuronal survival
(Braun et al., 2001;
Yu et al., 2002
;
Zhang et al., 2002
). Assuming
that the anti-AIF antibody has no additional effects (for instance on
AIF-related proteins), this suggests that AIF contributes to cell killing.
Similarly, local injection of Z-VAD.fmk fails to inhibit photoreceptor
apoptosis induced by retinal detachment, although injection of nerve cell
growth factor prevents the mitochondrio-nuclear translocation of AIF in
photoreceptors and maintains the photoreceptors functional, as far as can be
judged from electroretinograms (Hisatomi
et al., 2002
). In a model of neurotrauma, the translocation of AIF
in selected brain areas could be correlated with genomic DNA degradation to
50 kbp fragments (which is a hallmark of AIF-mediated nuclear apoptosis),
although the cells lacked oligonucleosomal DNA fragmentation (which is
mediated by caspase-activated DNase)
(Zhang et al., 2002
). Thus,
AIF could be involved in several paradigms of pathogenic cell death. The
conditional or neuron-specific knockout of AIF should clarify to what extent
AIF does indeed contribute to neuronal cell loss.
![]() |
Perspectives |
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![]() |
Acknowledgments |
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