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From the Department of Ophthalmology,*
Graduate School
of Medical Sciences, Kyushu University, Fukuoka, Japan; and the Centre
National de la Recherche Scientifique,
Institut Gustave Roussy, Villejuif, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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AIF is a novel, caspase-independent apoptogenic factor. In the absence
of apoptotic signals, AIF is normally confined to the mitochondrial
intermembrane space.9-11
However, when apoptosis is
induced in HeLa cells, Rat-1, or Jurkat cells in vitro, AIF
translocates to the cytosol and to the nucleus.9,10,12,13
When recombinant AIF is injected into the cytoplasm of intact cells or
added to purified nuclei from HeLa cells, it causes the nucleus to
undergo peripheral chromatin condensation and triggers large-scale DNA
degradation to fragments of 
50 kbp.9
AIF also induces
purified mitochondria to release cytochrome c and caspase-9,
suggesting that AIF, once released from mitochondria, accelerates
membrane permeabilization in a positive feedforward loop.9
Microinjection of AIF into the cytoplasm of the intact cells induced a
loss of the mitochondrial transmembrane potential and the exposure
of phosphatidylserine on the surface of the plasma
membrane.9
All these changes occur in the presence of
saturating doses of the wide-ranging caspase inhibitor Z-VAD.fmk,
indicating that AIF acts in a caspase-independent manner.
AIF is strongly conserved among mammalian species (>95% amino acid identity between mouse and human) and bears a highly significant homology with flavoprotein oxidoreductases from all eukaryotic and prokaryotic kingdoms in its C-terminal portion.10 Based on these findings, it is reasonable to speculate that AIF may be a phylogenetically old mediator participating in various aspects of the apoptotic process. However, all studies supporting this hypothesis have been performed in vitro. The role of AIF in apoptosis in vivo, especially in mammalian pathology, remains unknown.
Retinal photoreceptors are neuroectodermal cells essential for vision.14 A specific part of these polar cells, the ellipsoid, within the inner segment, is packed with regularly arranged mitochondria. Photoreceptors degenerate on traumatic or spontaneous retinal detachment (RD), which is one of the common causes of legal blindness in the young adult. Cell loss is reported to be because of apoptosis rather than because of necrosis.15-19 Given the fact that RD usually occurs without inflammation or destructive ischemia, it provides a suitable context for studying the morphological changes involved in apoptosis. In this study, we assessed the possible role of AIF in photoreceptor apoptosis induced by experimental RD. Our data provide the first description of a subcellular relocalization of AIF in vivo.
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Materials and Methods |
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DNA Nick-End Labeling by the TUNEL Method
Apoptotic photoreceptor degeneration was detected by TdT-dUTP terminal nick-end labeling (TUNEL). Four-µm-thick sections were made from samples fixed in 4% paraformaldehyde and embedded in paraffin. TUNEL staining was performed with the ApopTag fluorescein direct in situ apoptosis detection kit (Intergen Company, New York, NY) according to the manufacturer’s protocols. The sections were co-stained with propidium iodide (Molecular Probes, Eugene, OR), allowing observation of the cell nuclei by a fluorescence microscope (Olympus, Tokyo, Japan). Because the number of photoreceptors in each slide varied depending on the cutting angle, the number of apoptotic photoreceptors also varied. To avoid this sampling artifact, the rate of apoptotic photoreceptors was calculated using the following formula: apoptotic photoreceptor ratio (%) = total number of TUNEL-positive photoreceptors/total number of photoreceptors in the section. Ten sections for each eye specimen were randomly selected and observed by masked observers (six eyes for each time point).
AIF and Glial Fibrillary Acidic Protein (GFAP) Immunohistochemistry
Samples were fixed in 4% paraformaldehyde, embedded in paraffin, deparaffinized in xylene, rehydrated in ethanol, and washed in phosphate-buffered saline (PBS), as described above. A 1:100 dilution of anti-AIF rabbit serum was produced by a previously described method9 and incubated at 4°C overnight. A nonimmune serum and a pre-absorbed antiserum (with 1 µg/µl recombinant AIF) were used as negative controls. Cy5-labeled secondary antibody (Zymed Laboratories, San Francisco, CA) was used at a dilution of 1:200 for 20 minutes. The sections were co-stained by TUNEL and observed with a fluorescence microscope. Furthermore, to clarify the localization of AIF in photoreceptors or Müller cells, a double immunostaining was made for Müller cell marker, GFAP (1:100 dilution, Santa Cruz Biotechnology, CA) and Cy5-labeled secondary antibody (KPL, Gaithersburg, MD).
Cytochrome c Immunohistochemistry
Four-µm-thick sections were made from samples fixed in 4% paraformaldehyde and embedded in paraffin. Anti-cytochrome c antibody (PharMingen, St. Louis, MO) was used at a 1:200 dilution and the sections were incubated at 4°C overnight. Cy5-labeled secondary antibody (KPL, Gaithersburg, MD) was used at a dilution of 1:200 for 20 minutes and the sections were observed with a fluorescence microscope.
Electron Microscopy and Immunoelectron Microscopy
The eyes were enucleated and the posterior segments were fixed in 1% glutaraldehyde and 1% paraformaldehyde in PBS. The detached retinas were removed and postfixed in veronal acetate buffer osmium tetroxide (2%), dehydrated in ethanol and water, and embedded in Epon. Ultrathin sections were cut from blocks and mounted on copper grids. For immunoelectron microscopy, the eyes were fixed in 1% paraformaldehyde in PBS, and the detached retinas were rinsed with PBS, incubated in NH4Cl, and embedded in London Resin white blocks (London Resin, London, UK).20 Primary antibody for AIF was used at a 1:150 dilution, and the sections were incubated at 4°C overnight. Anti-rabbit antibody conjugated with 10 nm gold particles (British BioCell, Cardiff, UK) was used as a secondary antibody at a dilution of 1:30 for 90 minutes. The specimens were observed with a JEM 100CX electron microscope (JEOL, Tokyo, Japan). A nonimmune serum was used as a negative control.
Experimental RD
All procedures conformed to the standards set forth in the Association for Research in Vision and Ophthalmology’s statement for the Use of Animals in Ophthalmic and Vision Research. Brown Norway rats (Kyudo, Fukuoka, Japan), postnatal 8 weeks, were studied as follows.
The rats were anesthetized with an intraperitoneal injection of
pentobarbital and their pupils were dilated with topical 1%
tropicamide and 2.5% phenylephrine hydrochloride. The retinas were
detached using a subretinal injection of 1% sodium hyaluronate
(Pharmacia, Uppsala, Sweden). An anterior chamber puncture was
performed from the corneal limbus to lower the intraocular pressure.
Sclera was penetrated at the ocular nasal equator with a 30G needle,
and then the needle was slowly advanced into the vitreous space. Soft
retina was focally detached from comparatively hard retinal pigment
epithelium as the needle moved. Then the needle was pulled and advanced
into the subretinal space beneath the focally detached retina. Sodium
hyaluronate (0.05 ml) was injected gently to enlarge the RD. Because
the volume of the vitreous space of the rat eye is relatively small,
the injection of 0.05 ml of sodium hyaluronate reproducibly produced
similar RDs (half of the retina, Figure 1
). Biomicroscopy (Kowa, Tokyo)
demonstrated that the same portion of the retina remained detached for
more than 28 days after treatment. Detached retinas that reattached
spontaneously were excluded from further study. Eyes with anterior
chamber puncture, scleral incision, and no injection of sodium
hyaluronate were used as controls. The rats were sacrificed at 6 and 12
hours and on days 1, 3, 5, 7, 14, and 28 after treatment and their eyes
were harvested for the following studies. To evaluate the change of
outer nuclear layer thickness after RD, the thickness of outer nuclear
layer in histological sections (10 sections each day) was measured and
analyzed using analysis software (MacScope; Mitani, Fukui, Japan). The
results were expressed as the percentage of nondetached control retina.
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To investigate the role of CD95/CD-95 ligand system in apoptosis, RDs were created in CD95/CD-95 ligand gene mutation mice, C3H-lpr and C3H-gld mice (SLC, Shizuoka, Japan), postnatal age 8 weeks using the method just described. C3H-lpr mice, a model of lymphoproliferation with CD95 gene mutation, and C3H-gld mice, a model of generalized lymphoproliferative disease with CD95 ligand gene mutation have been shown to lack functional CD95 and CD95 ligand.21-27 Almost the entire retina was detached in these animals and remained detached. Our preliminary study showed that C3H wild-type mice showed a similar apoptotic time course as Brown Norway rats did, and apoptosis was evaluated on a representative day after detachment (day 3). Furthermore, to investigate the participation of caspases, RD was created in rats with sodium hyaluronate containing the wide-ranging caspase inhibitor, Z-VAD.fmk (25 ng per eye).
Neurotrophic Factor and AIF in RD
It is known that the outer layers of the retina containing the photoreceptor cells are supplied by diffusion from the choriocapillaris. To investigate whether apoptosis in RD and AIF depend on nutrition-dependent pathways, RDs were created with sodium hyaluronate containing a representative neurotrophic factor, brain-derived neurotrophic factor (BDNF, 2.5 ng per eye). BDNF and trkB expression have been found in ocular tissue,28,29 and BDNF became a particularly interesting candidate for trophic activity, especially in the retinal pigment epithelium (RPE), because of its inducibility,30 and its ability of photoreceptor-protection from degeneration.31,32
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After injection of sodium hyaluronate into the subretinal space of
Brown Norway rats, RD was subjected to a macroscopic and histological
follow-up for 28 days. In macroscopic terms, the surface of the
detached area remained unchanged during this period (Figure 1)
.
Histopathological examination revealed that the detached retinas
degenerated gradually throughout time, progressively losing
photoreceptors. No inflammatory cell infiltration was noted. Whereas
control retinas do not label with TUNEL, on RD, TUNEL-positive
apoptotic cells appeared in the photoreceptors of the outer retinal
layer starting 12 hours after RD, reached a maximum on day 3, and then
gradually diminished (Figure 2
and Figure 3
). Simultaneously, the outer
nuclear layer thickness of the retina, representing the photoreceptor
layer decreased gradually to 88% of the
control retina on day 3, 60% on day 7,
and 32% on day 28.
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Immunohistochemistry showed specific AIF staining in ganglion
cells, inner nuclear layer, outer plexiform layer and photoreceptors
(Figure 4A
, arrows). Immunostaining of
control retinas revealed a multilinear pattern of AIF (Figure 4A
,
arrowheads) within the inner segment of photoreceptors, that is the
mitochondrion-rich portion of the cells. This AIF-staining pattern did
not change during the first 6 hours after RD. However, 12 hours after
RD, we observed in some photoreceptors that AIF distributed in a
diffuse manner throughout the cytosol and the nucleus (Figure 4B
,
arrows). No positive staining was found either by nonimmune serum or a
pre-absorbed antiserum (with 1 µg/µl recombinant AIF; Figure 4, C and D
). The double immunostaining showed that AIF was not localized in
the GFAP-positive cells (Figure 4E)
. On the other hand, a double
staining for AIF and TUNEL experiments revealed that AIF-positive
nuclei from photoreceptor cells mostly are TUNEL-positive, at least
during the first days after RD (Figure 5
and Table 1
). Electron microscopy
confirmed RD-induced morphological alterations in the photoreceptor
layer, including chromatin condensation and cell shrinkage (Figure 6, A–E)
. Photoreceptors from control
retinas contain AIF in their mitochondria but not in the nucleus, as
revealed by immunogold electron microscopy (Figures 7 and 8)
. In contrast, dense AIF staining
of the nucleus was observed in apoptotic
cells, 3 days after RD (Figure 7)
. Thinning of the outer nuclear layer
because of loss of photoreceptors (Figure 2, F–H)
and deconstruction
of the inner and outer segments of the photoreceptors were also
observed (Figure 8, A and B)
. The regular arrangement of mitochondria
observed in the control retinas was lost, and AIF staining dispersed
from mitochondria to cytosol (Figure 8, A and B)
. The immunostaining
for cytochrome c showed that cytochrome c was
localized in the inner segment of photoreceptors of nondetached retina,
whereas it was diffusely dispersed in the cytosol of photoreceptors in
the detached (Figure 9)
. In conclusion,
in dying photoreceptor cells both AIF and cytochrome c
localization altered from mitochondria to an extramitochondrial
localization.
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In C3H mice, RD induced photoreceptor apoptosis, following a
similar time course as that observed in Brown Norway rats, with a
maximum of TUNEL-positive cells 3 days after RD. The double staining of
AIF and TUNEL confirmed that most of the nuclei from TUNEL-positive
photoreceptors also reacted with the AIF-specific antiserum (Figure 10A
, arrows). No significant difference
was found between these mouse strains as far as the RD-induced AIF- and
TUNEL-positive nuclei of photoreceptors (Table 2)
. The CD95 death receptor is concerned
to rapid activation of the caspases. To further exclude the implication
of CD95-like receptors in RD-induced apoptosis, RD was induced in rats
by subretinal injection of sodium hyaluronate, in the presence or
absence of the wide-ranging caspase inhibitor Z-VAD.fmk. No inhibitory
effect of Z-VAD.fmk was detected, both at the level of AIF
relocalization and at the level of TUNEL positivity. In strict
contrast, we found that subretinal application of BDNF significantly
reduced the frequency of mitochondrio-nuclear AIF relocalization and
TUNEL positivity (Figure 11
; day 3,
P < 0.05). Altogether, these data indicate that the
CD95/CD95 ligand system does not control photoreceptor apoptosis, at
least in this model. However, local shortage of trophic factors such as
BDNF is likely to be involved in RD-induced photoreceptor apoptosis.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunohistochemistry and immunoelectron microscopy revealed AIF to be normally confined to mitochondria, yet to be relocated to the extramitochondrial compartment (cytosol plus nucleus) when nuclear chromatin condensation is occurring. After RD, AIF was found diffusely in the cytosol and in a more patchy manner within areas of condensed chromatin of the nucleus. The double staining for AIF and GFAP showed that most of AIF-positive cells are not Müller cells. Thus, AIF might be involved in the apoptotic process affecting photoreceptor cells.
Susin and colleagues9 proved the subcellular translocation of AIF during apoptotic processes by comparing subcellular fractions of mouse liver cells in vitro. We also performed both Western blotting of total retinal extracts (with RD) and that of subcellular fraction of the retinal extract for AIF. The results showed that the amounts of total AIF protein remained unchanged for 7 days. We also examined reverse transcriptase-polymerase chain reaction for AIF, and the amount of mRNA for AIF was not significantly changed either. These data might support the translocation of AIF during apoptosis in RD. However the retinal extracts contain not only apoptotic photoreceptors but also photoreceptors with no apoptosis (<5.3% of photoreceptor shows apoptosis at greatest) and many other cellular components, and such other components might mask the intracellular changes of AIF of photoreceptors. Because it is practically impossible to collect the apoptotic photoreceptors exclusively from the detached retina, we could not show the perfect data to prove the translocation of AIF of photoreceptor apoptosis in RD. Therefore, we use the term relocalization of AIF, not the translocation of AIF in this article. From the previous in vitro study9 and the present morphological results, it is conceivable that AIF translocated from the mitochondria to nucleus in apoptosis, however, more evidence is necessary to prove this hypothesis.
Identifying the upstream signal that leads to the mitochondrial and
nuclear signs of apoptosis in photoreceptor cells is obviously an
important goal. Nonetheless, the mechanisms of photoreceptor apoptosis
in experimental RD remains unknown,18,33-37
and the
regulatory mechanism controlling neuronal survival and apoptosis is
just the beginning to be defined. In the present study, we found that
apoptosis was induced by experimental RD even in CD95/CD95
ligand-deficient animals and that AIF relocalization occurred in these
animals in a way undistinguishable from control animals. Photoreceptor
apoptosis also developed while downstream caspases were inhibited by
the wide-ranging caspase inhibitor, Z-VAD.fmk. Thus, apparently the
CD95/CD95 ligand system and downstream caspases are not involved in the
photoreceptor apoptosis. In addition, cytochrome c
immunohistochemistry indicated that photoreceptor apoptosis was
mediated by mitochondria via a caspase-independent pathway (Figure 9)
.
Because the inner layers of the retina are supplied by retinal circulation, their nutrient supply is not affected by RD. However, the outer layers, including the photoreceptor layer, are supplied by diffusion from the choriocapillaris, implying that RD greatly compromises their trophic supply and causes nutrients to be diluted in the subretinal space. Mervin and colleagues33 and Lewis and colleagues36 already reported that oxygen supplementation (hyperoxia) during detachment reduced photoreceptor death, maintaining the specialized structures of surviving photoreceptors, which is good evidence that photoreceptor death in detached retina is nutrition related. Interestingly, the supplement of a neurotrophic factor such as BDNF into the subretinal space inhibited both the AIF relocalization and the signs of nuclear apoptosis. Neuroprotection by growth factors and neurotrophins such as insulin, insulin-like growth factor-1, nerve growth factor, and BDNF has been studied as a means of regulating neuronal apoptosis.37 BDNF has been reported to activate extracellular signal-regulated kinase and the phosphatidylinositol-3 kinase (PI3-kinase) pathways. IGF-1-activated phosphoinositide 3-kinase (PI3-K) triggered the activation of the serine-threonine kinase Akt. Akt phosphorylation of the Bcl-2 family member BAD has been demonstrated to promote cell survival.38,39 The ras mitogen-activated protein kinase signaling pathway also apparently mediates growth-factor-dependent cell survival.40 However, at the present stage, it remains elusive which among these survival pathways is activated by BDNF in photoreceptor cells.
It remains also an open question whether inhibition of photoreceptor apoptosis will actually restore normal vision. Indeed, the decreased nutrition demands resulting from limited apoptosis might actually reduce total tissue damage. As a result, it will be important to study the long-term effects of apoptosis inhibition by BDNF, overexpression of Bcl-2-like mitochondrioprotective proteins, neutralization of AIF, and similar interventions, not only at the level of cell survival but also in functional terms.
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Acknowledgements |
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Footnotes |
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Supported in part by grant-in-aid no. 09671804 and no. 09470382 for Scientific Research from the Ministry of Education, Science, Sports, and Culture of the Japanese Government; the Japan National Society for the Prevention of Blindness (Tokyo); Fondation pour la Recherche Médicale; and a Special Grant from the League Nationale contre le Cancer (to G. K.).
Accepted for publication December 21, 2000.
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