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Neurochemistry International 40 (2002) 573–584
Optic nerve degeneration and mitochondrial dysfunction:genetic and acquired optic neuropathies
Valerio Carelli ∗, Fred N. Ross-Cisneros, Alfredo A. Sadun Doheny Eye Institute, USC Keck School of Medicine, DVRC 311, 1355 San Pablo Street, Los Angeles, CA 90033, USA
Accepted 30 October 2001
Abstract
Selective degeneration of the smallest fibers (papillo-macular bundle) of the human optic nerve occurs in a large number of optic
neuropathies characterized primarily by loss of central vision. The pathophysiology that underlies this peculiar pattern of cell involvementprobably reflects different forms of genetic and acquired mitochondrial dysfunction.
Maternally inherited Leber’s hereditary optic neuropathy (LHON), dominant optic atrophy (Kjer disease), the optic atrophy of Leigh’s
syndrome, Friedreich ataxia and a variety of other conditions are examples of inherited mitochondrial disorders with different etiologies.
Tobacco–alcohol amblyopia (TAA), the Cuban epidemic of optic neuropathy (CEON) and other dietary (Vitamins B, folate deficiencies)
optic neuropathies, as well as toxic optic neuropathies such as due to chloramphenicol, ethambutol, or more rarely to carbon monoxide,
methanol and cyanide are probably all related forms of acquired mitochondrial dysfunction.
Biochemical and cellular studies in LHON point to a partial defect of respiratory chain function that may generate either an ATP
synthesis defect and/or a chronic increase of oxidative stress. Histopathological studies in LHON cases and a rat model mimicking CEON
revealed a selective loss of retinal ganglion cells (RGCs) and the corresponding axons, particularly in the temporal-central part of the optic
nerve. Anatomical peculiarities of optic nerve axons, such as the asymmetric pattern of myelination, may have functional implications
on energy dependence and distribution of mitochondrial populations in the different sections of the nerve. Histological evidence suggests
impaired axonal transport of mitochondria in LHON and in the CEON-like rat model, indicating a possible common pathophysiology for
this category of optic neuropathies. Histological evidence of myelin pathology in LHON also suggests a role for oxidative stress, possibly
affecting the oligodendrocytes of the optic nerves. © 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Optic nerve; Mitochondria; Papillo-macular bundle; mtDNA; LHON
1. Vulnerability of small axons charaterizes
a group of optic neuropathies
The predominant involvement of the papillo-macular
bundle, represented by the smallest caliber axons, is a fea-
ture common to a wide range of optic neuropathies of either
genetic or acquired toxic/dietary etiology (Sadun, 1998;
Rizzo, 1995). The loss of central vision and color visionassociated, at fundus examination, with a roughly symmet-
rical dropout of the temporal fibers in the absence of any
sign of inflammation characterizes Leber’s hereditary optic
neuropathy (LHON), the prototypical form of this cate-
gory of optic neuropathies. The common end-point, despite
the different pace of natural history among these clinical
entities, is an optic atrophy with severely impaired central
vision and some degrees of still viable peripheral vision.
∗ Corresponding author. Present address: Dipartimento di Science Neu-
rologiche, Universita di Bologna, Via Ugo Foscolo 7, 40123 Bologna,
Italy. Fax: +1-232-442-6688/ +39-51-644-2190.
The etiology of LHON is now well-established as due
to point mutations in the mitochondrial DNA (mtDNA)
and a mitochondrial dysfunction is postulated for its patho-
physiology (Carelli, 2002). The preferential and earlier
involvement of the small caliber fibers documented in
LHON (Sadun et al., 2000) represents the paradigm for the
entire category of optic neuropathies, in which a mitochon-
drial dysfunction is suggested and in some cases demon-strated. We review the main genetic and acquired forms all
sharing the common involvement of papillo-macular bundle
and possibly associated to a mitochondrial dysfunction.
2. Genetic optic neuropathies
2.1. Leber’s hereditary optic neuropathy
LHON is a maternally inherited form of acute or suba-
cute loss of central vision affecting predominantly young
males (Carelli, 2002; Chalmers and Schapira, 1999).
0197-0186/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S 0 1 9 7 - 0 1 8 6 (0 1 )0 0 1 2 9 -2
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574 V. Carelli et al. / Neurochemistry International 40 (2002) 573–584
Three mtDNA point mutations, at positions 11778/ND4,
3460/ND1 and 14484/ND6, all affecting complex I of the
respiratory chain, are pathogenic in the large majority of
patients (Carelli, 2002; Chalmers and Schapira, 1999).
Recently, Chinnery et al. (2001) presented evidence for a
fourth LHON pathogenic mutation at position 14495/ND6
in two unrelated families. A fifth mutation at position14459/ND6 is also pathogenic for the variant phenotype of
LHON/dystonia/Leigh syndrome (Jun et al., 1994; Kirby
et al., 2000). In LHON, there is a highly variable penetrance,
even within the same family with the same pathogenic muta-
tion in homoplasmic fashion (all mtDNA copies are mutated)
(Howell and Mackey, 1998). It is believed that environmental
(Carelli, 2002; Chalmers and Schapira, 1999) or supplemen-
tary genetic factors, possibly in the nuclear DNA (Cock et al.,
1998), are needed to express the pathology. Tobacco and
alcohol consumption may play a role in determining which
members of an extended family manifest the disease, even if
contradictory results have been obtained from different se-
ries of patients investigated (Tsao et al., 1999; Cullom et al.,1993; Chalmers and Harding, 1996; Kerrison et al., 2000).
In the clinical expression of LHON, some fundus changes
such as a telangiectatic microangiopathy may precede the
onset of visual loss. This is usually bilateral, asynchronous
and evolves over few weeks/months toward an optic
atrophy with resultant permanent decreases of visual acuity
(Nikoskelainen, 1994). The early drop out of the papillo-
macular bundle, the edematous appearance of the adjacent
nerve fiber layer and the enlarged and tortuous peripap-
illar vessels are the main features at fundus examination
(Nikoskelainen, 1994). A cecocentral scotoma is the usual
Fig. 1. Retina, horizontal section (paraffin, H&E). (A) Control retina showing a normal RGC and nerve fiber layers (between arrows). (B) LHON/3460
retina showing very marked losses of RGC and nerve fiber layers (between arrows).
defect detected at visual field examination, with variable
degrees of peripheral vision preserved. Apart from rare cases
of spontaneous recovery, more frequent with the 14484/ND6
mutation (Carelli, 2002; Chalmers and Schapira, 1999), the
visual loss stabilizes within a year leaving the fundus pic-
ture of a pale optic disc, more marked on the temporal side
(Nikoskelainen, 1994).The histopathological findings of the eye, in three cases
with known mtDNA mutation (Sadun et al., 1994a; Kerri-
son et al., 1995; Carelli et al., 1999), all showed a dramatic
loss of retinal ganglion cells (RGCs) and nerve fiber layer
contrasting with an otherwise normal retina (Fig. 1). In the
optic nerve, there was a striking loss of fibers in the central
part with variable preservation of fibers in the far periph-
ery (Fig. 2). On electron microscopy examination (EM) rare
RGCs were found, only in one case, to display degenerative
features with presence of double-membrane bodies contain-
ing calcium and interpreted as “mitochondrial carcasses”
(Kerrison et al., 1995). At optic nerve level, EM investiga-
tion revealed frequent degenerating axons, wide variabilityof myelin thickness with demyelinated fibers, and frequent
patchy accumulation of swollen mitochondria in the myeli-
nated post-laminar portion of the optic nerve (Fig. 2) (Sadun
et al., 1994a; Carelli et al., 1999). Moreover, changes in
axoplasmic morphology, with condensation of cytoskeletal
elements and presence of various debris and bodies were
also noted (Sadun et al., 1994a; Carelli et al., 1999). Taken
together, these findings suggest a continuing low-grade but
active degenerative process, decades after the onset of visual
loss, with evidence of myelin pathology and remodeling,
and impaired axoplasmic transport (Carelli et al., 1999).
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V. Carelli et al. / Neurochemistry International 40 (2002) 573–584 575
Fig. 2. Optic nerve cross-section of a LHON/11778. (A) LHON/11778 optic nerve cross-section (epon, p-phylenedyamine) showing a peripheral pattern
of relative sparing of axons (arrows). The rest of the optic nerve demonstrates extensive gliosis. (B) Higher magnification reveals spared bundles of
peripheral axons and disorganized gliosis. (C) Electron microscopy shows variability in myelination of the spared axons with a few examples of very
thinly myelinated profiles (asterisks). (D) Example of a thinly myelinated axon extensively packed with mitochondria.
2.2. Autosomal dominant optic atrophy
(OPA1, Kjer disease)
Kjer disease, an insidious slowly progressive optic neuro-
pathy with onset in the first decade, is transmitted as an
autosomal dominant disorder (Votruba et al., 1998). Linkage
analysis revealed some heterogeneity and two loci have been
identified, one on chromosome 3 and the other on chromo-
some 18 (Eiberg et al., 1994; Kerrison et al., 1999). The
majority of families seem to be associated to the chromo-
some 3q28-q29 locus, and recently, mutations responsible
for the disease has been found in the OPA1 gene encod-
ing for a previously unrecognized dynamin-related GTPase
protein (Delettre et al., 2000; Alexander et al., 2000). Inter-
estingly, this protein presents the amino-terminal targeting
sequence to be imported into mitochondria and has a high
homology with yeast protein Mgm1, responsible for mi-
tochondrial maintenance and inheritance (Pelloquin et al.,
1998). Moreover, a mutation of another dynamin-related
GTPase protein, the human DRP1, has been shown to in-
duce changes in mitochondrial distribution and morphology
(Smirnova et al., 1998). Preliminary experiments with OPA1
mutants showed that the mitochondrial network in patient’s
monocytes undergo changes similar to those induced by
DRP1 mutants (Delettre et al., 2000), suggesting that a dys-
function of mitochondrial distribution may be implicated in
RGCs loss of autosomal dominant optic neuropathy.
The clinical evolution of Kjer’s disease is remarkably
different from LHON (Votruba et al., 1998). The onset
is in childhood, but patients are frequently recognized by
chance during routine vision testing because of subtle or
subclinical expression of the visual defect. The disease
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576 V. Carelli et al. / Neurochemistry International 40 (2002) 573–584
progression usually remains very slow, often stabilizes by
late adolescence, or sometimes, may undergo in adult life
more rapid evolution. The visual loss is characteristically
bilateral, symmetrical, with cecocentral scotomas, loss of
color vision (dyschromatopsia) and accompanied in most
cases by temporal optic nerve pallor. Variability of clinical
expression is mainly due to the degree of atrophy reachedby different patients. In a few cases mental retardation
has been reported to occur in conjunction with the optic
atrophy.
The endpoint of the pathological process in Kjer’s is
indistinguishable from LHON in form if not in degree, both
as visual defect and fundus appearance. Kjer’s histopatho-
logy, in the few cases examined, showed a remarkably selec-
tive loss of RGCs, in particular from the macular area, with
a substantially normal appearance of the rest of the retina
(Johnston et al., 1979; Kjer et al., 1983). This suggests that
like LHON there is in Kjer’s a particular vulnerability of the
smallest fibers of the papillo-macular bundle. However, in
Kjer’s optic atrophy, the clinical symptoms develop muchmore slowly and the optic atrophy is usually more limited
than in LHON.
2.3. Leigh syndrome (LS)
LS is the common clinical manifestation, usually with
infantile or childhood onset, of a wide range of different
genetic etiologies leading to a profound dysfunction of the
mitochondrial respiratory chain. A variety of molecular
defects in both nuclear DNA (nDNA) and mtDNA have
been recently identified (DiMauro, 1999). LS may be inher-
ited, depending on the particular defect, maternally (mtDNAdefects), as an X-linked recessive trait (pyruvate dehydroge-
nase complex, PDHC defect) or as an autosomal recessive
disease (defects in complexes I and II nuclear genes; defects
in SURF gene for complex IV assembly) (DiMauro,
1999).
Although the visual system is not usually emphasized,
optic atrophy is frequently reported as one of the clinical
features in LS, in addition to the classical bilateral necrotic
lesions affecting the periventricular white matter, basal gan-
glia and brainstem (Cavanagh and Harding, 1994). Given
the early onset of LS, it is difficult to document visual loss,
but according to the few histopathological reports of the
visual system there is a typical loss of RGCs and nerve
fiber layer dropout in the papillomacular bundle (Cavanagh
and Harding, 1994; Dayan et al., 1970; Grover et al., 1970;
Borit, 1971; Howard and Albert, 1972). In particular, a re-
cent report of ocular histopathology in a case of maternally
inherited LS with the mtDNA mutation T8993G/ATPase6
clearly showed a selective loss of RGCs in the macular
area with corresponding atrophy of the temporal side of the
optic nerve (Hayashi et al., 2000). The recent report that the
14459/ND6 mutation can lead to LHON, LHON/dystonia
or LS further establishes a link between these clinical
phenotypes (Kirby et al., 2000).
2.4. Friedreich’s ataxia (FRDA)
FRDA is the most common inherited ataxia with onset
before the age of 25; it is characterized by progressive gait
and limb ataxia, absence of deep tendon reflexes, extensor
plantar responses, and loss of position and vibration sense
in the lower limbs (Puccio and Koenig, 2000). Other fea-tures are hypertrophic cardiomyopathy, skeletal deformities
and diabetes mellitus. The inheritance pattern is autosomal
recessive and GAA triplet expansion or point mutations in
the frataxin gene on chromosome 9q13 are causative of the
disease.
Frataxin is a mitochondrial protein widely expressed in
tissues and thought to be involved in regulating mitochon-
drial iron transport and homeostasis (Puccio and Koenig,
2000). Biochemical investigations showed an increased mi-
tochondrial content in iron and a deficiency of iron–sulphur
(Fe–S) cluster-containing mitochondrial enzymes including
the respiratory complexes I, II and III and aconitase (Rotig
et al., 1997; Bradley et al., 2000). The selective damage of
such enzymatic activities seems to be related to oxidative
stress damage possibly triggered by the Fenton reaction in
presence of mitochondrial iron overload (Wong et al., 1999).
Furthermore, 31P-magnetic resonance spectroscopy (MRS)
studies indicated that ATP production in FDRA patients was
defective in vivo, probably as a result of the affected Fe–S
cluster-containing respiratory enzymes (Lodi et al., 1999).
Thus, FDRA is now regarded as a mitochondrial disorder
(Puccio and Koenig, 2000). A closely related disorder is
Vitamin E deficient ataxia, which may be due to mutations
in the ␣-tocopherol transfer protein (Ouahchi et al., 1995),
or to abetalipoproteinemia (Lodi et al., 1997a). Interestingly,a 31P-MRS study of a family with abetalipoproteinemia and
occurrence of LHON-like optic atrophy also demonstrated
a defective mitochondrial bioenergetic metabolism (Lodi
et al., 1997a; Carelli and Barboni, unpublished results).
Optic atrophy in FDRA is probably underestimated and
has been incompletely characterized (Carroll et al., 1980).
Old studies showed VEP abnormalities, temporal disc pal-
lor and moderate reduction of visual acuity, similar to the
clinical picture of the dominant optic atrophy (Carroll et al.,
1980). Visual pathway histopathology in FRDA has been
reported only in a few cases. Nerve fiber depletion, loss of
myelin and gliosis in the optic nerves, chiasm and tracts
were usually described with related loss of cells in the lat-
eral geniculate nucleus (Oppenheimer, 1976). Recently, a
single case report described visual loss and recovery closely
resembling LHON in a FRDA patient (Givre et al., 2000).
2.5. Other conditions with mitochondrial dysfunction
Optic atrophy may occur in mitochondrial encephalomy-
opathies due to mtDNA point mutations in tRNA genes, such
as myoclonic epilepsy, ragged-red-fibers (MERRF) (Chin-
nery et al., 1997), and mitochondrial encephalomyopathy,
lactic acidosis, and stroke-like syndrome (MELAS) (Hwang
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V. Carelli et al. / Neurochemistry International 40 (2002) 573–584 577
et al., 1997; Rigoli et al., 1999; Pulkes et al., 1999), or in
syndromes associated with mtDNA deletions (Rotig et al.,
1993) or in other, rarer, mtDNA defects (Bruno et al., 1999).
Optic atrophy has also been reported to occur in mitochon-
drial diseases dependent on nuclear defects such as hered-
itary spastic paraplegia due to mutations in the paraplegin
gene (Casari et al., 1998) or the deafness-dystonia-opticatrophy syndrome (Mohr–Tranebjaerg syndrome) due to
mutations in the X-linked DDP gene (Tranebjaerg et al.,
2000). These cases are less well characterized, but it is
tempting to speculate that given the common mitochondrial
pathogenesis of these neurological disorders the pathophys-
iology of the optic neuropathy may be similar. This is not
necessarily true in all cases as demonstrated by the different
pattern of optic atrophy noted to occur in a neurological
syndrome that is dependent on a mutation of a complex II
gene (Birch-Machin et al., 2000). Despite the mitochondrial
respiratory defect, these patients manifest an optic atrophy
associated with severely constricted visual fields (Taylor
et al., 1996), suggesting a pattern opposite to LHON andthe other optic neuropathies that affect primarily the central
visual field due to predominant loss of the papillo-macular
bundle.
3. Acquired optic neuropathies
3.1. Tobacco–alcohol amblyopia (TAA)
TAA is now rarely seen in the USA or Western Europe
(Rizzo and Lessell, 1993). In the past and still in some
Asian or African countries, it characteristically affectsmen with a history of heavy tobacco and/or alcohol use
(Traquair, 1930; Solberg et al., 1998). A subacute loss of
central vision with cecocentral scotomas, dyschromatopsia
and decreased visual acuity is typical in these patients. At
fundus examination there may be tortuosity of small retinal
vessels. Optic atrophy, frequently limited to the temporal
side becomes apparent in later stages. Early hydroxycobal-
amin administration and the cessation of smoking may
be effective for visual recovery (Rizzo and Lessell, 1993;
Solberg et al., 1998). Histopathological studies showed a
pronounced loss of RGCs in the macula, with marked loss
of papillomacular bundle fibers in the optic nerve (Victor
and Dreyfus, 1965; Smiddy and Green, 1987).
The pathogenesis of TAA remains elusive; there being
combined mechanisms proposed of toxic insults from
tobacco compounds and/or ethyl alcohol, concurrent with
nutritional deficiencies, as causing the optic neuropathy
(Rizzo and Lessell, 1993; Solberg et al., 1998). The sharp
decrease of new TAA cases, now seen in Western coun-
tries despite little change in tobacco consumption, points
to an important role for nutritional deficiencies. However,
cases with normal vitamin complement and no apparent
nutritional deficiency have been reported and the tobacco
toxicity was the putative factor (Rizzo and Lessell, 1993).
A wide body of evidence has been produced indicating
that tobacco-derived compounds including reactive oxygen
species (ROS) and cyanide reduce mitochondrial respira-
tory activity (Pryor et al., 1992), damage mtDNA (Ballinger
et al., 1996) and induce alterations of mitochondrial mor-
phology (Kennedy and Elliot, 1970). Given the remarkable
clinical similarities between LHON and TAA, it is notsurprising that checking for LHON-related mutations of
mtDNA in TAA patients revealed that a subset of TAA cases
were misdiagnosed cases of LHON (Cullom et al., 1993).
3.2. Cuban epidemic of optic neuropathy (CEON)
A recent epidemic of nutritional deficiency optic neuro-
pathy affected tens of thousands of severely malnourished
patients in Cuba between 1992 and 1993 (Sadun et al.,
1994b; Sadun and Martone, 1995). These patients all
reported marked weight loss associated with severe
deficiencies of protein and vitamin intake, in particular of
Vitamin B12 and folate. The most striking finding at fun-dus examination was the marked thinning of the nerve fiber
layer of the papillo-macular bundle forming a wedge defect
bordered by swollen nerve fibers above and below (Sadun
et al., 1994c). This finding was the most critical part of the
case definition, which required, in addition, three of the fol-
lowing five signs: bilateral progressive loss of visual acuity,
bilateral cecocentral scotomas, bilateral dyschromatopsia,
bilateral losses of high spatial frequency contrast sensitivity,
saccadic eye movements (Sadun et al., 1994c). In addi-
tion to the visual symptoms, over one-third of the patients
had neurological symptoms, consisting most frequently of
peripheral neuropathy, ataxia, and hearing loss.The prompt administration of cyanocobalamin (3 mg) and
folate (250mg) per day led to a recovery of visual acuity in
a significant number of cases and this and dietary supple-
mentation brought the epidemic to an end. In one study, 20
patients were examined just before and 3 months after the
therapy was established. Following treatment, their average
visual acuity went from 20/400 to 20/50 and their average
color vision from 2 of 8 to 7 of 8 American Optical Color
test plates (Sadun et al., 1994c).
3.3. Vitamin-related optic neuropathies
Central vision loss associated with dyschromatopsia,
cecocentral scotomas, and the selective loss of the papillo-
macular bundle commonly characterizes the following vita-
min deficiencies: Vitamin B12 (cobalamin) (Gleason and
Graves, 1974); Vitamin B1 (thiamin), often associated with
photophobia and eye pain (Hoyt and Billson, 1977); Vita-
min B2 (riboflavin); and folic acid (Miller, 1982). Mixed
deficiencies of this class of B vitamins are also not uncom-
mon. Malnourished prisoners of war have been described
to have an optic neuropathy in association with a peripheral
neuropathy (Cruickshank, 1946). Thus, paresthesias and
dysesthesias, ataxia and hearing loss were noted besides the
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578 V. Carelli et al. / Neurochemistry International 40 (2002) 573–584
visual symptoms (Osuntokun, 1968). In this case, the vita-
min deficiencies associated with poor diet may have been
compounded by the ingestion of cassava, which may lead
to elevated levels of cyanide (Osuntokun and Osuntokun,
1971). The CEON, as well as the most recent similar epi-
demic in Tanzania (Plant et al., 1997) and TAA probably
involve a combination of deficiencies and toxic exposures(Lessel, 1973).
3.4. Antibiotic-related optic neuropathies
Optic neuropathy characterized by sudden onset, bilateral
loss of central vision with cecocentral scotoma, prevalent
and selective involvement of the papillomacular bundle and
tortuosity of the retinal vessels may be precipitated by the
administration of at least two antibiotics, chloramphenicol
(Harley et al., 1970) and ethambutol (Alvarez and Krop,
1993).
Until 1970, chloramphenicol was used frequently to
treat children with cystic fibrosis (Harley et al., 1970).Chloramphenicol toxicity was soon recognized as many
cases of an associated optic neuropathy were reported. The
incidence and severity of chloramphenicol optic neuropa-
thy was dose-dependent. A peripheral neuropathy was also
frequently noted to accompany the visual problems. Prompt
cessation of the drug and Vitamin B complex treatment usu-
ally led to a recovery of visual function. Histopathological
studies demonstrated loss of RGCs and nerve fibers, with
demyelination of the optic nerve involving predominantly
the papillomacular bundle (Harley et al., 1970). Chloram-
phenicol is well known to inhibit mitochondrial protein
synthesis (Gilman et al., 1985).Ethambutol is an antimycobacterial agent used in the
treatment of tubercolosis (Alvarez and Krop, 1993). The
ocular toxicity is well established and dose-dependent.
This is also generally reversible by early withdrawal of the
drug administration. However, some permanent visual loss
may persist in conjunction with mild temporal pallor of
the optic disk. The only histopathological study of such a
patient showed demyelination in the optic chiasm (Shiraki,
1973). Administration of ethambutol in experimental an-
imals induces axonal swelling in the optic chiasm and in
the intracranial portion of the optic nerve (Shiraki, 1973).
Ethambutol is a metal chelator and might interact with
Cu-containing cytochrome c oxidase (COX, complex IV)
and Fe-containing NADH:Q oxidoreductase (complex I),
thus damaging the mitochondrial respiratory chain (Kozak
et al., 1998). However, a recent cell culture study suggested
that zinc might also play an important role in ethambutol
toxicity of RGCs (Yoon et al., 2000).
3.5. Toxic optic neuropathies
Toxins that are clearly established as producing an
optic neuropathy include arsacetin, carbon monoxide, clio-
quinol, cyanide, hexachlorophene, isoniazid, lead, methanol,
plasmocid, and triethyl tin (Sobel and Yanuzi, 1991). Most
of these are known to interfere with oxidative phosphorila-
tion. A number of other agents are less clearly established
as toxic to the optic nerve. These include carbon disulfide,
pheniprazine, quinine, and thallium (Sobel and Yanuzi,
1991). Other toxins are suspected but unproven as causes
of optic neuropathy, such as carbon tetrachloride, cassava,daspasone, and suramin (Sobel and Yanuzi, 1991).
4. Pathophysiology
LHON is probably the most carefully investigated of the
metabolic optic neuropathies. Biochemical studies carried
out on patient tissues (Carelli et al., 1997, 1999) and cell
lines, particularly the transmitochondrial cell constructs
called cybrids (Cock et al., 1998; Vergani et al., 1995;
Hofhaus et al., 1996; Brown et al., 2000; Jun et al., 1996),
all documented a partial impairment of respiratory chain di-
rectly related to complex I dysfunction. Whether this inducesa consistent decrease of ATP production at the level of the
target tissue is still unknown (Cock et al., 1999) and direct
measurements of mitochondrial ATP synthesis in LHON cell
lines have not been performed yet. However, “in vivo” func-
tional investigations using the 31P-MRS did show partially
impaired ATP synthesis in both central nervous system CNS
and muscle (Lodi et al., 1997b, 2000). The detailed char-
acterization of complex I function affected by the LHON
and LHON/dystonia/Leigh syndrome mtDNA pathogenic
point mutations (11778/ND4, 3460/ND1, 14484/ND6,
14459/ND6) suggests, as a common feature, an altered inter-
action with the quinone (CoQ) substrate (Carelli et al., 1997,1999; Jun et al., 1996; Majander et al., 1996). Aside from
the decreased respiratory chain efficiency, this most proba-
bly induces also a chronic increase of ROS production, pos-
sibly via destabilized ubisemiquinone radical dismutation
(Degli Esposti et al., 1994). Thus, both energy depletion and
chronic ROS overproduction may potentially derive from
the LHON-related mtDNA mutations. At issue remains the
question of how this would specifically target the optic nerve.
The axons contributed by RGCs converge towards the
optic nerve head as the unmyelinated retinal nerve fiber
layer. This turns and enters the optic nerve through the lam-
ina cribrosa. It should be noted that the myelin sheath starts
to wrap the axons only posterior to the lamina cribrosa. This
peculiar anatomical feature has profound functional impli-
cations. Mitochondria biogenesis occurs in the somata of
RGCs; they are then transported all the way down the axons
of the optic nerve to the synaptic terminals (Grafstein, 1995;
Hollenbeck, 1996). Histological and histoenzymatic evi-
dence has documented a non-homogeneous distribution of
mitochondria along the optic nerve axons (Hollander et al.,
1995; Andrews et al., 1999). The initial non-myelinated
part, including the nerve fiber layer of the retina, and the
portion of the nerve crossing the lamina cribrosa at the optic
nerve head are particularly rich in “docking” mitochondrial
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V. Carelli et al. / Neurochemistry International 40 (2002) 573–584 579
populations as directly shown by electron microscopy EM
(Hollander et al., 1995) and the intense COX staining (An-
drews et al., 1999). As soon as the axons acquire myelin,
posterior to the lamina cribrosa, the number of mitochondria
drastically decreases, as shown again by both EM and loss of
COX staining (Hollander et al., 1995; Andrews et al., 1999).
This asymmetry is most probably due to the functional needsof transmitting the action potentials along the unmyelinated
portion (highly energy demanding) in contrast to the salta-
tory conduction in the myelinated, postlaminar portion of the
optic nerve (less energy demanding) (Andrews et al., 1999).
Among the fibers composing the optic nerve, those with
the smaller caliber, mostly belonging to the papillomacular
bundle subserving the central vision, present the lowest vol-
ume (energy source) to surface area (energy demand) ratio.
They also have a thinner myelin sheath, and a rapid rate
of firing (Sadun, 1998). Thus, these fibers have the most
disadvantageous condition in terms of energy requirements
among the axons of the optic nerve (Sadun, 1998). Consid-
ering the energy depletion, possibly induced by the LHONpathogenic mutations, the most vulnerable component of
the nerve would be the papillo-macular bundle, particu-
larly at the prelaminar (unmyelinated) portion of the optic
nerve head. The clinical manifestations of disc swelling and
microangiopathy seen in LHON at the optic nerve head,
before and during the acute stage, provide evidence that
the prelaminar unmyelinated portion is mainly involved
(Nikoskelainen, 1994). Similar findings, particularly the
dropout of the papillo-macular bundle and the swelling
of the rest of the nerve fiber layer invariably characterize
most of the optic neuropathies here reviewed. Moreover,
histopathological evidence of nerve fiber layer swelling andvacuolation at the optic nerve head anterior to the lamina
cribrosa have been described in both a CEON patient and
the CEON-like rat model (Sadun, 1998).
Mitochondria are distributed asymetrically along the
optic nerve axons, compatibly with the functional needs
related to the nerve transmission. They are also transported
to the very end of the axons to accomplish the functional
needs related with synaptic transmission. Mitochondria
are transported bi-directionally (antero-retrograde) with the
“fast component” of the axonal transport (Grafstein, 1995;
Hollenbeck, 1996). Their “saltatory” movements are based
on motor proteins. Essentially, the microtubule (MT)-based
motility is supported by kinesin for anterograde transport
and by dynein for retrograde. Moreover, mitochondria
can also use actin microfilaments (MFs) which represent,
most likely, an auxiliary system involved in local trans-
port (Grafstein, 1995; Hollenbeck, 1996). Both kinesin and
dynein present an ATPase activity that is activated by mi-
crotubule binding. Thus, mitochondrial axonal transport is
an ATP-dependent process (Ochs and Hollingsworth, 1971;
Sabri and Ochs, 1972) and mitochondria are a major source
of ATP. It is conceivable that any energy depletion due to
mitochondrial dysfunction has the potential of affecting
axonal transport, including that of mitochondrial transport
itself. In fact, histopathological investigations of LHON
optic nerves showed features suggesting an ongoing im-
pairment of axonal transport (Fig. 2; Sadun et al., 1994a;
Carelli et al., 1999; Carelli et al., unpublished data). In
particular, the observation of frequent clumps of mitochon-
dria in spared axons in the retrolaminar myelinated portion
of the nerve, as well as accumulations of multivescicularbodies and debris, and cytoskeletal changes such as relative
depletion of microtubules, were all suggestive of impaired
axonal transport (Sadun et al., 1994a; Carelli et al., 1999).
Histopathological studies of CEON and a CEON-like rat
model described similar features (Sadun, 1998). Moreover,
the importance of mitochondrial distribution and transport
for RGCs life and death has recently been greatly strengthen
by the unexpected discovery that mutations in the OPA1 gene
are causative for a subset of Kjer’s optic neuropathy (Delet-
tre et al., 2000; Alexander et al., 2000). This mitochondrial
targeted protein, a dynamin-related GTPase, seems to be
relevant for mitochondrial interaction with the cytoskeleton
(Pelloquin et al., 1998; Smirnova et al., 1998) and pre-liminary experiments showed mitochondrial clumping as a
consequence of the mutant protein (Delettre et al., 2000).
However, the cascade of events leading to the RGCs death
is probably very complex and other potential players need to
be considered. The pure energy-depletion model of LHON
remains unsatisfactory. It fails to explain, for example,
why other energy-dependent cell types, such as the retinal
pigment epithelium (RPE) and the photoreceptors are not
normally involved. Biochemical investigations in LHON, as
already discussed, also suggest that chronic overproduction
of ROS may be an even more important consequence of
the pathogenic mutations. Recently, Barrientos and Moraesdeveloped a cellular model of partial complex I dysfunc-
tion mimicking the LHON complex I defect, and showing
that ROS overproduction represent a major consequence,
besides the partially impaired respiratory function (Barri-
entos and Moraes, 1999). Moreover, Wong and Cortopassi
(1997) showed that viability of a LHON cybrid cell line was
more sensible than the control parental cell line to exogenous
ROS. Studies of demyelination in Multiple Sclerosis (MS),
as well as in other conditions, indicate that olygodendrocytes
are particularly vulnerable to oxidative stress (Smith et al.,
1999). It is now evident from our histopathological investiga-
tions of LHON that a previously underestimated component
of the pathological process also affects the myelin sheath
(Sadun et al., 1994a; Carelli et al., 1999; Carelli et al., unpub-
lished data). We have shown evidence of axons, apparently
without ongoing degenerative features, that are profoundly
devoid of myelin, as well as few examples of denuded axons
with features of remyelination. This latter finding prompts
speculating that late visual recovery reported in some LHON
patients, especially those with the 14484/ND6 mutation,
may be due to the remyelination of denuded axons. In some
cases, degenerative features affecting the oligodendrocyte
cytoplasmic tongues that wrap about intact axons have been
noted. These features resemble descriptions of experimental
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580 V. Carelli et al. / Neurochemistry International 40 (2002) 573–584
models of demyelination using toxicants now well known to
interfere with mitochondrial metabolism such as cuprizone
or ethidium bromide (Ludwin, 1978, 1995; Blakemore,
1982). The possibility of a primary pathology of myelin in
LHON is also of interest considering that a subset of these
patients develop a more widespread myelin pathology in the
CNS, a Leber’s “plus” clinical condition indistinguishablefrom MS, commonly indicated as LHON/MS-like syndrome
(Carelli, 2002). Demyelination and features such as myelin
splitting and vacuolar degeneration have been observed in a
variety of mitochondrial diseases (Brown and Squier, 1996),
in particular, in LS, that includes among its pathological
features an LHON-like optic atrophy (Cavanagh and Hard-
ing, 1994; Dayan et al., 1970; Grover et al., 1970; Borit,
1971; Howard and Albert, 1972; Hayashi et al., 2000).
The link between LHON and LS has been re-enforced by
two recent studies. The first, a histopathological study of
the optic nerve in a Leigh case with the T8993G mtDNA
point mutation in the ATPase6 subunit gene (Hayashi et al.,
2000), showed features characteristic of LHON (Carelliand Sadun, 2001). The second study (Kirby et al., 2000)
reported that the same pathogenic mutation 14459/ND6
may lead to both the LHON/dystonia and Leigh phenotypes.
Thus, oxidative stress due to chronic ROS overproduc-
tion, postulated in LHON, would most probably affect the
retrolaminar myelinated portion of the optic nerve. In this
scenario, the capability of specific tissues and cell types
to counteract an increased oxidative stress is intuitively of
major relevance in determining the degree and distribution
of the ultimate damage. The establishment of two ani-
mal models with adenin-nucletide-translocator 1 (ANT1)
and manganese-superoxide-dismutase (MnSOD) knockoutgenes has recently underscored the importance of oxida-
tive stress in generating tissue-specific pathology (Esposito
et al., 1999; Melov et al., 1998). These studies suggest that
the level of antioxidant defenses, in particular the intramito-
chondrial MnSOD, and the capability of up-regulating these
enzymatic activities differs among tissues, rendering those
with low efficiency more vulnerable to suffer a pathological
damage (Esposito et al., 1999). Tissue-specific pathological
expression, as characteristic of the optic neuropathies here
reviewed, may then be also explained by the interaction of
the primary etiological factor (mtDNA mutations in LHON)
with these differences in cellular genetic and functional
expression. This seems to apply at least to the oligodendro-
cyte component (Smith et al., 1999). Moreover, genetically
determined variability in antioxidant enzyme activities, as
due to population polymorphisms, may also play a role in
penetrance or predisposition to manifest the ocular
pathology. For example, in regard to MnSOD, at least
two polymorphic variants (Rosenblum et al., 1996;
Shimoda-Matsubayashi et al., 1996; Borgsthal et al., 1996),
one relatively frequent in the Caucasian population (Van
Landeghem et al., 1999), have been reported to decrease
the enzymatic activity in normal individuals. This could be
a factor modulating disease penetrance in LHON, where a
nuclear-encoded factor is suspected, or in predisposing an
individual to TAA.
Whatever complex combination and timing of patho-
physiological pathways are truly operating, RGCs death
has been postulated to be apoptotic in LHON (Howell,
1999) and possibly in the other optic neuropathies sharing
similarities. RGCs apoptotic death has been documented inother pathological conditions including glaucoma (Kerrigan
et al., 1997; Levin and Louhab, 1996). Apoptotic RGCs
death is also seen after optic nerve axotomy (Berkelaar
et al., 1994). Interruption of axonal transport has been im-
plicated in all these pathological conditions, and the lack of
retrograde transport of neurotrophic factors has been sug-
gested to play a role (Bahr, 2000). However, other factors
have also been considered, including the activation of the
surrounding glial cells (Bahr, 2000). The role of glial cells
and their ability to up-regulate nitric oxide synthase (NOS)
when activated, is becoming increasingly relevant in the
cascade of events that may lead to RGCs death, as recently
shown in glaucoma (Liu and Neufeld, 2000). There ismounting evidence that astrocyte-derived nitric oxide (NO)
can damage the neuronal mitochondrial respiratory chain
(Stewart et al., 2000) targeting in particular complex I via
S -nitrosylation (Clementi et al., 1998), as well as inactivate
MnSOD through peroxynitrite-mediated tyrosine nitration
(Yamakura et al., 1998). Preliminary immuno-histochemical
studies on optic nerve specimens from a LHON patient in-
dicate increased nitrotyrosine labelling, and co-localization
studies are ongoing to identify the cell structures targeted
by peroxynitrite (Carelli et al., 2000).
All histopathological studies of LHON have been on
cases in which tissue became available decades after thepatient had loss of vision (Sadun et al., 1994a; Kerrison
et al., 1995; Carelli et al., 1999). The probability of catch-
ing RGCs undergoing apoptotic morphological changes
is very low (Sadun and Sadun, 1996). In one study the
observation of double-membrane-bound inclusions within
the spared RGCs were interpreted as calcified remnants of
mitochondria suggesting a role for calcium in the cell death
process (Kerrison et al., 1995). However, these findings
have not been seen in the other two LHON cases studied
in our laboratory (Carelli et al., unpublished data). Other
considerations suggest that RGCs die through the apoptotic
pathway in LHON. The clinical absence of inflammation,
confirmed by lack of leakage at fluorangiography and by
the histopathological investigations, characteristically dis-
tinguishes LHON from optic neuritis (Carelli, 2002) and
suggests an apoptotic, rather than necrotic, RGCs death.
Moreover, the above mentioned cellular model developed
by Barrientos and Moraes showed how oxidative stress and
consequent apoptotic cell death are main features of a par-
tial complex I deficiency (Barrientos and Moraes, 1999).
However, it should be kept in mind that intermediate forms
of cell death (necrapoptosis) are being identified (Lemasters
et al., 1999) and switching between one modality and the
other may occur (Leist et al., 1999). The different timing
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V. Carelli et al. / Neurochemistry International 40 (2002) 573–584 581
of cell death, ranging from acute/subacute in LS, LHON,
TAA and CEON, to gradually progressive in Kjer’s and
FRDA, probably reflects differences in the execution of
death pathways related to a similar, stereotyped sensitivity
to optic nerve injury mediated by mitochondrial dysfunc-
tion. Accordingly, it also remains to be seen if RGC death
occurs mainly in a retrograde process starting from distalaxons or is a primary event occurring in the RGC cell body.
5. Conclusions
The identification of a fairly homogeneous category of
optic neuropathies, characterized by a common pathologi-
cal hallmark that preferentially involves the papillo-macular
bundle, seems related to a possible common basic patho-
physiology mediated by a mitochondrial dysfunction.
Nonetheless, recent discoveries show the issue to be com-
plex. We expect to soon understand the exact biochemical
consequences of complex I dysfunction in LHON, in par-ticular the relative contribution of energy depletion and
oxidative stress to cell death. The relationship between
mitochondrial dysfunction and the physiology of axonal
transport, as well as of axon–myelin interactions are part of
the complex sequence of events that lead to the activation
of RGCs death. In this regard, glial cells probably play an
important role. Finally, the execution of death programs
may represent the last step that needs to be elucidated in or-
der to maximally design therapeutical strategies that could
mitigate these pathological conditions.
Acknowledgements
We would like to thank Michele Madigan, Hugo Hsu,
Hossein G. Saadati, Keith B. Heller, Scott O. Walker,
Marissa M. Cruz, Peter H. Win, Ruvdeep S. Randhawa,
Ernesto Barron and Anthony Rodriguez, that, over the
years, participated with our work on mitochondrial optic
neuropathies at Doheny Eye Institute, University of South-
ern California, Keck School of Medicine, Los Angeles.
We also thank Mauro Degli Esposti, Anna Ghelli, Laura
Bucchi, Giorgio Lenaz, Pasquale Montagna, Pietro Cortelli,
Piero Barboni, Elio Lugaresi, Agostino Baruzzi, Sabina
Cevoli, Maria Lucia Valentino and Simonetta Sangiorgi for
the long-lasting effort in studying LHON at the University
of Bologna, Bologna, Italy. Our research is supported by
Senior Investigator Award from Research to Prevent Blind-
ness, Inc. (AAS), by grant ROI EY11396 from the National
Institute of Health and by grant from the International Foun-
dation of Optic Nerve Diseases (IFOND). Our research is
also supported by Telethon-Italy grants for the study of
LHON (Grants 391 and 792 to Prof. Lugaresi, Grant 616
to Dr. Degli Esposti and Grant 876 to Prof. Lenaz) and by
the “Fondazione Gino Galletti” for the study of dementias
and other neuro-degenerative diseases in Italy.
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