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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.

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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).



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




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




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




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




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




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




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.

References

Alexander, C., Votruba, M., Pesch, U.E.A., Thiselton, D.L., Mayer, S.,

Moore, A., Rodriguez, M., Kellner, U., Leo-Kottler, B., Auburger,

G., Bhattacharya, S.S., Wissinger, B., 2000. OPA1, encoding a

dynamin-related GTPase, is mutated in autosomal dominant optic

atrophy linked to choromosome 3q28. Nat. Genet. 26, 211–215.

Alvarez, K.L., Krop, L.C., 1993. Ethambutol induced ocular toxicityrevisited. Ann. Pharmacother. 27, 102–103.

Andrews, R.M., Griffiths, P.G., Johnson, M.A., Turnbull, D.M., 1999.

Histochemical localization of mitochondrial enzyme activity in human

optic nerve and retina. Br. J. Ophthalmol. 83, 231–235.

Bahr, M., 2000. Live or let die—retinal ganglion cell death and survival

during development and in the lesioned adult CNS. Trends Neurosci.

23, 483–490.

Ballinger, S.W., Bouder, T.G., Davis, G.S., Judice, S.A., Nicklas, J.A.,

Albertini, R.J., 1996. Mitochondrial genome damage associated with

cigarette smoking. Cancer Res. 56, 5692–5697.

Barrientos, A., Moraes, C.T., 1999. Titrating the effects of mitochondrial

complex I impairment in the cell physiology. J. Biol. Chem. 274,

16188–16197.

Berkelaar, M., Clarke, D.B., Wang, Y.-C., Bray, G.M., Aguayo, A.J., 1994.

Axotomy results in delayed death and apoptosis of retinal ganglioncells in adult rats. J. Neurosci. 14, 4368–4374.

Birch-Machin, M.A., Taylor, R.W., Cochran, B., Ackrell, B.A.C., Turnbull,

D.M., 2000. Late-onset optic atrophy, ataxia, and myopathy asociated

with a mutation of a complex II gene. Ann. Neurol. 48, 330–335.

Blakemore, W.F., 1982. Ethidium bromide induced demyelination in the

spinal cord of the cat. Neuropathol. Appl. Neurobiol. 8, 365–375.

Borgsthal, G.E.O., Parge, H.E., Hickley, M.J., et al. 1996. Human

mitochondrial manganese superoxide dismutase polymorphic variant

Ile58Thr reduces activity destabilizing the tetrameric interface.

Biochemistry 35, 4287–4297.

Borit, A., 1971. Leigh’s necrotizing encephalomyelopathy:

neuro-ophthalmological abnormalities. Arch. Ophthalmol. 85, 438–442.

Bradley, J.L., Blake, J.C., Chamberlain, S., Thomas, P.K., Cooper, J.M.,

Schapira, A.H., 2000. Clinical, biochemical and molecular genetic

correlations in Friedreich’s ataxia. Hum. Mol. Genet. 9, 275–282.Brown, G.K., Squier, M.V., 1996. Neuropathology and pathogenesis of

mitochondrial diseases. J. Inher. Metab. Dis. 19, 553–572.

Brown, M.D., Trounce, I.A., Jun, A.S., Allen, J.C., Wallace, D.C., 2000.

Functional analysis of lymphoblast and cybrid mitochondria containing

the 3460, 11778 or 14484 Leber’s hereditary optic neuropathy. J. Biol.

Chem. 275, 39831–39836.

Bruno, C., Martinuzzi, A., Tang, Y., Andreu, A.L., Pallotti, F., Bonilla, E.,

Shanske, S., Fu, J., Sue, C.M., Angelini, C., DiMauro, S., Manfredi,

G., 1999. A stop-codon mutation in the human mtDNA cytochrome c

oxidase I gene disrupts the functional structure of complex IV. Am J.

Hum. Genet. 65, 611–620.

Carelli, V., 2002. Leber’s hereditary optic neuropathy. In: Schapira,

A.H.V., DiMauro, S. (Eds.), Mitochondrial Disorders in Neurology,

2nd Edition. Blue Book series in Neurology, Butterworth–Heinemann,

in press.Carelli, V., Sadun, A.A., 2001. Optic neuropathy in LHON and Leigh

syndrome: a common pathogenic mechanism. Ophthalmology 108,

1172–1173.

Carelli, V., Saadati, H.G., Madigan, M., Valentino, M.L., Ho Win, P.,

Barboni, P., Cortelli, P., Baruzzi, A., Sadun, A.A., 1999. Leber’s

hereditary optic neuropathy hystopathology suggests optic nerve

axoplasmic stasis as the key pathophysiologic feature. Presented at

“EUROMIT 4”, 16–19 September, Queens College, Cambridge, UK,

Abstract book #P92.

Carelli, V., Ghelli, A., Ratta, M., Bacchilega, E., Sangiorgi, S., Mancini,

R., Leuzzi, V., Cortelli, P., Montagna, P., Lugaresi, E., Degli Esposti,

M., 1997. Leber’s hereditary optic neuropathy: biochemical effect of

the 11778/ND4 and 3460/ND1 mutations and correlation with the

mitochondrial genotype. Neurology 48, 1623–1632.




Carelli, V., Ghelli, A., Bucchi, L., Montagna, P., De Negri, A., Leuzzi,

V., Carducci, C., Lenaz, G., Lugaresi, E., Degli Esposti, M., 1999.

Biochemical features of mtDNA 14484 (ND6/M64V) point mutation

associated with Leber’s hereditary optic neuropathy. Ann. Neurol. 45,

320–328.Carelli, V., Sadun, A.A., Ross-Cisneros, F., Rao, N., Qi, X., Guy, J., 2000.

Reactive oxygen species in the pathogenesis of Leber’s hereditary optic

neuropathy. Invest. Ophthalmol. Vis. Sci. 41 (4), 1650–B1025.Carroll, W.M., Kriss, A., Baraitser, M., Barrett, G., Halliday, A.M., 1980.

The incidence and nature of visual pathway involvement in Friedreich’s

ataxia. Brain 103, 413–434.Casari, G., DeFusco, M., Ciarmatori, S., Zeviani, M., Mora, M., Fernandez,

P., De Michele, G., Filla, A., Cocozza, S., Marconi, R., Durr, A.,

Fontaine, B., Ballabio, A., 1998. Spastic paraplegia and OXPHOS

impairment caused by mutations in Paraplegin, a nuclear-encoded

mitochondrial metalloprotease. Cell 93, 973–983.Cavanagh, J.B., Harding, B.N., 1994. Pathogenic factors underlying

the lesions in Leigh’s disease. Tissue responses to cellular energy

deprivation and their clinico-pathological consequences. Brain 117,

1357–1376.Chalmers, R.M., Harding, A.E., 1996. A case-control study of Leber’s

hereditary optic neuropathy. Brain 119, 1481–1486.Chalmers, R.M., Schapira, A.H.V., 1999. Clinical, biochemical and

molecular genetic features of Leber’s hereditary optic neuropathy.

Biochim. Biophys. Acta 1410, 147–158.Chinnery, P.F., Howell, N., Lightowlers, R.N., Turnbull, D.M., 1997.

Molecular pathology of MELAS and MERRF: the relationship between

mutation load and clinical phenotypes. Brain 120, 1713–1721.Chinnery, P.F., Brown, D.T., Andrews, R.M., Singh-Kler, R., Riordan-Eva,

P., Lindley, J., Applegarth, D.A., Turnbull, D.M., Howell, N., 2001.

The mitochondrial ND6 gene is a hot spot for mutations that cause

Leber’s hereditary optic neuropathy. Brain 124, 209–218.Clementi, E., Brown, G.C., Feelisch, M., Moncada, S., 1998. Persistent

inhibition of cell respiration by nitric oxide: crucial role of

S -nitrosylation of mitochondrial complex I and protective action of

glutathione. Proc. Natl. Acad. Sci. U.S.A. 95, 7631–7636.Cock, H.R., Tabrizi, S.J., Cooper, J.M., Schapira, A.H.V., 1998. The

influence of nuclear background on the biochemical expression of 3460

Leber’s hereditary optic neuropathy. Ann. Neurol. 44, 187–193.Cock, H.R., Cooper, J.M., Schapira, A.H.V., 1999. Functional

consequences of the 3460-bp mitochondrial DNA mutation associated

with Leber’s hereditary optic neuropathy. J. Neurol. Sci. 165, 10–17.Cruickshank, E.K., 1946. Painful feet in prisoners-of-war in the Far East.

Review of 500 cases. Lancet 2, 369–372.Cullom, M.E., Heher, K.L., Miller, N.R., Savino, P.J., Johns, D.R., 1993.

Leber’s hereditary optic neuropathy masquerading as tobacco–alcohol

amblyopia. Arch Ophthalmol. 111, 1482–1485.Dayan, A.D., Ockenden, B.G., Crome, L., 1970. Necrotizing

encephalomyelopathy of Leigh: neuropathological findings in 8 cases.

Arch. Dis. Child. 45, 39–48.Degli Esposti, M., Carelli, V., Ghelli, A., Ratta, M., Crimi, M., Sangiorgi,

S., Montagna, P., Lenaz, G., Lugaresi, E., Cortelli, P., 1994. Functional

alterations of the mitochondrially encoded ND4 subunit associated with

Leber’s hereditary optic neuropathy. FEBS Lett. 352, 375–379.Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C.,

Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret,

E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun,

B., Kaplan, J., Hamel, C.P., 2000. Nuclear gene OPA1, encoding a

mitochondrial dynamin-related protein, is mutated in dominant optic

atrophy. Nat. Genet. 26, 207–210.DiMauro, S., 1999. Mitochondrial encephalomyopathies: back to

mendelian genetics. Ann. Neurol. 45, 693–694.Eiberg, H., Kjer, B., Kjer, P., Rosenberg, T., 1994. Dominant optic atrophy

(OPA1) mapped to chromosome 3q region. I. Linkage analysis. Hum.

Mol. Genet. 3, 977–980.Esposito, L.A., Melov, S., Panov, A., et al. 1999. Mitochondrial disease

in mouse results in increased oxidative stress. Proc. Natl. Acad. Sci.

U.S.A. 96, 4820–4825.

Gilman A.G., et al. (Eds), 1985. Goodman and Gilman’s the

Pharmacological Basis of Therapeutics, 7th Edition. Macmillan, New

York, pp. 1179–1183.Givre, S.J., Wall, M., Kardon, R.H., 2000. Visual loss and recovery in a

patient with Friedreich ataxia. J. Neuro-Ophthalmol. 20, 229–233.Gleason, M.H., Graves, P.S., 1974. Complications of dietary deficiency of

vitamin B-12 in young Caucasian. Post. Grad. Med. J. 50, 462–464.Grafstein, B., 1995. Axonal transport: function and mechanism. In:

Waxman, S.G., Kocsis, J.D., Stys, P.K. (Eds.), The Axon: Structure,

Function and Pathophysiology. Oxford University Press, Oxford,

pp. 185–199.Grover, W.D., Green, W.R., Pileggi, A.J., 1970. Ocular findings in subacute

necrotizing encephalomyelitis. Am. J. Ophthalmol. 70, 599–603.Harley, R.D., Huang, N.N., Macri, C.H., Green, W.R., 1970. Optic neuritis

and optic atrophy following chloramphenicol in cystic fibrosis patients.

Tr. Am. Acad. Ophth. Otol. 74, 1011–1031.Hayashi, N., Geraghty, M.T., Green, W.R., 2000. Ocular histopathologic

study of a patient with the T 8993-G point mutation in Leigh’s

syndrome. Ophthalmology 107, 1397–1402.Hofhaus, G., Johns, D.R., Hurko, O., Attardi, G., Chomyn, A., 1996.

Respiration and growth defects in transmitochondrial cell lines

carrying the 11778 mutation associated with Leber’s hereditary optic

neuropathy. J. Biol. Chem. 271, 13155–13161.

Hollander, H., Makarov, F., Stefani, F.H., Stone, J., 1995. Evidenceof constriction of optic nerve axons at the lamina cribrosa in the

normotensive eye in human and other mammals. Ophthalmic Res. 27,

296–309.Hollenbeck, P.J., 1996. The pattern and mechanism of mitochondrial

transport in axons. Front Biosci. 1, d91–d102.Howard, R.O., Albert, D.M., 1972. Ocular manifestations of subacute

necrotizing encephalomyelopathy. Am. J. Ophthalmol. 74, 386–393.

Howell, N., 1999. Human mitochondrial diseases: answering question and

questioning answers. Int. Rev. Cytol. 186, 49–116.Howell, N., Mackey, D.A., 1998. Low-penetrance branches in matrilinear

pedigrees with Leber hereditary optic neuropathy. Am. J. Hum. Genet.

63, 1220–1224.Hoyt, C.S., Billson, F.A., 1977. Low carbohydrate diet optic neuroathy.

Med. J. Aust. 1, 65–66.

Hwang, J.M., Park, H.W., Kim, S.I., 1997. Optic neuropathy associatedwith mitochondrial tRNA [Leu(UUR)] A3243G mutation. Ophthalmic

Genet. 18, 101–105.Johnston, P.B., Gaster, R.N., Smith, V.C., Tripathi, R.C., 1979. A

clinicopathologic study of autosomal dominant optic atrophy. Am. J.

Ophthalmol. 88, 868–875.Jun, A.S., Brown, M.D., Wallace, D.C., 1994. A mitochondrial DNA

mutation at np 14459 of the ND6 gene associated with maternally

inherited Leber’s hereditary optic neuropathy and dystonia. Proc. Natl.

Acad. Sci. U.S.A. 91, 6206–6210.Jun, A.S., Trounce, I.A., Brown, M.D., Shoffner, J.M., Wallace, D.C.,

1996. Use of transmitochondrial cybrids to assign a complex I defect

to the mitochondrial DNA-encoded NADH deydrogenase subunit 6

gene mutation at nucleotide pair 14459 that causes Leber hereditary

optic neuropathy and dystonia. Mol. Cell Biol. 16, 771–777.

Kennedy, J.R., Elliot, A.M., 1970. Cigarette smoke: the effect of residueon mitochondrial structure. Science 168, 1097–1098.

Kerrigan, L.A., Zack, D.J., Quigley, H.A., Smith, S.D., Pease, M.E.,

1997. TUNEL-positive ganglion cells in human primary open-angle

glaucoma. Arch. Ophthalmol. 115, 1031–1035.

Kerrison, J.B., Howell, N., Miller, N.R., Hirst, L., Green, W.R., 1995.

Leber hereditary optic neuropathy. Electron microscopy and molecular

genetic analysis of a case. Ophthalmology 102, 1509–1516.Kerrison, J.B., Arnould, V., Barmada, M.M., 1999. Genetic heterogeneity

of dominant optic atrophy, Kjer type: identification of a second locus

on chromosome 18q12.2-12.3. Arch. Ophthalmol. 117, 805–810.Kerrison, J.B., Miller, N.R., Hsu, F., Beaty, T.H., Maumenee, I.H., Smith,

K.H., Savino, P.J., Stone, E.M., Newman, N.J., 2000. A case-control

study of tobacco and alcohol consumption in Leber’s hereditary optic

neuropathy. Am. J. Ophthalmol. 130, 803–812.




Kirby, D.M., Kahler, S.G., Freckmann, M.L., Reddihough, D., Thorburn,

D.R., 2000. Leigh disease caused by the mitochondrial DNA G14459A

mutation in unrelated families. Ann. Neurol. 48, 102–104.

Kjer, P., Jensen, O.A., Klinken, L., 1983. Histopathology of eye, optic

nerve and brain in a case of dominant optic atrophy. Acta Ophthalmol.

61, 300–312.

Kozak, S.F., Inderlied, C.B., Hsu, H.Y., Heller, K.B., Sadun, A.A.,

1998. The role of copper on ethambutol’s antimicrobial action

and implications for ethambutol-induced optic neuropathy. Diagn.

Microbiol. Infect. Dis. 30, 83–87.

Leist, M., Single, B., Naumann, H., Fava, E., Simon, B., Kuhnle, S.,

Nicotera, P., 1999. Inhibition of mitochondrial ATP generation by nitric

oxide switches apoptosis to necrosis. Exp. Cell Res. 249, 396–403.

Lemasters, J.J., Qian, T., Bradham, C.A., Brenner, D.A., Cascio, W.E.,

Trost, L.C., Nishimura, Y., Nieminen, A.-L., Herman, B., 1999.

Mitohcondrial dysfunction in the pathogenesis of necrotic and apoptotic

cell death. J. Bioenerg. Biomembr. 31, 305–319.

Lessel, S., 1973. Toxic and deficient optic neuropathies. In: Smith, J.L.,

Glaser, J.S. (Eds.), Neuro-Ophthalmol Symposium at the University

of Miami and Bascom Palmer Eye Institute, Vol. 7. Mosby, St. Louis,

pp. 2–37.

Levin, L.A., Louhab, A., 1996. Apoptosis of retinal ganglion cells in

anterior ischemic optic neuropathy. Arch. Ophthalmol. 114, 488–491.Liu, B., Neufeld, A.H., 2000. Expression of nitric oxide synthase-2

(NOS-2) in reactive astrocytes of the human glaucomatous optic nerve

head. Glia 30, 178–186.

Lodi, R., Rinaldi, R., Gaddi, A., Iotti, S., D’ Alessandro, R., Scoz,

N., Battino, M., Carelli, V., Azzimondi, G., Zaniol, P., Barbiroli,

B., 1997a. Brain and skeletal muscle bioenergetic failure in familial

hypobetalipoproteinemia. J. Neurol. Neurosurg. Psychiatr. 62, 574–580.

Lodi, R., Taylor, D.J., Tabrizi, S.J., Kumar, S., Sweeney, M., Wood, N.W.,

Styles, P., Radda, G.K., Schapira, A.H.V., 1997b. In vivo skeletal

muscle mitochondrial function in Leber’s hereditary optic neuropathy

assessed by 31P magnetic resonance spectroscopy. Ann. Neurol. 42,

573–579.

Lodi, R., Cooper, J.M., Bradley, J.L., Manners, D., Styles, P., Tayor,

D.J., Schapira, A.H.V., 1999. Deficit of in vivo mitochondrial ATP

production in patients with Friedreich ataxia. Proc. Natl. Acad. Sci.U.S.A. 96, 11492–11495.

Lodi, R., Montagna, P., Cortelli, P., Iotti, S., Cevoli, S., Carelli, V.,

Barbiroli, B., 2000. “Secondary” 4216/ND1 and 13708/ND5 Leber’s

hereditary optic neuropathy mitochondrial DNA mutations do not

further impair in vivo mitochondrial oxidative metabolism when

associated with the 11778/ND4 mitochondrial DNA mutation. Brain

123, 1896–1902.

Ludwin, S.K., 1978. Central nervous system demyelination and

remyelination in the mouse. An ultrastructural study of cuprizone

toxicity. Lab. Invest. 39, 597–612.

Ludwin, S.K., 1995. Pathology of the myelin sheath. In: Waxman, S.G.,

Kocsis, J.D., Stys, P.K. (Eds.), The Axon: Structure, Function and

Pathophysiology. Oxford University Press, Oxford, pp. 412–437.

Majander, A., Finel, M., Savontaus, M.-L., Nikoskelainen, E., Wikstrom,

M., 1996. Catalytic activity of Complex I in cell lines that possessreplacement mutations in the ND genes in Leber’s hereditary optic

neuropathy. Eur. J. Biochem. 239, 201–207.

Melov S., Schneider J.A., Day B.J., et al. 1998. A novel neurological

phenotype in mice lacking mitochondrial manganese superoxide

dismutase. Nat. Genet. 18, 159–163.

Miller, N.R., 1982. Retrobulbar toxic and deficiency optic neuropathies. In:

Miller, N.R. (Ed.), Walsh and Hoyt’s Clinical Neuro-Ophthalmology,

4th Edition, Vol. 1. Williams and Wilkins, Baltimore, MD, pp. 289–307.

Nikoskelainen, E.K., 1994. Clinical picture of LHON. Clin. Neurosci. 2,

115–120.

Ochs, S., Hollingsworth, D., 1971. Dependence of fast axoplasmic trans-

port in nerve on oxidative metabolism. J. Neurochem. 18, 107–114.

Oppenheimer, D.R., 1976. Disease of the basal ganglia, cerebellum

and motor neurons. In: Blackwood, W., Corsellis, J.A.N. (Eds.),

Greenfield’s Neuropathology, 3rd Edition. Edward Arnold, London,

pp. 626–692.

Osuntokun, B.O., 1968. Ataxic neuropathy in Nigeria. A clinical and

electrophysiological study. Brain 91, 215–248.

Osuntokun, B.O., Osuntokun, O., 1971. Tropical amblyopia in Nigerians.

Am. J. Ophthalmol. 72, 708–716.

Ouahchi, K., Arita, M., Kayden, H., Hentati, F., Ben Hamida, M., Sokol,

R., Arai, H., Inoue, K., Mandel, J.L., Koenig, M., 1995. Ataxia

with isolated Vitamin E deficiency is caused by mutations in the

alpha-tocopherol transfer protein. Nat. Genet. 9, 141–145.

Pelloquin, L., Belenguer, P., Menon, Y., Ducommun, B., 1998.

Identification of a fission yeast dynamin-related protein involved in

mitochondrial DNA maintenance. Biochem. Biophys. Res. Commun.

251, 720–726.

Plant, G.T., Mtanda, A.T., Arden, G.B., Johnson, G.J., 1997. An epidemic

of optic neuropathy in Tanzania: characterization of the visual disorder

and associated peripheral neuropathy. J. Neurol. Sci. 145, 127–140.

Pryor, W.A., Arbour, N.C., Upham, B., Church, D.F., 1992. The inhibitory

effect of extracts of cigarette tar on electron transport of mitochondria

and submitochondrial particles. Free Radic. Biol. Med. 12, 365–372.

Puccio, H., Koenig, M., 2000. Recent advances in the molecular

pathogenesis of Friedreich ataxia. Hum. Mol. Genet. 9, 887–892.

Pulkes, T., Eunson, L., Patterson, V., Siddiqui, A., Wood, N.W., Nelson,I.P., Morgan-Hughes, J.A., Hanna, M.G., 1999. The mitochondrial

DNA G13513A transition in ND5 is associated with a LHON/MELAS

overlap syndrome and may be a frequent cause of MELAS. Ann.

Neurol. 46, 916–919.

Rigoli, L., Salpietro, D.C., Caruso, R.A., Chiarenza, A., Barbieri, I., 1999.

Mitochondrial DNA mutation at np 3243 in a family with maternally

inherited diabetes mellitus. Acta Diabetol. 36, 163–167.

Rizzo III, J.F., 1995. Adenosine triphosphate deficiency: a genre of optic

neuropathy. Neurology 45, 11–16.

Rizzo III, J.F., Lessell, S., 1993. Tobacco amblyopia. Am. J. Ophthalmol.

116, 84–87.

Rosenblum, J.S., Gilula, N.B., Lerner, R.A., 1996. On signal sequence

polymorphism and disease of distribution. Proc. Natl. Acad. Sci. U.S.A.

93, 4471–4473.

Rotig, A., Cormier, V., Chatelain, P., Francois, R., Saudubray, J.M., Rustin,P., Munnich, A., 1993. Deletion of mitochondrial DNA in a case of

early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram

syndrome, MI 222300). J. Clin. Invest. 91, 1095–1098.

Rotig, A., de Lonlay, P., Chretien, D., Foury, F., Koenig, M., Sidi,

D., Munnich, A., Rustin, P., 1997. Aconitase and mitochondrial

iron–sulphur protein deficiency in Friedreich ataxia. Nat. Genet. 17,

215–217.

Sabri, M.I., Ochs, S., 1972. Relation of ATP and creatine phosphate

to fast axoplasmic transport in mammalian nerve. J. Neurochem. 19,

2821–2828.

Sadun, A.A., 1998. Acquired mitochondrial impairment as a cause of

optic nerve disease. Trans. Am. Ophthalmol. Soc. 46, 881–923.

Sadun, A.A., Martone, J.F., 1995. Cuba: response of medical science to a

crisis of optic and peripheral neuropathy. Int. Ophthalmol. 18, 373–378.

Sadun, A.A., Sadun, F., 1996. Leber’s hereditary optic neuropathy.Ophthalmology 103, 201–202.

Sadun, A.A., Kashima, Y., Wurdeman, A.E., Dao, J., Heller, K., Sherman,

J., 1994a. Morphological findings in the visual system in a case of

Leber’s hereditary optic neuropathy. Clin. Neurosci. 2, 165–172.

Sadun, A.A., Martone, J.F., Reyes, L., Roman, G., Caballero, B., 1994b.

Epidemic of optic neuropathy in Cuba. JAMA 271, 663–664.

Sadun, A.A., Martone, J.F., Muci-Mendoza, R., Reyes, L., DuBois,

L., Silva, J.C., Roman, G., Caballero, B., 1994c. Epidemic optic

neuropathy in Cuba: eye findings. Arch. Ophthtalmol. 112, 691–699.

Sadun, A.A., Win, P.H., Ross-Cisneros, F.N., Walker, S., Carelli, V., 2000.

Leber’s hereditary optic neuropathy differentially affects smaller axons

in the optic nerve. Trans. Am. Ophthalmol. Soc. 98, 223–232.

Shimoda-Matsubayashi, S., Matsumine, H., Kobayashi, T., et al. 1996.

Structural dimorphism in the mitochondrial targeting sequence in the




human manganese superoxide dismutase gene: a predictive evidence

for conformartional change to influence mitochondrial transport and a

study of allelic association in Parkinson disease. Biochem. Biophys.

Res. Commun. 226, 561–565.

Shiraki, H., 1973. Neuropathy due to intoxication with anti-tuberculous

drugs from neuropathological viewpoint. Adv. Neurol. Sci. 17, 120.

Smiddy, W.E., Green, W.R., 1987. Nutritional ambyopia. A

histopathological study with retrospective clinical correlation. Graefe’s

Arch. Clin. Exp. Ophthalmol. 225, 321–324.

Smirnova, E., Shurland, D.-L., Ryazantsev, S.N., van der Bliek, A.M.,

1998. A human dynamin-related protein controls the distribution of

mitochondria. J. Cell Biol. 143, 351–358.

Smith, K.J., Kapoor, R., Felts, P.A., 1999. Demyelination: the role of

reactive oxygen and nitrogen species. Brain Pathol. 9, 69–92.

Sobel, R.S., Yanuzi, R.A., 1991. In: Singerman, L.J., Jampol, L.M.

(Eds.), Optic Nerve Toxicity: A Classification in Retinal and Choroidal

Manifestations of Systemic Disease. Williams and Wilkins, Baltimore,

MD, pp. 226–250.

Solberg, Y., Rosner, M., Belkin, M., 1998. The association between

cigarette smoking and ocular diseases. Surv. Ophthalmol. 42, 535–547.

Stewart, V.C., Sharpe, M.A., Clark, J.B., Heales, S.J.R., 2000.

Astrocyte-derived nitric oxide causes both reversible and irreversible

damage to the neuronal mitochondrial respiratory chain. J. Neurochem.75, 649–700.

Taylor, R.W., Birch-Machin, M.A., Schaefer, J., Taylor, L., Shakir, R.,

Ackrell, B.A.C., Cochran, B., Bindoff, L.A., Jackson, M.J., Griffiths,

P., Turnbull, D.M., 1996. Deficiency of complex II of the mitochondrial

respiratory chain in late-onset optic atrophy and ataxia. Ann. Neurol.

39, 224–232.

Tranebjaerg, L., Hamel, B.C., Gabreels, F.J., Renier, W.O., Van Ghelue,

M., 2000. A de novo missense mutation in a critical domain of the

X-linked DDP gene causes the typical deafness-dystonia-optic atrophy

syndrome. Eur J. Hum. Genet. 8, 464–467.

Traquair, H.M., 1930. Toxic amblyopia including retrobulbar neuritis.

Trans. Ophthalmol. Soc. UK 50, 351–385.

Tsao, K., Aitken, P.A., Johns, D.R, 1999. Smoking as an aetiological

factor in a pedigree with Leber’s hereditary optic neuropathy. Br. J.

Ophthalmol. 83, 577–581.

Van Landeghem, G.F., Tabatabaie, P., Kucinskas, V., Saha, N., Beckman,

G., 1999. Ethnic variation in the mitochondrial targeting sequence

polymorphism of MnSOD. Hum. Hered. 49, 190–193.

Vergani, L., Martinuzzi, A., Carelli, V., Cortelli, P., Montagna, P.,

Schievano, G., Carrozzo, R., Angelini, C., Lugaresi, E., 1995. MtDNA

mutations associated with Leber’s hereditary optic neuropathy: studies

on cytoplasmic hybrid (cybrid) cells. Biochem. Biophys. Res. Commun.

210, 880–888.

Victor, M., Dreyfus, P.M., 1965. Tobacco–alcohol amblyopia. Arch.

Ophthal. 74, 649–657.

Votruba, M., Moore, A.T., Bhattacharya, S.S., 1998. Clinical features,

molecular genetics, and pathophysiology of dominant optic atrophy. J.

Med. Genet. 35, 793–800.

Wong, A., Cortopassi, G., 1997. mtDNA mutations confer cellular sensiti-

vity to oxidant stress that is partially rescued by calcium depletion

and cyclosporin A. Biochem. Biophys. Res. Commun. 239, 139–145.

Wong, A., Yang, J., Cavadini, P., Gellera, C., Lonnerdal, B., Taroni, F.,

Cortopassi, G., 1999. The Friedreich’s ataxia mutation confers cellularsensitivity to oxidant stress which is rescued by chelators of iron and

calcium and inhibitors of apoptosis. Hum. Mol. Genet. 8, 425–430.

Yamakura, F., Taka, H., Fujimura, T., Murayama, K., 1998. Inactivation

of human manganese-superoxide dismutase by peroxynitrite is caused

by exclusive nitration of tyrosine 34 to 3-nitrotyrosine. J. Biol. Chem.

273, 14085–14089.

Yoon, Y.H., Jung, K.H., Sadun, A.A., Shin, H.-C., Koh, J.-Y., 2000.

Ethabutol-induced vacuolar changes and neuronal loss in rat retinal

cell culture: mediation by endogenous zinc. Toxicol. Appl. Pharmacol.

162, 107–114.

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