Mitochondrial dysfunction in optic neuropathies: animal models and therapeutic options : Current Opinion in Neurology

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NEURO-OPHTHALMOLOGY AND NEURO-OTOLOGY: Edited by François-Xavier Borruat and Michael Strupp

Mitochondrial dysfunction in optic neuropathies

animal models and therapeutic options

Carelli, Valerioa,b,c; La Morgia, Chiaraa,b; Sadun, Alfredo A.c

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Current Opinion in Neurology: February 2013 - Volume 26 - Issue 1 - p 52-58
doi: 10.1097/WCO.0b013e32835c5f0b
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Mitochondrial optic neuropathies (MONs) are now recognized as a wide category of disorders associated by the common pattern of retinal ganglion cell (RGC) dysfunction and loss, with particular predilection for the small RGCs that give origin to the papillomacular bundle, and leading to loss of central vision (for reviews see [1,2]). The two major nonsyndromic and genetically determined forms of MON are dominant optic atrophy (DOA) and Leber's hereditary optic neuropathy (LHON), respectively associated with mutations in the nuclear OPA1 gene that encodes for a mitochondrial-targeted protein and mutations in the mitochondrial DNA (mtDNA) that affect different subunit genes of the respiratory chain complex I [1,2]. Other MONs may be determined by environmental or iatrogenic causes, such as tobacco–alcohol amblyopia, ethambutol or linezolid-induced optic neuropathies, or may be part of more complex genetic neurological syndromes such as Leigh syndrome, bilateral striatal necrosis, mitochondrial encephalomyopathy, lactic acidosis, stroke-like (MELAS) syndrome, DOA ‘plus’, Charcot–Marie–Tooth disease, Costeff syndrome, Friedreich ataxia or spastic paraplegia (for reviews see also [3,4]).

Box 1:
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Respiratory complex I dysfunction, leading to energy deficiency and increased production of reactive oxygen species (ROS), and abnormal mitochondrial network dynamics, seems to play a major role for the specific vulnerability of RGCs to mitochondrial disease. This vulnerability is probably related to the exceedingly long segment of the retinal nerve fibre that is unmyelinated as it runs in the inner retina, and then turns at the optic nerve head before penetrating the lamina cribrosa, after which myelination starts [1,2]. This anatomical feature implies an uneven energy requirement (continuous vs saltatory conduction of action potentials) and consequently uneven mitochondrial distribution along these axons. Thus, all these metabolic, anatomical and functional factors contribute to setting a threshold for RGC loss, most probably by apoptotic death [1–4].

In this review, we will focus on DOA and LHON, considering in particular the issue of animal models that have been generated and studied to understand the pathophysiology of these disorders, as well as to test therapeutic options. Considering the topic of therapy, we will also review the most recent advances on therapies proposed for patients with DOA and LHON, including the first clinical trials in humans.


Two mouse models, carrying mutant OPA1, have been generated in 2007 to study the details of the pathogenic mechanisms of RGC loss in DOA, and many studies have characterized these animals (for a review see [5▪]). Both models have been generated by screening an ENU-mutagenized DNA library of mouse DNA, and both recapitulate genetic defects inducing haploinsufficiency – the B6;C3-Opa1Q285STOP mutant mouse [6] and the B6;C3-Opa1329-355del mutant mouse – leading to a splice error with skipping of exon 10, which ultimately causes an in-frame deletion of 27 amino acid residues in the dynamin GTPase domain [7]. Both models are characterized by about 50% reduction of OPA1 expression, and in both cases the homozygous condition is embryonically lethal, emphasizing the crucial role played by OPA1 during foetal development.

In heterozygous animals, both models induce a usually mild, age-dependent ocular phenotype with well documented evidence of RGC dysfunction, but limited loss of RGCs, clearly documented only for the B6;C3-Opa1329-355del mutant mouse [5▪,6,7]. At histopathology, both models showed some degenerative features in the optic nerves, including demyelination, various degrees and quality (dark and watery) of axonal degeneration and ultrastructural abnormalities of mitochondria. Interestingly, increased autophagy in RGCs was reported for the B6;C3-Opa1Q285STOP mutant mouse, suggesting that defective fusion leads to an increased number of depolarized mitochondria, which are then targeted to autophagic elimination [8]. Ultimately, the phenotype in both models resembles but does not completely match the human disease, which is always characterized by loss of RGCs and optic nerve atrophy. However, DOA may show a wide range of clinical severity, going from severe congenital cases to very mild, subclinical disease, disclosed only by accurate ophthalmological investigations, similar to the murine models [1,2]. Interestingly, careful systemic examination of both models revealed mild neuromuscular signs and symptoms, such as decreased locomotor activity, abnormal clutching reflex and tremor, just as seen in a small subset of human patients in the clinical spectrum ranging from DOA to DOA ‘plus’ [9].

Most recently, interesting results have been obtained by studying the retinal RGC synaptic connectivity in the B6;C3-Opa1Q285STOP mutant animals, thus looking at their dendrites instead of focusing on the axons [10▪,11▪]. This counterintuitive approach has been fruitful in showing that the earliest pathological changes in RGCs occur in the form of dendritic pruning and marked reduction in synaptic connectivity, qualifying as a dendropathy [10▪,11▪]. This should not be surprising, considering previous studies demonstrating the crucial role played by OPA1 and mitochondrial fusion in maintaining dendrites and their synapses [12]. Thus, a new perspective on the sequence of pathologic events has been provided by these studies, reflecting the complex molecular basis underlying RGC dysfunction and loss.

Modelling of DOA has also been carried out in Drosophila, emphasizing the role played by increased ROS production in leading to the pathologic phenotype and showing how this could be partially neutralized by antioxidant therapy [13]. This latter result has been instrumental in prompting the first therapeutic approaches in human patients with DOA (see section on quinone therapies). Further studies on this OPA1 mutant Drosophila model showed an age-dependent multisystemic disorder, resembling the syndromic forms of DOA ‘plus’ [9,14].


Historically, major difficulties have been encountered in modelling molecular defects affecting mtDNA, given the lack of techniques allowing the import of this multicopy genome within mitochondria, as well as of vectors able to insert DNA constructs within the multitude of mtDNA molecules. A few such animal models of mtDNA defects (mito-mice) have been created with ingenious strategies (for a review see [15▪]), but ocular characterization has been minimal in these animal studies [16].

Different approaches have been adopted to reproduce RGC selective disease in rodents, in the attempt to recapitulate LHON. Biochemical approaches included the use of the classic complex I inhibitor rotenone, directly injected through the vitreous [17], thus exposing the RGCs that are close to the vitreous in the inner retina. Recently, a more sophisticated approach has been achieved, by injecting slowly releasing, rotenone-loaded microspheres directly into the optic layer of the rat superior colliculus, which led to rotenone uptake at the optic nerve axonal terminals and its retrograde transport [18]. By these means, the authors successfully induced RGC cell death and optic atrophy, which in many respects mimicked LHON, particularly the optic nerve histopathology [18]. The authors exploited this animal model to show feasibility and efficiency of xenotopic expression of the yeast alternative NADH dehydrogenase, Ndi1, in preserving RGCs from cell death and restoring visual function. The injection of an adeno-associated virus (AAV, type 5) carrying the mitochondrially targeted NDI1 gene (rAAV5-NDI1) was first attempted through the vitreous, but due to unsatisfactory efficiency, the rAAV5-NDI1 was then administered by the same route as rotenone, in the superior colliculus [18]. The single subunit Ndi1, once in the mitochondria, directly shuttles electrons to ubiquinone, bypassing complex I and restoring electron flow downstream to complex III, but missing the energy conserving function due to lack of the proton pumping translocating site [19]. This approach, which has been previously shown to be effective in vitro, ameliorating ATP synthesis and respiration, as well as limiting ROS production by mutant complex I [19], is now applied in vivo in this rodent model of LHON [18]. More recently, a different research group successfully applied the same trans-kingdom therapeutic approach to the more traditional rotenone-induced murine model of LHON-like optic neuropathy, by directly delivering through the vitreous both the rotenone toxicant and the gene therapy [20].

The most studied gene therapy approach in LHON has been the nuclear allotopic expression of mtDNA-encoded genes, which once recoded to be expressed as a nuclear gene and adequately targeted for mitochondrial protein import can be delivered to cells by AAV vectors [21,22]. In recent years, two groups have used this approach to generate a mouse model of LHON by the topical, intravitreous delivery of an AAV vector carrying the mutant 11778/ND4 human recoded gene, as well as to provide the rescue of RGCs through the delivery of an AAV vector containing the wild-type ND4[23,24]. These experiments led to currently pending human clinical trials that will soon start by using this approach in LHON patients [25,26]. However, the literature reflects a lively discussion on the feasibility and efficiency of this approach, and some problems remain to be resolved [27,28].

Recent studies have attempted to take one step further on the issue of gene therapy for mtDNA-based human disorders, with direct immediate application to LHON, taking advantage of the fact that the retina is a fairly convenient tissue for gene therapy due to its direct accessibility. Two studies [29▪▪,30▪▪] are potential breakthroughs, by showing the successful direct delivery within mitochondria of the whole mtDNA in one case or of an AAV vector containing the mtDNA-encoded ND4 subunit gene in the other case. The first study adopted a strategy on the basis of direct delivery to cells, and then importing within their mitochondria of mtDNA molecules complexed with recombinant human mitochondrial transcription factor A (rhTFAM), the major mtDNA nucleoid coating protein. This strategy applied to LHON cybrids led to activation of mitochondrial biogenesis, which in turn improved mitochondrial respiration, rescuing the pathologic cell phenotype [29▪▪]. The second study [30▪▪] used a different strategy based on redirecting to mitochondrial import an AAV vector containing the human ND4 subunit gene, having fused the adeno-associated capsid VP2 with a mitochondrial targeting sequence. The construct was engineered by inserting the heavy strand promoter to the ND4 subunit gene in order to be expressed. The authors showed that this approach led to mitochondrial internalization of the AAV vector, and expression of its genetic content was able to complement the pathologic phenotype both in vitro and in a mouse model of optic atrophy done by allotopic expression of the human 11778/ND4 mutant subunit [30▪▪]. The same group also did the reverse experiment by delivering the 11778/ND4 mutant subunit to the mice eye with the same approach as before, demonstrating that in this case, the mutant gene induced an optic neuropathy recapitulating the hallmarks of LHON [31]. These studies contradict the conventional wisdom that mtDNA cannot be delivered to mitochondria and introduced a very important technical achievement in the field of mitochondrial medicine. However, both studies need to be considered with caution as we await confirmatory experiments by independent investigators that should also clarify the many unclear elements regarding the exact mechanism underlying the mitochondrial delivery of mtDNA or AAV construct containing mtDNA-encoded genes. Furthermore, as the authors freely acknowledge, it remains unclear whether the possible homologous recombination between the human ND4 subunit and the mouse mitochondrial genome actually occurred in their experiments [30▪▪].

Overall, notwithstanding all the models above described, a true genetic mouse model of LHON should demonstrate the presence of a homoplasmic mtDNA complex I mutation in all tissues of the animal, with a selective expression of the disease in the RGCs, and this has not yet been accomplished. Yokota et al. [32] reported to have successfully generated such an animal carrying the G13997A mtDNA mutation affecting complex I. Even at 3 months, these animals were shown to have defective complex I function and high lactate levels. However, these animals did not display any clinical phenotype; in particular, they did not develop optic neuropathy as in LHON [32]. The G13997A mutation is equivalent to the human ND6 G14600A (P25L) mutation, which was reported in a case of Leigh syndrome, whose heteroplasmic maternal aunt suffered LHON-like optic atrophy and cerebellar ataxia [33]. A second group of investigators have also generated a mito-mouse carrying this same homoplasmic mutation in all tissues and studied animals at older ages (14 and 24 months) [34▪▪]. The histological characterization of the retina and optic nerves from these animals showed all the hallmarks of human LHON, including increased number of abnormal mitochondria within axons, mitochondrial degeneration in demyelinated axons, axonal swelling followed by degeneration and preferential involvement of the smallest calibre axons. At 24 months, there was a reduction of about 30% of the optic nerve axons [34▪▪]. Thus, a mouse model of LHON reproducing genetic, biochemical and histological hallmarks of this disease has been finally established and this provides a platform for further studies that may elucidate some of the unexplained features of human LHON and allow for the proper testing of potential therapies.


At least two other animal models deserve to be mentioned because of their potential in understanding RGC disease that is due to different types of mitochondrial dysfunction. In both cases, the optic neuropathy is one of the clinical features of a syndromic multisystem disease.

The first mouse model, previously described as Harlequin mouse [35], is generated by the loss of function of apoptosis-inducing factor (AIF) and its clinical phenotype resembles the human complex I deficiency, including RGC loss and consequent optic atrophy [36▪▪]. The histopathological assessment of the optic nerves revealed progressive RGC loss in the retina with a concurrent decrease of axonal density in optic nerve cross-sections, accompanied by demyelination and reactive gliosis. The authors exploited this clear-cut model of mitochondrial optic neuropathy that was due to a loss of function of a nuclear gene, AIF, to test the feasibility and efficacy of gene replacement therapy. They delivered, by intravitreal injection, the full-length, open reading frame and the 3’-untranslated region of the AIF1 gene contained in an AAV2 vector [36▪▪]. This is the first proof of principle that replacement gene therapy is feasible for nuclear gene defects leading to RGC death. This approach has been successfully used in humans in a retinal dystrophy, Leber's congenital amaurosis, in which the delivery of the viral vector was on the choroidal side of the retina near the photoreceptors in the outer retina, and this is more difficult than the intravitreal route that would be more appropriate for access to RGCs [37]. This proof of principle may have future application in human optic nerve disorders that are due to nuclear genetic defects such as DOA with OPA1 mutations. In this latter case, it will be essential to first elucidate the functional role played by the eight OPA1 isoforms to identify which one may have the best therapeutic potential.

The second mouse model is the B6;C3-Opa3L122P mouse that carries a missense mutation in exon 2 (c.365T>C; p.L122P) of the Opa3 gene, which recapitulates the pathological features of recessive 3-methylglutaconic aciduria type III, the Costeff syndrome: impaired visual function consistent with loss of RGCs and degeneration of the optic nerve, elevated serum organic acids, dilated cardiomyopathy, extrapyramidal dysfunction and gross neuromuscular defects [38,39]. Another study [40] focused on the eye of this OPA3 mouse model and showed that the splice variants Opa3a and Opa3b were expressed in the lenses and the retinas in the Opa3−/− mice, with predominant expression of the Opa3a isoform. Opa3 protein increased as the lenses aged, suggesting the importance of this protein for the development of cataract in the DOA and cataract phenotype, that is, autosomal dominant optic atrophy and cataract (ADOAC) [41]. OPA3 localized to mitochondria in all analysed tissues from the Opa3−/− mice, inducing altered mitochondrial cristae morphology in the retina [40]. Despite these studies, the characterization of OPA3 function remains poor at this point, as well as the pathopysiology of Costeff syndrome and ADOAC, and further investigations on this Opa3−/− mouse model are warranted.


Coenzyme Q-10 (CoQ) has been used as one of the few therapeutic options in mitochondrial disorders [42]. CoQ is a cofactor that shuttles electrons from complexes I and II to complex III, being potentially useful in bypassing the complex I defect characterizing LHON and DOA. Anecdotal reports of CoQ treatment in LHON have been published [43], but clinical trials in large cohorts of patients are still lacking. One likely limitation of treatment with CoQ relates to its lipophilic nature, with a possible poor delivery to mitochondria after oral administration [42].

Idebenone, a quinone analogue of CoQ [42], was first reported as possibly effective in LHON about two decades ago [44]. This was followed by a few other anecdotal reports [45,46]. In 2011, the results of the first controlled clinical trial with idebenone in LHON were published [47▪▪], as well as a retrospective evaluation of a large series of LHON-treated patients compared with untreated cases [48▪▪]. Both studies supported the partial effectiveness of idebenone in ameliorating the final outcome in LHON patients, mostly by increasing the rate of visual recovery, especially in the early-treated patients [49,50]. Recent studies have clarified some aspects on how idebenone works in the cell, and in particular within mitochondria, showing that to be effective and most importantly not toxic idebenone needs to be maintained in the reduced state [51–53]. This task appears to be performed in the cell by NAD(P)H:quinone oxidoreductase 1 (NQO1) [51].

A new molecule, an α-tocotrienol quinone coded as EPI-743, has been reported to exert a potent antioxidant effect in vitro[54]. EPI-743, in a small, open-label trial with five consecutively treated LHON patients, arrested disease progression and reversed, to a variable extent, some vision loss in all except one patient, showing promising results that need to be confirmed by a properly designed clinical trial [55].

Defective complex I-driven ATP synthesis has also been documented in fibroblasts derived from DOA patients carrying OPA1 mutations leading to haploinsufficiency [56]. This observation suggested at least one common pathogenic mechanism between LHON and DOA, which prompted the recent use of idebenone also in DOA patients [57▪▪]. This small, open-label clinical trial included seven consecutive DOA patients who were treated for at least 1 year with idebenone, showing some improvement in visual function in five of them [57▪▪]. These results are particularly promising in consideration of the lack of spontaneous visual recovery in DOA patients, though this study needs to be validated by a properly designed clinical trial.


Recent studies have emphasized the relationship between respiratory defects, ROS production and compensatory activation of mitochondrial biogenesis, a strategy adopted by cells in mitochondrial disorders [58,59]. Successful compensation by mitochondrial biogenesis has been shown in a mouse model with muscle-specific TFAM deficiency, in which ragged red fibres, a hallmark of mitochondrial myopathy, were reproduced [60]. Thus, the activation of mitochondrial biogenesis as a possible therapeutic strategy for mitochondrial disorders has recently drawn a considerable interest [61,62]. In particular, this strategy may be sufficient to compensate the mild mitochondrial defect in MON, in which spontaneously occurring slight increases of mitochondrial biogenesis may be further enhanced by specific therapies [63,64]. Experiments in vitro and in animal models have used some old drugs, such as bezafibrate and rosiglitazone, and also novel molecules such as resveratrol and AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) [65]. It has been shown recently that oestrogens ameliorate the biochemical cellular defect in LHON cybrids, again by activating mitochondrial biogenesis, suggesting the potential therapeutic use of oestrogen-like molecules [66▪▪]. We look forward to upcoming clinical trials in human patients to explore this therapeutic approach.


We are witnessing major advancements in the understanding of MON. Major progress includes the possibility of delivering mtDNA or vectors containing mtDNA genes directly into mitochondria, and the establishment of faithful animal models, which will be further exploited for understanding the pathophysiology of MON and for testing therapeutic options.

Note added in proof

While this review was in press, a study documenting the protective effect of idebenone on RGC loss in a rotenone-based mouse model of LHON was published [67].


Research on MON in Italy (V.C.) is supported by Telethon-Italy, grants GPP1005, GGP06233 and GGP11182 and by European consortium on optic atrophies. Research on MON in the USA (A.A.S.) is supported by Research to Prevent Blindness, International Foundation for Optic Nerve Diseases, Struggling Within Leber's, The Poincenot Family and the National Eye Institute Grant EY03040.

Conflicts of interest

There are no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 105–106).


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This study documents for the first time the creation of a faithful genetic mtDNA-based model of LHON in mouse, showing clinical, biochemical and anatomical features closely reproducing the human disease.

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See [48▪▪].

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This study, albeit limited to seven patients, provides the first evidence that idebenone may be a therapeutic option also for DOA patients.

58. Moreno-Loshuertos R, Acín-Pérez R, Fernandez-Silva P, et al. Differences in reactive oxygen species production explain the phenotypes associated with common mouse mitochondrial DNA variants. Nat Genet 2006; 38:1261–1268.
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64. Sitarz KS, Almind GJ, Horvath R, et al. OPA1 mutations induce mtDNA proliferation in leukocytes of patients with dominant optic atrophy. Neurology 2012; 79:1515–1517.
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66▪▪. Giordano C, Montopoli M, Perli E, et al. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. Brain 2011; 134:220–234.

This study demonstrates that oestrogens directly influence mitochondrial metabolism by activating mitochondrial biogenesis, compensating the LHON biochemical defect. These findings prove a potential explanation for male prevalence in LHON and suggest a possible therapeutic option.

67. Heitz FD, Erb M, Anklin C, et al. Idebenone protects against retinal damage and loss of vision in a mouse model of Leber's hereditary optic neuropathy. PLoS One 2012; 7:e45182.

animal models; dominant optic atrophy; Leber's hereditary optic neuropathy; mitochondria; therapy

© 2013 Lippincott Williams & Wilkins, Inc.