Elsevier

Pharmacology & Therapeutics

Volume 165, September 2016, Pages 132-152
Pharmacology & Therapeutics

Associate editor: G. Dusting
Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies

https://doi.org/10.1016/j.pharmthera.2016.06.004Get rights and content

Abstract

Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron—the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated.

Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function.

Introduction

Optic neuropathies are an important cause of chronic visual impairment and have in common the degeneration of retinal ganglion cells, whose axons form the optic nerve (Pascolini & Mariotti, 2012). Optic nerve dysfunction can present as the only manifestation of disease or it can be part of other systemic or neurological disorders; it can result from ischemic insults, damage by shock, toxins, radiation, trauma or hereditary factors (Miller & Newman, 2004). Hereditary optic neuropathies are a group of disorders that typically present as symmetric, bilateral and central visual loss. Clinical features include damage of the papillomacular nerve fiber bundle—a collection of retinal ganglion cell axons that carry information from the macula (the central retina) to the optic nerve and on to the brain, and central scotomas—areas where vision is lost surrounded by a field of preserved vision (Newman & Biousse, 2004). Autosomal dominant optic atrophy (ADOA) and Leber hereditary optic neuropathy (LHON) are the most common hereditary optic neuropathies. In both cases, mitochondrial dysfunction is directly related to visual impairment and therefore, the study of these diseases has greatly contributed to our understanding of the role of mitochondrial dysfunction in the etiology and molecular mechanisms of optic neuropathy.

Mitochondrial function is a central component of cellular health, as the organelles integrate the metabolic response to a variety of changes in the cellular and extracellular environments. Neurons rely on mitochondrial function for a number of essential processes, including ATP production, intracellular calcium homeostasis, generation of reactive oxygen species (ROS) and apoptosis signaling, and disruption of mitochondrial function and dynamics has been associated with a variety of neurodegenerative diseases (Cozzolino et al., 2015, Lionaki et al., 2015, Witte et al., 2014, Zorzano and Claret, 2015). The study of optic neuropathies is providing important insights into pathogenic mechanisms in neurodegenerative diseases and interventions that preserve or enhance mitochondrial function have become an important target for the development of therapeutic strategies. Here, we provide an overview of aspects of mitochondrial biology that are relevant to retinal ganglion cell function and optic neuropathies. Secondly, we cover the relevant molecular, physiological and clinical features of optic neuropathies with primary, secondary and suspected mitochondrial involvement, with a particular focus on LHON, ADOA and glaucoma. Finally, we discuss therapeutic strategies currently available for the treatment of mitochondrial dysfunction in optic neuropathies, including the beneficial potential and risks associated with the use of emerging technologies.

Mitochondria produce most of the energy necessary for cellular function through oxidative phosphorylation (OXPHOS). Neurons in particular need to maintain a constant energy supply and mitochondria are responsible for generating most ATP in the axon (Zala et al., 2013). The OXPHOS system consists of five multimeric protein complexes—nicotinamide adenine dinucleotide hydrogen (NADH): ubiquinone oxidoreductase (complex I), succinate dehydrogenase (complex II), ubiquinol cytochrome c reductase (complex III), cytochrome c oxidase (complex IV) and the ATP synthase (complex V), located within the inner mitochondrial membrane. ATP is produced by the shuttling of electrons by carrier molecules along the respiratory complexes, which is accompanied by the pumping of protons from the mitochondrial matrix into the intermembrane space. Acetyl-CoA, an intermediate product of glycolysis and β-oxidation, is metabolized by the citric acid cycle to the reducing equivalents NADH and flavin adenine dinucleotide dihydrogen (FADH2) (DiMauro & Schon, 2003). Electrons are transferred via NADH and FADH2 into complexes I and II, respectively. Coenzyme Q10 (CoQ10) and cytochrome c are two additional electron carriers that undergo reduction–oxidation (redox) reactions to enable the transfer of electrons. Complex II is a second entry point for electrons directly to CoQ10, which delivers electrons via complex III and cytochrome c to the final electron acceptor, complex IV. Electrons lose energy after each transfer step, which is harnessed in complexes I, III and IV, and coupled to the movement of protons from the matrix to the intermembrane space. This electrochemical gradient across the inner mitochondrial membrane is used by the ATP synthase to catalyze the conversion of ADP and inorganic phosphate to ATP (Smeitink et al., 2001).

Mitochondria are thought to be the main intracellular source of ROS as a by-product of OXPHOS (Murphy, 2009). ROS include oxygen radicals and derived oxidizing molecules such as H2O2, which are highly reactive molecules that interact with and damage nucleic acids, proteins, carbohydrates and lipids and therefore, under normal physiological conditions, ROS production is tightly regulated (Bedard and Krause, 2007, Ray et al., 2012). Electron leakage out of the electron transport chain at complexes I and III results in the release of superoxide in the mitochondrial matrix and intermembrane space (Murphy, 2009). Mitochondrial complex II and other mitochondrial and cellular enzymes, such as nicotinamide adenine dinucleotide phosphate-oxidase, also contribute to ROS generation in cells (Bedard and Krause, 2007, Brown and Borutaite, 2012). In a physiological range, ROS play an important role in retrograde redox signaling from the organelle to the cytosol and nucleus (Murphy, 2009). However, in disease models, increased mitochondrial ROS production has been linked to chronic oxidative damage and has been shown to induce cell death and neurotoxicity (Shukla et al., 2011, Uttara et al., 2009, Valencia and Moran, 2004).

The large majority of proteins involved in OXPHOS and other mitochondrial functions are encoded in the nucleus, synthesized in the cytosol and transported into the organelle. It is estimated that the mitochondrial proteome consists of between 1000 and 1500 proteins and among them, only a minute fraction are encoded by the mitochondrial genome (Calvo & Mootha, 2010). Human mitochondrial DNA (mtDNA) is a circular 16,569 base pair, double-stranded genome located in the mitochondrial matrix (Anderson et al., 1981). It encodes 13 essential protein subunits of the respiratory complexes I, III, IV and ATP synthase (Fig. 1). The genes encoding complex II subunits are exclusively nuclear. In addition to mRNAs, mtDNA encodes 2 rRNAs and 22 tRNAs required for the translation of mtDNA-encoded mRNAs within the matrix (Smeitink et al., 2001). MtDNA is a very compact molecule devoid of introns and contains only a 1.1 kb non-coding region, known as the D-loop, involved in mtDNA transcription and replication. Despite the apparent simplicity of the mitochondrial genome, recent studies have revealed a surprising complexity in its expression and regulation, highlighting the importance of post-transcriptional processes in mitochondrial gene expression and function (Antonicka et al., 2013, Borowski et al., 2010, Mercer et al., 2011, Sanchez et al., 2011, Sasarman et al., 2010).

MtDNA is exclusively transmitted through maternal inheritance and does not undergo germ line recombination (Giles et al., 1980, Hagstrom et al., 2014, Sato and Sato, 2013). It is present in hundreds to thousands of copies in each cell and unlike nuclear DNA (nDNA), it replicates continuously in both mitotic and post-mitotic cells, such as neurons. In the majority of cases, the sequence of each copy of mtDNA is identical, a state known as homoplasmy. However, the high copy number of mtDNA in cells opens the possibility to heteroplasmy, a situation in which not all copies of mtDNA are identical, resulting in the coexistence of wild-type and mutant DNA within a single mitochondrion and potentially between cells. Heteroplasmy can result from inefficient repair mechanisms in mtDNA, the oxidative environment in the mitochondrial matrix and constant DNA replication in the organelle, which makes somatic mtDNA mutations frequent (Wallace & Chalkia, 2013). Although low levels of heteroplasmy are common in normal individuals and vary markedly from tissue to tissue, mtDNA heteroplasmy is also associated with a variety of diseases (Wallace & Chalkia, 2013).

Section snippets

Mitochondrial dysfunction and neurodegeneration

It is well established that mitochondrial function is essential for neuronal growth, function, maintenance and survival. Indeed, disruption of mitochondrial function and dynamics is a central feature of neurodegenerative disorders (Cozzolino et al., 2015, Lionaki et al., 2015, Witte et al., 2014, Zorzano and Claret, 2015) and has been clearly associated with the development and progression of optic neuropathies (Carelli et al., 2004, Newman and Biousse, 2004, Noval et al., 2012, Yu-Wai-Man et

Current mitochondrial therapeutic targets

Retinal ganglion cell death is the final common pathway that leads to loss of vision in most optic neuropathies. However, there is evidence of the existence of a window of time prior to cell death during which dysfunction may still be reversible or arrested, in particular in diseases such as glaucoma (Crowston et al., 2015, Morgan, 2012) and LHON. Clinical approaches for the treatment of optic neuropathies are currently limited and most treatment approaches are supportive and focus on

Genetic therapy

Emerging targets for the treatment of mitochondrial optic neuropathies include the use of molecular tools to correct or “edit” the genetic abnormality responsible for the disease. Gene therapy consists in inactivating or replacing a mutated gene with a healthy copy or introducing a new gene into the body to prevent disease. A variety of gene therapy approaches have been pursued for mtDNA-related diseases because of the lack of effective drug-based treatments, however, most approaches are

Stem cell therapy for retinal ganglion cell regeneration and disease modeling

Insights into the potential of stem cell therapy as a treatment for damaged retinal ganglion cells has largely relied on studies using mesenchymal stem cells (MSCs) derived from bone marrow (Johnson et al., 2010, Levkovitch-Verbin et al., 2010, Yu et al., 2006). MSCs are multipotent and have the ability to differentiate into a variety of cells, including osteoblasts, chondrocytes, adipocytes and stromal cells. Neuroprotective effects have been reported following MSC transplantation in a variety

Exercise, caloric restriction and optic nerve protection

Caloric restriction and exercise have long been recognized for their lifespan-extending and neuroprotective properties against injury, oxidative damage and inflammation (Ahlskog, 2011, Austin et al., 2014, Maalouf et al., 2009, Mair and Dillin, 2008). Interestingly, reports associate caloric restriction or consumption of a ketogenic diet—high fat and low carbohydrate intake—with a significant improvement in metabolic function (Gano et al., 2014). The mechanism that mediates protection in the

Conclusion

Experimental evidence highlights an important role for mitochondrial dysfunction in retinal ganglion cell impairment in a variety of optic neuropathies. Common features of optic neuropathy include OXPHOS defects, chronic oxidative stress and altered mitochondrial transport and quality control processes. We and others hypothesize that primary or secondary mitochondrial dysfunction is a contributing factor to the pathogenesis of glaucoma and that mitochondrial dysfunction with aging may be

Conflict of interest

The authors declare that there are no conflicts of interest.

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