Associate editor: G. DustingEmerging Mitochondrial Therapeutic Targets in Optic Neuropathies
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.
References (371)
- et al.
The mitochondrial RNA-binding protein GRSF1 localizes to RNA granules and is required for posttranscriptional mitochondrial gene expression
Cell Metab
(2013) - et al.
Aerobic exercise effects on neuroprotection and brain repair following stroke: A systematic review and perspective
Neurosci Res
(2014) - et al.
Neurodegenerative disorders in humans: The role of glutathione in oxidative stress-mediated neuronal death
Brain Res Brain Res Rev
(1997) - et al.
Distribution and breakdown of labeled coenzyme Q10 in rat
Free Radic Biol Med
(2003) - et al.
Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations
Mitochondrion
(2007) - et al.
Specific elution from hydroxylapatite of the mitochondrial phosphate carrier by cardiolipin
Biochim Biophys Acta
(1984) - et al.
Choosing the right tool for the job: RNAi, TALEN, or CRISPR
Mol Cell
(2015) - et al.
RNA turnover in human mitochondria: More questions than answers?
Biochim Biophys Acta
(2010) - et al.
There is no evidence that mitochondria are the main source of reactive oxygen species in mammalian cells
Mitochondrion
(2012) - et al.
Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778, or 14484 Leber's hereditary optic neuropathy mitochondrial DNA mutation
J Biol Chem
(2000)
Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons
Curr Biol
Methylene blue improves brain oxidative metabolism and memory retention in rats
Pharmacol Biochem Behav
Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders
Biochim Biophys Acta
Optic nerve degeneration and mitochondrial dysfunction: Genetic and acquired optic neuropathies
Neurochem Int
Mitochondrial dysfunction as a cause of optic neuropathies
Prog Retin Eye Res
Optic neuropathy in Lhon and Leigh syndrome
Ophthalmology
Gluthatione level is altered in lymphoblasts from patients with familial Alzheimer's disease
Neurosci Lett
Effect of valproic acid on mitochondrial epigenetics
Eur J Pharmacol
Comparing EPI-743 treatment in siblings with Leber's hereditary optic neuropathy mt14484 mutation
Can J Ophthalmol
Forced exercise protects the aged optic nerve against intraocular pressure injury
Neurobiol Aging
Oxidative stress and mitochondrial dysfunction in glaucoma
Curr Opin Pharmacol
Dietary phytoestrogens and health
Phytochemistry
An acute intraocular pressure challenge to assess retinal ganglion cell injury and recovery in the mouse
Exp Eye Res
Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss
Mol Ther Methods Clin Dev
Neuroprotective effects of brimonidine treatment in a rodent model of ischemic optic neuropathy
Exp Eye Res
Peroxisome proliferator activated receptor-gamma agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: Effects on mitochondrial functions and differentiation
Exp Neurol
Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: A randomised, placebo-controlled trial
Lancet Neurol
Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction
Am J Hum Genet
Initial experience in the treatment of inherited mitochondrial disease with EPI-743
Mol Genet Metab
Oxygen delivery, consumption, and conversion to reactive oxygen species in experimental models of diabetic retinopathy
Redox Biol
Gene therapy for Leber hereditary optic neuropathy: Initial results
Ophthalmology
What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes
Mitochondrion
The neuro-ophthalmology of mitochondrial disease
Surv Ophthalmol
OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion
Cell
Ketogenic diets, mitochondria, and neurological diseases
J Lipid Res
Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: Rationale and comparative benefits
Mol Genet Metab
Does vigorous exercise have a neuroprotective effect in Parkinson disease?
Neurology
A mitochondrial therapeutic reverses visual decline in mouse models of diabetes
Dis Model Mech
OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28
Nat Genet
Oxidants, antioxidants, and the degenerative diseases of aging
Proc Natl Acad Sci U S A
Sequence and organization of the human mitochondrial genome
Nature
Histochemical localisation of mitochondrial enzyme activity in human optic nerve and retina
Br J Ophthalmol
Metformin directly acts on mitochondria to alter cellular bioenergetics
Cancer Metab
Mitochondrial dynamics—mitochondrial fission and fusion in human diseases
N Engl J Med
The neuroprotective actions of oestradiol and oestrogen receptors
Nat Rev Neurosci
Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and parkin
J Cell Biol
The pathways of mitophagy for quality control and clearance of mitochondria
Cell Death Differ
Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs
Nat Med
Advances in the genomics of common eye diseases
Hum Mol Genet
Idebenone treatment in patients with OPA1-mutant dominant optic atrophy
Brain
Cited by (64)
Low mitochondrial DNA copy number in buffy coat DNA of primary open-angle glaucoma patients
2023, Experimental Eye ResearchGlaucomatous optic neuropathy: Mitochondrial dynamics, dysfunction and protection in retinal ganglion cells
2023, Progress in Retinal and Eye ResearchGAD1 alleviates injury-induced optic neurodegeneration by inhibiting retinal ganglion cell apoptosis
2022, Experimental Eye ResearchCitation Excerpt :It has been reported that activation of SIRT1-regulated lipid metabolism can reverse certain features of optic nerve injury (Zhang et al., 2015b). In addition, alterations in glucose and mitochondrial metabolism have been associated with various neurodegenerative diseases, such as glaucoma, optic neuritis, and ischemic optic neuropathy (Lopez Sanchez et al., 2016; Maresca et al., 2013; Miller and Newman, 2004; Wang et al., 2018). Although these studies have improved our understanding of the pathogenesis, there is still a lack of systemic analysis of key regulators and pathways of optic neurodegeneration.