Eye and Brain Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Mitochondrial disorders and the eye Nicole J Van Bergen Abstract: The clinical significance of disturbed mitochondrial function in the eye has emerged Rahul Chakrabarti since mitochondrial DNA (mtDNA) mutation was described in Leber’s hereditary optic Evelyn C O’Neill neuropathy. The spectrum of mitochondrial dysfunction has become apparent through increased Jonathan G Crowston understanding of the contribution of nuclear and somatic mtDNA mutations to mitochondrial Ian A Trounce dynamics and function. Common ophthalmic manifestations of mitochondrial dysfunction include optic atrophy, pigmentary retinopathy, and ophthalmoplegia. The majority of patients Centre for Eye Research Australia, with ocular manifestations of mitochondrial disease also have variable central and peripheral Department of Ophthalmology, University of Melbourne, Victoria, nervous system involvement. Mitochondrial dysfunction has recently been associated with age- Australia related retinal disease including macular degeneration and glaucoma. Therefore, therapeutic For personal use only. targets directed at promoting mitochondrial biogenesis and function offer a potential to both preserve retinal function and attenuate neurodegenerative processes. Keywords: mitochondria, disease, retina, eye, aging, neuroprotection Introduction The importance of optimal mitochondrial function for ocular health has been clear since the first mitochondrial DNA (mtDNA) disease mutation was discovered in Leber’s hereditary optic neuropathy (LHON).1 Other syndromic mtDNA diseases often have retinal involvement together with variable central nervous system pathology. A second Eye and Brain downloaded from https://www.dovepress.com/ by 54.191.40.80 on 20-Jun-2017 major disease grouping classified as “mitochondrial” disease is due to mutations in nuclear genes that result in mitochondrial dysfunction, including autosomal dominant optic atrophy (ADOA), Friedreich’s ataxia, Mohr-Tranebjaerg syndrome, and Char- cot-Marie-Tooth disease subtype CMT2A. These disorders commonly display optic neuropathy together with variable central nervous system involvement, and have been described in detail elsewhere.2,3 The neuro-ophthalmic manifestations of mitochondrial diseases have also been extensively reviewed by Newman et al.4 With our increased awareness, the spectrum of “mitochondrial disease” has expanded from describing mtDNA disease, to diseases secondary to improper function of any protein located in the organelle resulting in abnormal mitochondrial function. Correspondence: Ian A Trounce Centre for Eye Research Australia, Moreover, mitochondrial dysfunction is attracting growing attention as contributing Department of Ophthalmology, to the pathogenesis of many common sporadic age-related neurodegenerative University of Melbourne, Royal Victorian diseases, including Alzheimer’s disease, Parkinson’s disease, and glaucoma.5–8 While Eye and Ear Hospital, 32 Gisborne Street, East Melbourne, Victoria, Australia 3002 controversy exists as to whether mitochondrial impairment in these diseases is primary Tel +613 9929 8160 or secondary to upstream disease pathways, the mitochondrion is emerging as pivotal Fax +613 9662 3859 Email [email protected] in disease pathogenesis and as an important target of novel therapeutic approaches. submit your manuscript | www.dovepress.com Eye and Brain 2011:3 29–47 29 Dovepress © 2011 Van Bergen et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/EB.S16192 which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 1 / 1 Van Bergen et al Dovepress The eye can therefore be viewed as a model for energetic mtDNA and oxidative phosphorylation impairment in the central nervous system, often being the Mitochondrial DNA is a circular, double-stranded DNA first neuronal tissue affected by mitochondrial failure. The molecule residing in the mitochondrial matrix. It is the eye may become a model of therapeutic experimentation, only non-nuclear DNA in mammalian cells, coding 13 with direct implications for degenerative brain diseases. of the approximately 90 protein subunits of the oxida- Here we discuss the variable ocular involvement in inherited tive phosphorylation complexes. The majority of the mitochondrial diseases, the possible role of mitochondrial protein machinery required for mitochondrial replication, dysfunction in the common age-related ophthalmic diseases, transcription, translation, and assembly is encoded by including glaucoma and age-related macular degeneration, nuclear genes,12 whilst mtDNA contributes a 12SrRNA, and finally we review emerging therapeutic approaches to a 16SrRNA, and 22 tRNAs.13 The oxidative phosphory- improving mitochondrial function. lation pathway produces the majority of ATP for use in all cells. It comprises five multisubunit enzyme com- Mitochondria and neurons plexes: complex I, the NADH:ubiquinone oxidoreductase The accurate cliché of the mitochondrion being the (.45 subunits, seven from mtDNA); complex II, the “powerhouse of the cell” has been complicated by the growing succinate dehydrogenase (four nuclear subunits); com- recognition that this organelle is a central node of key cellular plex III, the ubiquinone:cytochrome c oxidoreductase pathways governing not only intermediary metabolism, but (11 subunits, one from mtDNA); complex IV, cytochrome c also stress responses and cell death.9 We first consider the oxidase (13 subunits, three from mtDNA); and complex V, traditional energetic role of the organelle and the effects on H+ATPsynthase (15 subunits, two from mtDNA). Electrons retinal neurons resulting from mtDNA mutations. enter the respiratory chain at either complex I from the oxi- Neurons require large amounts of adenosine triphosphate dation of NADH or complex II from oxidation of FADH2. (ATP) supplied by the mitochondria. Energetic needs are As pairs of electrons travel via redox centers in complexes greatest at dendritic regions where ATP-dependent ion I, III, and IV, protons are extruded into the intermembrane For personal use only. pumping reinstates the plasma membrane electrical potential space where the proton gradient is harnessed by complex V consequent to impulse transmission.10 Neuronal anatomy, to phosphorylate ADP to ATP.14 with long processes extending from the cell body where Dysfunction of oxidative phosphorylation consequent mitochondria are synthesized, requires the purposeful to mtDNA or nuclear gene mutations can result in a transport of organelles along axons and dendrites to the sites reduction in maximal ATP production rate and increased of ATP usage. This transport is accomplished by energy- reactive oxygen species production by complexes I and dependent bidirectional transport along microtubules. Kinesin III,15,16 heightening oxidative stress within the cell.17 moves mitochondria in the anterograde direction, whereas mtDNA is highly susceptible to damage by reactive oxygen Eye and Brain downloaded from https://www.dovepress.com/ by 54.191.40.80 on 20-Jun-2017 retrograde transport is via dynein motors.11 Mitochondrial species due in part to the lack of protective DNA binding network dynamics is a growing area in mitochondrial histones,18 limited DNA repair mechanisms,19,20 and the research, with the discovery of genes involved in the close proximity of mtDNA to the site of production of constant fission and fusion of organelles. The optic atrophy 1 reactive oxygen species, the oxidative phosphorylation (autosomal dominant) gene (OPA1), the most common gene machinery. And unlike nuclear genes, mtDNA exists in mutated in ADOA, encodes a dynamin-related GTPase of hundreds to thousands of copies per cell, is replicated the mitochondrial inner membrane that directs fusion of this throughout life, and is maternally inherited. The extent membrane. Why disruption of mitochondrial dynamics due to which mtDNA mutations produce pathologic changes to loss of OPA1 function results in specific loss of retinal in tissues depends on the balance between normal ganglion cells remains unknown. and mutant mtDNA populations in cells and tissues The simplistic idea that different degrees of energetic (heteroplasmy) and the resilience of tissues to impairment impairment lead to a hierarchy of neuronal populations of oxidative phosphorylation (threshold effect), resulting being adversely affected does not adequately explain the in varied phenotypes and affected tissues in mitochondrial pathological changes in the central nervous system in diseases.21,22 The differential expression of components mitochondrial diseases. Retinal ganglion cells appear to be of the electron transport chain in various tissues and the one of the most sensitive neurons to mitochondrial failure, segregation of mitochondria during development23 has also although the reasons for this susceptibility remain unclear. been implicated in tissue-specific diseases.24 30 submit your manuscript | www.dovepress.com Eye and Brain 2011:3 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Mitochondrial disorders and the eye mtDNA haplogroups apoptotic signals leading to neuronal death. Neuronal cells The mtDNA genome accumulates mutations at a much higher have markedly high expression levels of dynamin-related rate than nuclear DNA, and during human evolution certain protein 1 and OPA1 compared with non-neuronal