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Show STATE OF THE ART The Eyes of Mito- Mouse: Mouse Models of Mitochondrial Disease Valerie Biousse, MD, Machelle T. Purdue, PhD, Douglas C. Wallace, PhD, and Nancy J. Newman, MD The recent creation of several mouse models of mitochondrial diseases has provided new insights into the understanding of human mitochondrial disorders. Whether these animals have clinical or histologic ophthalmologic abnormalities is of great interest given the high frequency of such abnormalities in humans with mitochondrial disorders. In this article, we describe the currently available mouse models for mitochondrial diseases with special emphasis on their ocular phenotype. These mouse models demonstrate multiple and varied ophthalmologic manifestations. ( JNeuvo- Ophthalmol 2002; 22: 279- 285) itochondrial disorders manifest a broad and varied clinical phenotype, frequently including neuro-ophthalmic symptoms and signs ( 1,2). Mitochondrial diseases are unique in that they reflect not only the classic dual influences of genetics and the environment, but they may have contributions from two genomes, the nuclear chromosomes, and the mitochondrial genome itself ( Fig. l, Table 1) ( 3- 6). The degree to which each of these factors influences the expression of a mitochondrial disorder varies from disease to disease and from patient to patient. Mammalian mitochondria generate most of the adenosine triphosphate ( ATP) for cells by the process of oxidative phosphorylation ( OXPHOS) ( 3- 6). Any defect in OXPHOS can lead to a disruption in ATP production and an overabundance of reactive oxygen species ( ROS). The Departments of Ophthalmology ( VB, MTP, NJN), Neurology ( VB, NJN), and Neurological Surgery ( NJN), Atlanta VA Medical Center ( MTP), Center for Molecular Medicine ( DCW), Emory University School of Medicine, Atlanta, Georgia. Address correspondence to Valerie Biousse, MD, Neuro-ophfhalmology Unit, Emory Eye Center, 1365- B Clifton Road, Atlanta, GA 30322, USA; E- mail: vbiouss@ emory. edu Acknowledgments: This study was supported in part by National Institutes of Health Grants AG13154, HL45572, and NS21328 ( DCW); CORE Grant P30- EY06360 ( Department of Ophthalmology); and a departmental grant ( Department of Ophthalmology) from Research to Prevent Blindness, Inc. NJN is a recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award, and DCW is a recipient of a Johnson & Johnson Focused- Giving Grant. concept of OXPHOS diseases was first formulated in 1962, and the mitochondrial DNA ( mtDNA) was discovered in 1963 ( 6). However, 25 years passed before the significance of this genome in the pathogenesis of OXPHOS diseases was recognized. In 1988, the understanding of mitochondrial diseases changed dramatically when the first pathogenic mtDNA mutations were reported. Large mtDNA deletions that removed several thousand base pairs were found in patients who had chronic progressive external ophthalmoplegia, structurally abnormal mitochondria, and abnormal OXPHOS biochemistry ( 7). Shortly after this study was published, a mtDNA point mutation in the ND4 gene was shown to be a common cause of Leber hereditary optic neuropathy ( LHON) ( 8). Within 2 years, the major classes of pathogenic mtDNA mutations were identified. Deletions, duplications, and point mutations in the mtDNA were recognized as causes of OXPHOS diseases ( 3,4,6). More recently, nuclear genetic abnormalities have also been identified as causal in mitochondrial disorders ( 3,5,6). Our current understanding of mitochondrial diseases has derived primarily from human studies, revealing much about the genetics of mitochondrial disorders. However, the pathophysiological mechanisms that underlie the complex array of symptoms remain mysterious. Recently, new insights into this topic have been obtained by the creation and analysis of several mouse models for mitochondrial diseases ( 9,10). These mouse models have been extensively studied from a genetic and biochemical point of view ( 9,10). Whether these animals have clinical or histologic neuro- ophthalmologic abnormalities is of great interest, especially given the high frequency of such abnormalities in humans with mitochondrial disorders ( 1,2). In this article, we present an overview of currently available mouse models for mitochondrial diseases, with special emphasis on those studies that have evaluated their ocular phenotypes. SOD2 MUTANT MICE Superoxide dismutase- deficient mice represent a model of increased mitochondrial production of ROS ( 9,10). These ROS ( superoxide anions, hydrogen peroxide, peroxynitrite, and hydroxy radicals) are particularly Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 279 JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 Biousse et al. • Fig. 1. Schematic of nuclear and mitochondrial transcription. Mitochondrial proteins are encoded by nuclear genes ( proteins synthesized on cytoplasmic ribosomes and transported into mitochondria) and mitochondrial genes ( proteins synthesized within the mitochondrion on mitochondrial ribosomes). A mitochondrial disorder could result from a nuclear or mitochondrial DNA abnormality. Published with permission ( 2). detrimental to mitochondrial function. Indeed, one of the proposed pathophysiologic mechanisms of mitochondrial diseases in humans is decreased mitochondrial ATP production and toxicity resulting from increased mitochondrial ROS generation ( 6,9). Mitochondrially generated ROS can result in a significant reduction of activity of components of the respiratory chain with severe consequences for tissues, especially those with high metabolic rates ( 6,9). In the course of normal metabolism, approximately 0.1% to 4% of all oxygen consumed during respiration is spontaneously converted to superoxide. When superoxide is produced in excess, such as in patients with complex I deficiency, free radicals are generated that participate in producing cell damage and cell death ( 11- 14). Superoxide dismutase ( SOD) catalyzes the conversion of superoxide anion and water to hydrogen peroxide, which is the first step in the normal metabolic defense against oxidative stress. The enzyme manganese Sod ( Sod2) is found in the mitochondrial matrix, whereas forms containing both copper and zinc are found in nuclear and cytoplasmic compartments ( Sodl) or extracellularly ( Sod3) ( 11,12,15- 18). All three nuclear genes that code for the various forms of superoxide dismutase ( Sodl, Sod2, and Sod3) have been inactivated in mice through homologous recombination ( 9,10). Inactivation of Sod2 has resulted in the most severe phenotype and represents the first model of mitochondrial disease based on increased mitochondrial ROS generation ( 9,10- 12). Tissues that are heavily dependent onmitochon-drial function, such as the brain and the heart, are most severely affected in the Sod2 mutant mouse ( 9,10- 12). Mice lacking Sod2 die of dilated cardiomyopathy at a mean of 8 days ( 9,10- 12). They also have defects in the liver, bone marrow, and brain ( 11,12). Biochemical abnormalities of Sod2 mutant mice ( Sod2tmlc-' e~/~) include a tissue- specific inhibition of the respiratory chain enzymes NADH- dehydrogenase ( complex I) and succinate dehydrogenase ( complex II), mitochondrial aconitase defects in the brain and heart, an organic aciduria in conjunction with a partial defect in the ketogenic enzyme 3- hydroxy- 3- methyl- glutaryl- CoA lyase, and a heart- specific reduction in the tricarboxylic acid cycle enzymes ( 15). In addition, oxidative damage to DNA has been observed in the brain and heart of Sod2 mutant mice ( 15). In contrast to the homozygous mutant animals, heterozygous animals for the Sod2 mutant allele with 50% of wild- type Sod2 activity are phenotypically normal, although they do have demonstrable biochemical abnormalities ( 17). Sod2 mutant mice also represent a powerful tool for demonstrating the efficacy of antioxidants in the treatment of increased endogenous mitochondrial ROS ( 16). Both the cardiomyopathy and the accumulation of lipid in the liver of Sod2 mutant mice are rescued effectively by the treatment TABLE 1. Genetic and biochemical classification of mitochondrial disorders Nuclear DNA defects Defects directly or indirectly involving the integrity and function of the respiratory chain complexes: Defects of substrate transport Defects of substrate utilization Defects of the Krebs cycle Defects of the electron transport chain Defects of oxidation- phosphorylation coupling Defects of translocases Defects of protein importation Defects of intergenomic signaling: Defects affecting mtDNA transcription, translation or replication Mitochondrial DNA defects Sporadic large- scale rearrangements ( deletions, depletions, duplications) Transmitted large- scale rearrangements ( deletions, depletions, duplications) Point mutations in tRNA or rRNA genes Point mutations in protein- coding genes Data adapted from DiMauro et al. [ 4]. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 280 © 2002 Lippincott Williams & Wilkins STATE OF THE ART JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 of these animals with the synthetic oxidant manganese 5,10,15,20- tetrakis ( 4- benzoic acid) porphyrin ( MnTBAP) ( 16). When treated with MnTBAP ( which does not cross the blood- brain barrier), mice survive to day 16- 20 and have severe neurologic disease, including a pronounced movement disorder and spongiform encephalopathy ( 16). The eyes of homozygous Sod2- deficient mice ( Sod2tmlcje"/") have recently been evaluated ( 18). Although ROS toxicity has been implicated in the occurrence of cataract in other mice models ( 19) and in humans with complex I deficiency and the syndrome of cardiomyopathy and cataract ( 13,20), the anterior segments of our mutant Sod2 mice were normal without evidence of cataract, both in untreated and MnTBAP- treated mice. This may be explained by the short life spans of these mice. We did observe a relative thinning of the retinas of MnTBAP- treated Sod2 mutant mice with particular involvement of the inner retinal layers and an effect on the photoreceptor layer ( 18). However, electroretinograms performed on MnTBAP- treated Sod2 Fig. 2. Extraocular muscle of 16- day old untreated showing normal extraocular muscle ( black arrow) and i animal showing normal extraocular muscle ( black a ( magnification x 15,000). Published with permission ( mutant mice aged 15 days did not show any abnormalities ( Pardue et al, Personal communication, December 2001). Optic nerve cross- sectional area was decreased in 20- to 21- day- old MnTBAP- treated Sod2 mutant animals compared with control animals ( 18). Mitochondrial morphologic abnormalities ( swelling, pale matrix, and disorganized cristae) were found predominantly in the retinal pigment epithelium of older mutant animals ( 16 and 20 to 21 days) and in the extraocular muscles of a 16- day- old untreated mutant ( Fig. 2) ( 18). These morphologic findings are reminiscent of those seen in some humans with Kearns- Sayre and the mitochondrial encephalopathy overlap syndromes ( 21- 25). These studies indicate that, in addition to extensive abnormalities in other organ systems, Sod2 mutant mice manifest pathologic changes in the retina and extraocular muscles similar to those reported in human mitochondrial disease. Detailed morphologic and functional studies of the optic nerve of these mice have yet to be performed. It is Sod2- deficient mouse. A: Longitudinal section of control animal lormal mitochondria ( empty arrow). B: Oblique section from mutant row) and pale mitochondria with distorted cristae ( empty arrow) 18). Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 281 JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 Biousse et al. possible that potential ocular findings resulting from the absence of Sod2 may not be fully evolved in these animals because of death before maturity. The use of antioxidant therapies, combined with further analyses of the biochemical and genetic profiles of Sod2 mutant mice, may provide new insights into the role of free radicals in the pathogenesis of mitochondrial diseases. ANTI- DEFICIENT MICE Targeted inactivation of the nuclear- encoded adenine nucleotide translocator ( ANT) gene has provided a model for chronic ATP- deficiency ( 26- 28). ANT is a transporter protein that imports adenosine diphosphate ( ADP) and exports ATP across the inner mitochondrial membrane, providing mitochondrial energy to the cytosol. ANT plays a central role in OXPHOS. In mice, there are two ANT iso-forms, ANT1 and ANT2, with tissue specific distributions of both proteins ( 9,10,26- 28). ANT1 is expressed at high levels in skeletal muscles and in the heart, and at a lower level in the brain, whereas ANT2 is expressed in all tissues except skeletal muscle ( 9,10,26- 28). Bothisoforms ( ANT1 and ANT2) are expressed within the eyes and the optic nerves ( 29). Transgenic mice lacking ANT1 ( ANT1-/- mice) have been generated to demonstrate the role of ATP deficiency in the development of mitochondrial myopathy and cardiomyopathy ( 26,27). These mice have complete ANT deficiency in skeletal muscles, partial deficiency in the heart, and normal levels in the liver. Elimination of ANT 1 limits the import of ADP, thereby inhibiting oxidative phosphorylation and stopping the production of ATP ( 26,27). Therefore, ANT- deficient mice provide a model for the phenotypic consequences of decreased mitochondrial ATP production in specific tissues. ANTl- deficient mice are viable, although they develop classic mitochondrial myopathy and hypertrophic cardiomyopathy similar to that seen in humans ( 9,10,26- 29). The skeletal muscles of ANTl- deficient mice exhibit classic ragged- red fibers and decreased succinate dehydrogenase and cytochrome c oxidase activities in the type I oxidative muscle fibers ( 9,10,26- 29). Elevated OXPHOS enzyme activities correlate with a massive proliferation of giant mitochondria in the skeletal muscle fibers, degeneration of the contractile fibers, and a marked exercise fatigability. The hypertrophic cardiomyopathy is also associated with mitochondrial proliferation. ANTl- deficient mice also have elevated serum levels of lactate, alanine, and succinate, consistent with inhibition of the respiratory chain ( 9,10,26- 29). The mtDNA of the hearts of ANTl- deficient mice shows a dramatic increase in mtDNA rearrangements ( 29). This supports the hypothesis that mtDNA rearrangements result from increased levels of ROS, even at levels that do not result in lethality ( 9,10,26- 29). The eyes of ANTl- deficient mice are currently under evaluation. While Levy et al. ( 30) have shown the presence and expression of both isoforms within the eyes and optic nerves, it is not known if there are regional differences within the eye and how the ANT1 mutation affects the ocular tissues. ANTl- deficient mice older than 12monthshave posterior subcapsular and nuclear lens opacities, but these opacities do not appear to differ from those observed in age-matched controls ( 31). Electroretinograms show a trend toward larger b- wave amplitudes for higher light stimulus intensities but no difference in a- wave responses in old ANTl- deficient mice as compared with age- matched controls ( 31). These supranormal responses in mutant mice are surprising given the often normal or decreased amplitudes of electroretinograms in humans with various mitochondrial diseases ( 32). Pathologic examination of the retinal structure of the ANTl- deficient mice has revealed no gross abnormalities at the light microscopy level ( 31). However, electron microscopy has shown smaller and more numerous mitochondria in the photoreceptors of mutant mice compared with control mice ( 31). Detailed examination of the optic nerves and extra ocular muscles of ANTl- deficient mice has yet to be performed. Mice deficient in ANT1 exhibit the classic anatomic, histologic, biochemical, metabolic, and physiological features associated with mitochondrial myopathy and cardiomyopathy in humans. Furthermore, this mutant animal has provided the first cause- and- effect demonstration that a defect in mitochondrial energy metabolism can result in skeletal and cardiac muscle disease. ANTl- deficient mice may offer further opportunities to examine the consequences of chronic ATP- deficiency on the eyes, optic nerves, and extraocular muscles. TFAM- DEFICIENT MICE Another mouse model of mitochondrial disease was created by inactivation of the nuclear gene for mitochondrial transcription factor ( Tfam) ( 9,10,33). Tfam- deficient mice may provide a model for syndromes associated with mtDNA deletions, such as Kearns- Sayre syndrome and the chronic progressive external ophthalmoplegias. Tfam is a nuclear- encoded gene involved in the regulation of mtDNA replication and transcription ( 33). Tfam- deficient mice have some of the phenotypic features of mitochondrial disease in humans, including cytochrome c oxidase- negative fibers, hypertrophy of the heart, and dilated cardiomyopathy ( 9,10,33). As is the case with Sod2- and ANTl- deficient mutant mice, the heart seems to be prone to mitochondrially mediated pathology, likely reflecting its high requirement for ATP. Heterozygous Tfam- deficient mice are viable and re-productively competent. They have a 50% reduction in Tfam transcript and protein levels, a 34% reduction in Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 282 © 2002 Lippincott Williams & Wilkins STATE OF THE ART JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 mtDNA copy number, a 22% reduction in mitochondrial transcript levels, and a partial reduction in COX protein levels in heart but not liver. Homozygous Tfam- deficient mice die between embryonic days 8.5 and 10.5. They show a complete absence of Tfam protein and very little detectable mtDNA transcripts. Mitochondria in the homozygous Tfam- deficient mice have been found to be enlarged, with abnormal cristae deficient in cytochrome c oxidase but not succinate dehydrogenase ( 9,10,33). Wang et al. ( 34) created a mutant mouse with selective ablation of the Tfam function in heart and skeletal muscles. The hearts of 18.5- day mutant embryos had reduced levels of Tfam but were otherwise morphologically and biochemically normal. However, the mutant mice died of dilated cardiomyopathy about 3 weeks after birth. Under anesthesia, the mice developed atrioventricular conduction block. They also showed reduced levels of Tfam protein and mtDNA transcripts in heart and skeletal muscles, a reduced level of heart and skeletal muscle mtDNA, and reduced activity of respiratory complexes I and IV. Finally, some of the cardiomyocytes were lacking in cytochrome c oxidase and replete with succinate dehydrogenase, comparable with the mosaic OXPHOS deficiencies seen in human mitochondrial myopathy patients ( 34). Hence, these animals exhibit many of the features seen in the chronic ophthalmoplegia mtDNA deletion syndromes, disorders also believed to be the result of a nuclear- encoded abnormal protein. No study has specifically evaluated the eyes, optic nerves, or extra ocular muscles of Tfam- deficient animals. CAP- RESISTANT MICE Although the mouse models described above exhibit certain phenotypic characteristics of mitochondrial diseases, they cannot recapitulate all of the unique features of primary mtDNA mutations, such as maternal inheritance, heteroplasmy, and bioenergetic threshold expression, which are essential to understanding mitochondrial disease. With the goal of creating a model that accurately reflects the genetic complexity of mtDNA diseases, efforts have been made to introduce deleterious mtDNA mutations into the mouse female germ line. Initially, the mtDNA was introduced in whole animal systems ( 35) from cultured mouse cells resistant to chloramphenicol ( CAP), a mitochondrial ribosome inhibitor. This technique yielded chimeric mice with varying levels of CAP- resistant ( CAPR) and wild type mtDNA ( a state known as heteroplasmy) ( 36,37), but transmission through the maternal germ line was not achieved until recently ( 38). Sligh e? a/. ( 38) introduced mtDNA mutations into the mouse female germ line by means of embryonic stem cell cybrids. Starting with transgenic chimeric female mice, Sligh et al. ( 38) demonstrated transmission of mtDNA mutations to succeeding generations, producing heteroplasmic mice with sufficiently high levels of the CAP mutation to express phenotypic abnormalities. These are the first mice with a transmitochondrial mtDNA point mutation to express an abnormal phenotype suggestive of mitochondrial disease ( 39). CAPR chimeric mice manifested dilated cardiomyopathy, abnormal mitochondria in heart and skeletal muscle, and ocular abnormalities ( 38). They had bilateral nuclear cataracts when they opened their eyes in the second week of life. In most cases, the fetal nucleus of the lens had a dense opacity, and in some mice the opacity extended into the cortex ( Fig. 3). It is currently unknown why the CAPR mutation induces cataract formation. It is possible that an energetic defect alters the development of the lens fibers during the fetal stage of lens development ( 40). The CAPR mutation could also result in increased mitochondrial production of ROS throughout the early development of the eye, thereby altering the lens crystalline proteins. Retinal function of the CAPR mice was evaluated with electroretinography ( 38). There was a 50% b- wave amplitude reduction in the chimeric mice compared with controls. Cones and rods were similarly affected. Although the light microscopic retinal histology was normal, the retinal pigment epithelium showed vacuoles throughout all the CAPR chimeric specimens examined. Because there was no evidence of degeneration in the photoreceptors, Sligh et al. ( 38) explained this functional retinopathy by proposing a metabolic defect. The most striking ocular abnormality in the CAPR mice was a hamartomatous- like change of the optic nerve head with protrusion into the vitreous space and a gliotic membrane emanating from the surface of the optic nerve head covering the inner retinal surface ( Fig. 4). Fig. 3. Slit lamp biomicroscopic examination of a 9 month- old CAPR chimeric mouse showing a dense nuclear cataract. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 283 JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 Biousse et al. Fig. 4. Retinal histology of a 6 month- old CAPR chimeric mouse. A: Preservation of retinal layers and a gliotic membrane on the inner retina { arrow) ( magnified x 400). B: Retinal pigment epithelial vacuolization and full preservation of photoreceptors ( magnified x 600). C: Optic nerve head ( ONH) light microscopic histology demonstrates hamar-tomatous- like changes intraocularly, with a gliotic membrane emanating from the ONH surface { arrow) ( magnified x 200). D: A similar ONH finding but with the presence of an optic pit { arrow).( magnified x 300) in a CAPR chimeric mouse. GC, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; ONL, outer nuclear layer; IS, inner segment; OS, outer segment of photoreceptors; PE, pigment epithelium. Published with permission ( 38). In contrast to the CAPR mice, the transgenic mitochondrial mice produced by Inoue et al. ( 41) harbor large-scale rearrangements of mtDNA, which is analogous to the typical mtDNA profile of patients with Kearns- Sayre syndrome, sporadic chronic progressive external ophthalmoplegia, and Pearson syndrome ( 6,42). However, most mice harboring high proportions of the mtDNA deletions die of renal failure, a surprising finding given that renal dysfunction is uncommon in human mitochondrial diseases ( 6). Nevertheless, the mice had a decrease in the activity of cytochrome c oxidase, ragged red fibers in muscle, and lactic acidosis, all indicative of mitochondrial dysfunction ( 41). The CAPR mice produced by Sligh et al. ( 38) and the transmitochondrial mice generated by Inoue et al. ( 41) support the principle that transmitochondrial mice harboring pathogenic mtDNA point mutations and mtDNA deletions can be produced and transmitted through germ lines with sufficiently high levels of the mutations to express clinical phenotypes. Correlation between pathologic changes and levels of heteroplasmy in various organs may demonstrate higher levels of mutant mtDNA in those tissues most severely affected, a feature frequently observed in human mitochondrial disorders ( 39). The prominent ocular abnormalities found in all the CAPR mice are of great interest and warrant further study. CONCLUSIONS The currently available mouse models for mitochondrial diseases demonstrate multiple and varied ophthalmologic manifestations. Further clinical, electrophysiologic, and histopathologic studies are ongoing to better delineate their neuro- ophthalmologic phenotype. Mitochondrial diseases are unique in that they may result from nuclear or mitochondrial DNA defects. With the exception of the CAPR mice ( 38) and the transgenic mice produced by Inoue et al. ( 41), all currently available mouse models discussed in this review are the result of nuclear gene defects that cause increased ROS or deficient proteins/ enzymes involved in mitochondrial function. Some of these nuclear defects result, either directly or indirectly, in damage to the mtDNA itself ( 41,42). However, many human mitochondrial diseases, especially those limited to primary abnormalities in the mtDNA, such as mis-sense point mutations, would be better served by a mouse model in which the primary defect is in the mitochondrial genome itself. For example, an animal model for LHON would ideally be created by a point mutation in the mtDNA itself, especially within the genes encoding protein components of complex I. Recently, a genetically induced mouse model of complex I deficiency has shown histopathologic features of optic nerve degeneration similar to that seen in patients with LHON ( 43). Such mouse models should better facilitate the understanding of the pathogenesis of human mitochondrial disorders and could provide a way to test therapeutic agents potentially efficacious in human mitochondrial diseases. REFERENCES 1. Biousse V, Newman NJ. Neuro- ophthalmology of mitochondrial diseases. Sent Neurol 2001; 21: 275- 91. 2. Newman NJ. Mitochondrial disease and the eye. Ophthalmol Clin NA 1992; 5: 405- 24. 3. Chinnery PF, Turnbull DM. Mitochondrial DNA and disease. Lancet 1999; 354: SI17- 21. 4. DiMauro S, Andreu AL, Musumeci O, et al. Diseases of oxidative Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 284 © 2002 Lippincott Williams & Wilkins STATE OF THE ART JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 phosphorylation due to mtDNA mutations. Sem Neurol 2001; 21: 251- 60. 5. Shoubridge EA. Nuclear gene defects in respiratory chain disorders. Sem Neurol 2001; 21: 261- 7. 6. Shoffner JM. An introduction: oxidative phosphorylation diseases. Sem Neurol 2001; 21: 237- 50. 7. Holt IJ, Harding AE, Morgan- Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Na-ture 1988; 331: 717- 9. 8. Wallace DC, Singh G, Lot MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242: 1427- 30. 9. Wallace DC. Mitochondrial diseases in man and mouse. Science 1999; 283: 1482- 8. 10. Melov S, Coskun PE, Wallace DC. Mouse models of mitochondrial disease, oxydative stress, and senescence. Mutation Res 1999; 434: 233- 42. 11. Li Y, Huang TT, Carlson EJ, et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking maganese superoxide dis-mutase. Nat Genet 1995; 11: 376- 81. 12. Lebovitz RM, Zhang H, Vogel H, et al. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dis-mutase- deficient mice. Proc Natl Acad Sci USA 1996; 93: 9782- 7. 13. Robinson BH. Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect. Biochem Biophys Acta 1998; 1364: 271- 86. 14. Luo X, Pitkanen S, Kassovska- Bratinova S, et al. Excessive formation of hydroxyl radicals and aldehydic lipid peroxidation products in cultures skin fibroblasts from patients with complex I deficiency. J Clin Invest 1997; 99: 2877- 82. 15. Melov S, Coskun P, Patel M, et al. Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc Natl Acad Sci USA 1999; 96: 846- 51. 16. Melov S, Schneider JA, Day BJ, et al. A novel neurologic pheno-type in mice lacking mitochondrial manganese superoxide dismutase. Nat Genet 1998; 8: 159- 63. 17. Williams MD, Van Remmen H, Conrad CC, et al. Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 1998; 273: 28510- 5. 18. Sandbach JM, Coscun PE, Grossniklaus HE, et al. Ocular pathology in mitochondrial superoxide dismutase ( Sod2)- deficient mice. Invest Ophthalmol Vis Sci 2001; 42: 2173- 8. 19. Al- Ghoul KJ, Novak LA, Kuszak JR. The structure of posterior subcapsular cataracts in the Royal College of Surgeons ( RCS) rats. Exp EyeRes 1998; 67: 163- 77. 20. Pitkanen S, Merante F, McLeod DR, et al. Familial cardiomyopathy with cataracts and lactic acidosis: a defect in complex I ( NADH-dehydrogenase) of the mitochondrial respiratory chain. Pediatr Res 1996; 39: 513- 21. 21. Eagle RC, Hedges TR, Yanoff M. The atypical pigmentary retinopathy of Kearns- Sayre syndrome: a light and electron microscope study. Ophthalmology 1982; 89: 1433^ 10. 22. McKechnie NM, King M, Lee WR. Retinal pathology in the Kearns- Sayre syndrome. Br J Ophthalmol 1985; 69: 63- 75. 23. Isashiki Y, Nakagawa M, Ohba N, et al. Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scand 1998; 76: 6- 13. 24. Chang TS, Johns DR, Walker D, et al. Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes. Arch Ophthalmol 1993; 111: 1254- 62. 25. Carta A, D'Adda T, Carrara F, et al. Ultrastructural analysis of extraocular muscle in chronic progressive external ophthalmoplegia. Arch Ophthalmol 2000; 118: 1441- 5. 26. Graham BH, Waymire KG, Cottrell B, et al. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/ muscle isoform of the adenine nucleotide trans-locator. Nat Genet 1997; 16: 226- 34. 27. Wang J, Wilhelmsson H, Graff C, et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart- specific inacti-vation of mitochondrial DNA gene expression. Nat Genet 1999; 21: 133- 7. 28. Esposito LA, Melov S, Panov A, et al. Mitochondrial disease in mouse results in increased oxidative stress. Proc Natl Acad Sci USA 1999; 96: 4820- 5. 29. Napoli L, Bordoni A, Zeviani M, et al. A novel missense adenine nucleotide translocator- 1 gene mutation in a Greek adPEO family. Neurology 2001; 57: 2295- 8. 30. Levy SE, Chen YS, Graham BH, et al. Expression and sequence analysis of the mouse adenine nucleotide translocase 1 and 2 genes. Gene 2000 254: 57- 66. 31. Pardue MT, Barnett T, Phillips MJ, et al. Ocular characteristics of a mouse model of mitochondrial disease. Invest Ophthalmol Vis Sci, in press. 32. Mullie MA, Harding AE, Petty RK, et al. The retinal manifestations of mitochondrial myopathy: a study of 22 cases. Arch Ophthalmol 1985; 103: 1825- 30. 33. Larsson NG, Wang J, Wilhemsson H, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogen-esis in mice. Nat Genet 1998; 18: 231- 6. 34. Wang J, Wilhelmsson H, Graff C, et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart- specific inacti-vation of mitochondrial DNA gene expression. Nat Genet 1999; 21: 133- 7. 35. Blanc H, Adams CW, Wallace DC. Different nucleotide changes in the large rRNA gene of the mitochondrial DNA confer chloramphenicol resistance on two human cell lines. Nucleic Acids Res 1981; 9: 5785- 95. 36. Marchington DR, Barlow D, Poulton J. Transmitochondrial mice carrying resistance to chloramphenicol on mitochondrial DNA: developing the first mouse model of mitochondrial DNA disease. Nature Med 1999; 5: 957- 60. 37. Levy SE, Waymire KG, Kim YL, et al. Transfer of chlorampheni-col- resistant mitochondrial DNA into the chimeric mouse. Transgenic Res 1999 ; 8: 137'- 45. 38. Sligh JE, Levy SE, Waymire KG, et al. Maternal germ- line transmission of mutant mtDNAs from embryonic stem cell- derived chimeric mice. Proc Natl Acad Sci USA 2000; 97: 14461- 6. 39. Hirano M. Transmitochondrial mice: proof of principle and promises. Proc Natl Acad Sci USA 2001; 98: 401- 3. 40. McAvoy JW, Chamberlain CG, de Iongh RU, et al. Lens development. Eye 1999; 13: 425- 37. 41. Inoue K, Nakada K, Ogura A, et al. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nat Genet 2000; 26: 176- 81. 42. Shoubridge EA. A debut for mito- mouse. Nat Genet 2000; 26: 132^ 1. 43. Qi X, Lewin A, Guy J. Ribozymes against mitochondrial genes induce optic nerve degeneration in the mouse: an animal model for Leber hereditary optic neuropathy. ( Abstract) Neurology 2002; 58 ( Suppl 3): A507. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 285 |
