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(Investigative Ophthalmology and Visual Science. 2001;42:2173-2178.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Ocular Pathology in Mitochondrial Superoxide Dismutase (Sod2)–Deficient Mice

Jennifer M. Sandbach1, Pinar E. Coscun2, Hans E. Grossniklaus1, Jason E. Kokoszka2, Nancy J. Newman1,3,4 and Douglas C. Wallace2

1 From the Departments of Ophthalmology, 3 Neurology, and 4 Neurologic Surgery and the 2 Center for Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To characterize the pathologic features in retina, optic nerve, and extraocular muscle of mitochondrial superoxide dismutase (Sod2)–deficient mice, a model of increased mitochondrial production of reactive oxygen species.

METHODS. Morphometric and ultrastructural study of eyes of 43 homozygous sod2tm1Cje-/- mice and wild-type control animals. For retinal morphometric analysis, 32 manganese 5,10,15,20-tetrakis (4-benzoic acid) porphyrin (MnTBAP)–treated animals aged either 9 to 10 days or 20 to 21 days were studied. Ultrastructural examination was performed on tissue from the treated animals, and 11 additional untreated mutant and control animals.

RESULTS. In treated Sod2-deficient animals, the photoreceptor layer was thinner centrally at 9 to 10 days than in control animals (mean 8.8 vs. 14.7 µm). By 20 to 21 days, all retinal layers apart from the outer nuclear layer and retinal pigment epithelium (RPE) were thinner centrally in mutant animals (total retinal thickness, 233.2 vs. 272.6 µm; combined nerve fiber layer, ganglion cell layer, and inner plexiform layer, 86.2 vs. 103.4 µm; inner nuclear layer, 51.8 vs. 60.3 µm; photoreceptors, 26.7 vs. 35.6 µm). Optic nerve cross-sectional area was less in 20- to 21-day-old treated Sod2-deficient animals than in control animals. Mitochondrial morphologic abnormalities (swelling, pale matrix, and disorganized cristae) were found predominantly in older mutant animals’ (16 and 20 to 21 days) RPE and in extraocular muscle of a 16-day-old untreated mutant.

CONCLUSIONS. In sod2tm1Cje-/- mice, there is relative progressive retinal thinning, with particular involvement of the inner retinal layers and an early effect on the photoreceptor layer, as well as mitochondrial morphologic abnormalities, all consistent with mitochondrial disease.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Oxidative stress may be considered as the cytopathic consequence of the generation of excess reactive oxygen species (ROS) beyond the capacity of a cell to defend against them.1 Oxidative stress is widely regarded as a potential causative factor in the aging process and other degenerative diseases.1 2

Mitochondria are the major endogenous source of ROS (superoxide anions, hydrogen peroxide, peroxynitrite, and hydroxyl radicals).1 2 Whenever the mitochondrial electron transport chain is inhibited, electrons accumulate in the early stages at complex I and coenzyme Q, where they can be directly donated to molecular oxygen, to form superoxide anions.2 Even under normal aerobic conditions, between 0.4% and 4% of molecular oxygen is converted into superoxide.3

Superoxide dismutase catalyzes the conversion of superoxide anion and water to hydrogen peroxide, which is the first step in metabolic defense against cellular oxidative stress. Manganese Sod (Sod2) is found in the mitochondrial matrix, whereas forms containing both copper and zinc are found in nuclear and cytoplasmic compartments (Sod1) or extracellularly (Sod3).2 Mouse lines with genetic inactivation of Sod2 represent the first models of mitochondrial disease based on increased mitochondrial ROS generation.3

Hepatic lipids accumulate in Sod2tm1Cje-/- mice, and they die of dilated cardiomyopathy at a mean of 8 days.4 Nearly all die by 10 days.4 They also manifest tissue-specific mitochondrial enzyme deficiencies of heart, brain, and liver. Total DNA from heart and brain of 4- to 6-day-old animals shows accumulation of oxidative DNA damage.3 Heterozygote animals have increased oxidative damage to mitochondrial but not nuclear DNA.5 No morphologic mitochondrial abnormalities have been noted in 4- to 5-day-old mutant mice.4

Treatment of Sod2tm1Cje-/- mice with the Sod mimetic, manganese 5,10,15,20-tetrakis (4-benzoic acid) porphyrin (MnTBAP), doubles animal survival time to 16.4 days. The animals display a pronounced movement disorder and spongiform encephalopathy develops, perhaps because MnTBAP is not thought to cross the blood–brain barrier.6 Although occasional ballooned mitochondria with distorted cristae have been noted in axon terminals, brain mitochondrial morphology is otherwise normal.6

The retina has a high level of oxidative metabolism with attendant ROS production. Retinal oxidative stresses include lipid peroxidation and direct photic injury.7 8 If mitochondrial ROS production is a major cause of retinal degeneration in mammals, then absence of Sod2 should result in the development of additional degenerative changes in the retina. We chose to study the ocular tissues of Sod2tm1Cje-/- mice, to characterize the ocular pathologic features.

Treatment with MnTBAP enabled study of older and therefore potentially more abnormal Sod2-deficient animals closer to maturity than would otherwise have been possible. A comparison of treated with untreated animals in a younger age group permitted evaluation for MnTBAP treatment effects.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The older experimental subjects included ten 20- to 21-day-old MnTBAP-treated Sod2tm1Cje-/- mice, 10 treated and 2 untreated control mice, and one 16-day-old untreated Sod2tm1Cje-/- mouse of unusual longevity and an age-matched control mouse. Younger subjects included five 9- to 10-day-old MnTBAP-treated Sod2tm1Cje-/- mice, seven treated control mice, two untreated 9- to 10-day-old Sod2tm1Cje-/- mice, and five untreated control mice. Older untreated animals were not used for morphometric analysis, but all were used in the ultrastructural study.

Animals were maintained on a 12-hour light–12-hour dark cycle, treated with MnTBAP, and genotyped as previously described.6 During light exposure the mean illumination was 130 lux. All procedures with animals were performed under a protocol in accordance with Emory University’s ethical guidelines and conforming to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Eyes of killed animals were marked at the nasal limbus and enucleated. Tissue was fixed for four hours in 4% paraformaldehyde and 1% glutaraldehyde in phosphate-buffered saline (PBS). After washing in PBS, eyes were bisected along the horizontal meridian passing through the optic nerve and nasal and temporal limbi. The optic nerve was transected behind the globe and processed separately. Tissues were postfixed with 1% osmium tetroxide, washed in PBS, and then stained with 2% uranyl citrate. After repeat washing, specimens were dehydrated and embedded in epoxy resin. Thick sections (1.5 µm) were stained with 1% toluidine blue and examined under light microscopy. When necessary, blocks were recut to obtain sections passing through both the central cornea and optic nerve. Thin sections (70 nm) of retina, optic nerve, and extraocular muscle were stained with uranyl citrate and lead citrate and studied by electron microscopy (H-7500; Hitachi, Tokyo, Japan). For retinal ultrastructural analysis, thin sections were centered on the same locations used for retinal thickness measurements, as will be described later.

A single observer (JMS), masked to age and genotype, performed the retinal morphometric analysis using a calibrated filer micrometer from the thick sections. The mean of seven consecutive measurements of each parameter was used in further analyses. Measurements were taken in three locations: central retina (one optic nerve diameter from the optic nerve margin) and both nasal and temporal peripheral retina (at the junction of the central two thirds and peripheral one third of the retina). Measurements from the two peripheral regions in each animal were averaged for statistical analysis. The strong correlation found between central and peripheral thicknesses supported the validity of the measurement technique (e.g., photoreceptor layer in mutant animals, r = 0.939, P = 0.0000; in control animals, r = 0.951, P = 0.0000). The following parameters were measured: thickness of total retina; combined nerve fiber layer, ganglion cell layer, and inner plexiform layer (NFL/GCL/IPL); inner nuclear layer (INL); outer nuclear layer (ONL); photoreceptor layer; and combined photoreceptor layer and retinal pigment epithelium (photoreceptor/RPE; Fig. 1 ). Optic nerve cross-sectional area was calculated from the shortest diameter (dshort) and the longest perpendicular diameter (dlong), excluding meningeal coverings, according to the following equation: area = {pi} (dshort/2)2 + (dlong - dshort) · dshort.



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  		Figure 1. Toluidine blue–stained thick section of a 21-day-old control mouse eye illustrating the retinal parameters measured. The optic nerve is shown on the left. Original magnification, x100.

 
All comparisons between groups were performed using analysis of variance (ANOVA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The results of the retinal morphometric analyses of MnTBAP-treated animals are presented in Tables 1 2 3 4 and are illustrated in Figure 2 . In young (9- to 10-day-old) MnTBAP-treated mice, the only significant difference between Sod2-deficient and control animals was thinning of the central photoreceptor layer in Sod2-deficient animals. However, by 20 to 21 days, measurements for NFL/GCL/IPL, INL, photoreceptors, and total retinal thickness were all reduced in Sod2tm1Cje-/- mice compared with control animals. The ONL and RPE thickness did not differ. Peripheral total retinal thickness was also less in Sod2tm1Cje-/- mice (Tables 1 2) .


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  		Table 1. Central Retinal Thickness of MnTBAP-Treated Animals

 

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  		Table 2. Peripheral Retinal Thickness of MnTBAP-Treated Animals

 

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  		Table 3. Change in Central Retinal Thickness of MnTBAP-Treated Animals with Age

 

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  		Table 4. Change in Peripheral Retinal Thickness of MnTBAP-Treated Animals with Age

 


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  		Figure 2. Central retinal thickness parameters of MnTBAP-treated mutant and control mice. Total retinal thickness is shown at a different scale (x0.5) from other measures (*P < 0.01).

 
Between 9 to 10 and 20 to 21 days, the thickness of the photoreceptor layer increased to a similar extent, both centrally and peripherally, in control and Sod2tm1Cje-/- mice. The thickness of NFL/GCL/IPL also increased in both Sod2-deficient and control mice, although the relative change centrally was greater in control animals. In contrast, although the total retinal thickness for control mice increased significantly between 9 to 10 days and 20 to 21 days, there was no significant increase for the Sod2-deficient mice over this period. In both mutant and control animals, peripheral INL and ONL actually decreased in thickness with increasing age. Mutant animals also demonstrated thinning of the INL centrally with increasing age. There were no changes in RPE thickness with age in either controls or Sod2tm1Cje-/- animals (Tables 3 4) .

The optic nerve cross-sectional area of MnTBAP-treated 20- to 21-day-old Sod2-deficient animals was smaller than in control animals (mean ± SEM, 54,546.7 ± 6,120.9 µm2 versus 66,830.2 ± 7,408.4 µm2; ANOVA df = 1,11; F = 8.930; P = 0.01).

Mutant animals in the 9- to 10-day age groups, both MnTBAP-treated and untreated, had normal retinal and extraocular muscle ultrastructure. Occasional plump mitochondria with pale matrix but normal cristae were seen in the RPE, photoreceptor inner segments, and extraocular muscle of both Sod2-deficient and control animals. In all age groups there were no differences in RPE basement membrane, basal infoldings, or phagocytic activity between control and mutant mice. Lipofuscin granules were rare in both.

At ages 16 and 20 to 21 days, mitochondrial numbers were normal, but mitochondrial morphologic abnormalities were more frequent in the RPE of Sod2tm1Cje-/- animals than in control animals (Fig. 3) . The abnormalities consisted of foci of mitochondrial swelling, matrix pallor, and disorganization of the cristae. No mitochondrial inclusions were seen. In the control animals, mitochondrial abnormalities when present, were seen almost exclusively in the setting of cellular degeneration (manifest by increased electron density of cytoplasm and nucleus, ruffling of the nuclear membrane, and cell shrinkage). However, abnormal mitochondria were seen in both degenerating and otherwise normal-appearing cells in mutant animals.



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  		Figure 3. Micrographs of RPE. (A) A 16-day-old untreated control animal; (B) a 16-day-old untreated mutant animal showing pale, swollen mitochondria with abnormal cristae; (C) a 21-day-old MnTBAP-treated control animal; (D) a 21-day-old MnTBAP-treated mutant animal with abnormal mitochondria. Original magnification, x10,000.

 
Abnormal mitochondrial morphology was rare in the inner segments of 20- to 21-day-old Sod2tm1Cje-/- animals. Plump mitochondria with pale matrix but predominantly normal cristae were common in the inner segments of the 16-day-old untreated mutant (Fig. 4) . No differences in mitochondrial morphology between mutant and control animals were seen in other retinal layers. There were no differences in photoreceptor outer segment morphology between mutant and control animals.



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  		Figure 4. Photoreceptor inner segments of 16-day-old untreated mice. (A) Longitudinal section from control animal showing normal elongated mitochondria. (B) Oblique section from mutant animal showing swollen mitochondria with normal cristae and a degenerating photoreceptor with osmiophilic cytoplasm. Original magnification, x15,000.

 
The appearance of extraocular muscle was normal in the 20- to 21-day-old Sod2-deficient, MnTBAP-treated animals. In the 16-day-old Sod2tm1Cje -/- untreated animal, abnormally pale and swollen mitochondria with disorganized cristae were seen more commonly than in the age-matched control animal (Fig. 5) . There was no proliferation of mitochondria or any disturbance of muscle architecture in the mutant animal.



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  		Figure 5. Extraocular muscle of 16-day-old untreated mice. (A) Longitudinal section from control animal. (B) Oblique section from mutant animal showing pale mitochondria with distorted cristae. Original magnification, x15,000.

 
Optic nerve ultrastructure was normal in all three age groups of Sod2-deficient mice. There were no mitochondrial morphologic abnormalities or splitting of the myelin sheath of axons observed in any animal. The proportion of myelinated axons increased from age 9 to 10 days to age 20 to 21 days in both mutant and control animals.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Deficiency of Sod2 in mice causes relative progressive retinal thinning, with prominent involvement of the inner retinal layers and early changes within the photoreceptor layer. In albino rats, the NFL, GCL, IPL, and RPE are formed at birth.9 A single neuroblastic layer of cells occupies the remainder of the retinal thickness.9 By 14 to 17 days the adult laminar structure is formed, and outer segments begin to appear.9 10 The photoreceptor layer and the IPL do not reach full thickness until 30 to 40 days.9 In the Sod2tm1Cje-/- and control mice, the adult retinal laminar structure was formed by 9 to 10 days, with subsequent increase in thickness of the photoreceptor and NFL/GCL/IPL layers. The final phase of retinal development, an increase in thickness of photoreceptor and inner retinal layers, developed in Sod2-deficient mice, but to a lesser extent than in control animals. Therefore, Sod2 deficiency may retard this final phase of normal retinal development, which occurs in the rat between 2 to 5 weeks of age and in the mouse, slightly earlier.

Our calculated results of optic nerve cross-sectional area are of a magnitude similar to those obtained by computerized image analysis in a study of (C57BLxCBA)F1 hybrid mice, in which the mean optic nerve cross-sectional area of 3-week-old mice was 42,560 ± 3,576 µm2 (SEM).11 This finding indicates that our simplified technique probably provided a good estimate of cross-sectional area. The optic nerve comprises axons that are continuous with the NFL and whose cell bodies are retinal ganglion cells. Therefore, the reduced optic nerve cross-sectional area in the 20- to 21-day-old Sod2-deficient mice is keeping with the relative NFL/GCL/IPL attenuation found in the central retina.

Treatment with MnTBAP appears to have a protective effect on the extraocular muscle of treated 20- to 21-day-old Sod2-deficient animals. No mitochondrial morphologic abnormalities were seen in extraocular muscle of these mice, whereas there were foci of abnormal mitochondria seen in the younger, 16-day-old, untreated Sod2-deficient animal. This is consistent with the known protective effect of MnTBAP treatment on tissue external to the blood–brain barrier.

Given that MnTBAP is not thought to cross the blood–brain or blood–retinal barriers in significant quantity,3 all retinal layers of MnTBAP-treated animals should be exposed to the effects of Sod2 deficiency, with the exception of the RPE. The terminal bars joining the apices of adjacent RPE cells form the outer blood–retinal barrier, so the basal surfaces of pigment epithelial cells are external to the blood–retinal barrier. Therefore the RPE, but not other retinal layers may be at least partially protected by MnTBAP treatment. Our finding of mitochondrial morphologic change mainly in the RPE of treated Sod2-deficient mice is not explained by the anatomy of the blood–retinal barrier. It appears instead that the (albino) RPE is particularly susceptible to oxidative stress in Sod2 deficiency.

Finding mitochondrial morphologic change in the RPE preferentially is consistent with the ocular pathologic findings reported in patients with Kearns-Sayre and the mitochondrial encephalomyopathy overlap syndromes.12 13 14 Extensive loss of the photoreceptor layer and RPE is also a classic finding, often with early involvement of the central retina.12 13 14 15 The early and maintained relative central photoreceptor layer thinning in Sod2tm1Cje-/- mice is consistent with this pattern.

A recent clinical report has associated Sod2 polymorphism in humans with exudative age-related macular degeneration.16 Pathologic changes in the RPE that are associated with aging include accumulation of lipofuscin in the RPE in both humans and rodents, as well as RPE cell height increase, RPE basement membrane thickening, deposition of collagen in Bruch’s membrane, pleomorphism of basal infoldings (either focal enlargement or loss), and shortening and thickening of apical microvilli in rats.9 17 18 In both albino and pigmented rats, the cell density of all three retinal nuclear layers falls with age, with greatest loss in the ONL.9

In this study of sod2tm1Cje-deficient mice, the ultrastructural changes previously described in animal models of aging were not seen. The INL and the ONL became thinner in sod2tm1Cje-/- mice with time. However, the greatest change was in the INL of the Sod2-deficient animals, rather than the ONL, as with aging. These findings suggest that oxidative stress produced by increased mitochondrial ROS generation may not provide a good model for aging change in the mouse retina in the age groups studied. However, the ocular features caused by absence of Sod2 may not be fully evolved in these animals because of death before maturity, caused by the devastating effects on other organ systems.

In summary, in addition to extensive abnormalities in other organ systems, Sod2tm1Cje-/- mice manifest pathologic changes in retina and extraocular muscle, more similar to human mitochondrial disease than aging.


   Footnotes
 
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. JMS is a recipient of a Royal Australian College of Ophthalmologists/OPSM fellowship, 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.

Submitted for publication December 12, 2000; revised May 7, 2001; accepted May 10, 2001.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Nancy J. Newman, Neuro-Ophthalmology Unit, Emory Eye Center, 1365B Clifton Road, Atlanta, GA 30322. ophtnjn{at}emory.edu


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Simonian, NA, Coyle, JT (1996) Oxidative stress in neurodegenerative diseases Annu Rev Pharmacol Toxicol 36,83-106[Medline][Order article via Infotrieve]
  2. Wallace, DC (1999) Mitochondrial disease in man and mouse Science 283,1482-1488[Abstract/Free Full Text]
  3. Melov, S, Coskun, P, Patel, M, et al (1999) Mitochondrial disease in superoxide dismutase 2 mutant mice Proc Natl Acad Sci USA 96,846-851[Abstract/Free Full Text]
  4. Li, Y, Huang, TT, Carlson, EJ, et al (1995) Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase Nat Genet 11,376-381[Medline][Order article via Infotrieve]
  5. Williams, MD, Van Remmen, H, Conrad, CC, Huang, TT, Epstein, CJ, Richardson, A. (1998) Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice J Biol Chem 273,28510-28515[Abstract/Free Full Text]
  6. Melov, S, Schneider, JA, Day, BJ, et al (1998) A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase Nat Genet 8,59-163
  7. Cai, J, Nelson, KC, Wu, M, Sternberg, P, Jr, Jones, DP (2000) Oxidative damage and protection of the RPE Prog Retinal Eye Res 19,205-221[Medline][Order article via Infotrieve]
  8. Katz, ML, Stone, WL, Dratz, EA (1978) Fluorescent pigment accumulation in retinal pigment epithelium of antioxidant-deficient rats Invest Ophthalmol Vis Sci 17,1049-1058[Abstract/Free Full Text]
  9. Weisse, I. (1995) Changes in the aging rat retina Ophthalmic Res 27(suppl 1),154-163
  10. Braekevelt, CR, Hollenberg, MJ (1970) The development of the retina of the albino rat Am J Anat 127,281-302[Medline][Order article via Infotrieve]
  11. Dangata, YY, Findlater, GS, Kaufman, MH (1996) Postnatal development of the otic nerve in (C57BLxCBA)F1 hybrid mice: general changes in morphometric parameters J Anat 189,117-125
  12. Chang, TS, Johns, DR, Walker, D, de la Cruz, Z, Maumenee, I, Green, R. (1993) Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes Arch Ophthalmol 111,1254-1262[Abstract/Free Full Text]
  13. Eagle, RC, Hedges, TR, Yanoff, M. (1982) The atypical pigmentary retinopathy of Kearns-Sayre syndrome: a light and electron microscope study Ophthalmology 89,1433-1440[Medline][Order article via Infotrieve]
  14. McKechnie, NM, King, M, Lee, WR (1985) Retinal pathology in the Kearns-Sayre syndrome Br J Ophthalmol 69,63-75[Abstract/Free Full Text]
  15. Isashiki, Y, Nakagawa, M, Ohba, N, et al (1998) Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation Acta Ophthalmol Scand 76,6-13[Medline][Order article via Infotrieve]
  16. Kimura, K, Isashiki, Y, Sonoda, S, Kakiuchi-Matsumoto, T, Ohba, N. (2000) Genetic association of manganese superoxide dismutase with exudative age related macular degeneration Am J Ophthalmol 130,769-773[Medline][Order article via Infotrieve]
  17. Katz, ML, Robison, WG, Jr (1984) Age-related changes in the retinal pigment epithelium of pigmented rats Exp Eye Res 38,137-151[Medline][Order article via Infotrieve]
  18. Feeney, L. (1978) Lipofuscin and melanin of human retinal pigment epithelium: fluorescence, enzyme cytochemical, and ultrastructural studies Invest Ophthalmol Vis Sci 17,583-600[Abstract/Free Full Text]



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