Mitochondrial DNA Damage as a Potential Mechanism for Age-Related Macular Degeneration

Karunadharma, Pabalu; Nordgaard, Curtis L.; Olsen, Timothy W.; Ferrington, Deborah A.

doi:10.1167/iovs.10-5429

Cited by 215 publications

(207 citation statements)

References 44 publications

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“…11 Increased mitochondrial damage and generation of reactive oxygen species (ROS) are associated with AMD, suggesting that damaged mitochondria and other oxidatively modified components are not efficiently removed by the aged-RPE cell. 11,12 Autophagy is especially crucial in the maintenance of homeostasis of the RPE since these cells are exposed to sustained oxidative stress. 6 A number of studies have reported that autophagy occurs in the RPE.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

et al. 2014

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Autophagic dysregulation has been suggested in a broad range of neurodegenerative diseases including agerelated macular degeneration (AMD). To test whether the autophagy pathway plays a critical role to protect retinal pigmented epithelial (RPE) cells against oxidative stress, we exposed ARPE-19 and primary cultured human RPE cells to both acute (3 and 24 h) and chronic (14 d) oxidative stress and monitored autophagy by western blot, PCR, and autophagosome counts in the presence or absence of autophagy modulators. Acute oxidative stress led to a marked increase in autophagy in the RPE, whereas autophagy was reduced under chronic oxidative stress. Upregulation of autophagy by rapamycin decreased oxidative stress-induced generation of reactive oxygen species (ROS), whereas inhibition of autophagy by 3-methyladenine (3-MA) or by knockdown of ATG7 or BECN1 increased ROS generation, exacerbated oxidative stress-induced reduction of mitochondrial activity, reduced cell viability, and increased lipofuscin. Examination of control human donor specimens and mice demonstrated an age-related increase in autophagosome numbers and expression of autophagy proteins. However, autophagy proteins, autophagosomes, and autophagy flux were significantly reduced in tissue from human donor AMD eyes and 2 animal models of AMD. In conclusion, our data confirm that autophagy plays an important role in protection of the RPE against oxidative stress and lipofuscin accumulation and that impairment of autophagy is likely to exacerbate oxidative stress and contribute to the pathogenesis of AMD.

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Section: Introductionmentioning

confidence: 99%

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

et al. 2014

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“…The daily phagocytosis of photoreceptor outer segments by the RPE leads to the accumulation of the phototoxin N-retinyl-N-retinylidene ethanolamine (A2E) and other compounds that can inhibit mitochondrial function (13,14,17), possibly through oxidative damage (18). mtDNA isolated from macular RPE of individuals with AMD exhibits significantly more damage than that from age-matched controls (19). Genetic studies implicate several mtDNA haplotypes (20,21) and a nuclear gene encoding a mitochondria-associated protein (22) as AMD risk factors.…”

Section: Introductionmentioning

confidence: 99%

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Zhao

Yasumura²,

Li³

et al. 2011

J. Clin. Invest.

267

285

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Retinal pigment epithelial (RPE) cell dysfunction plays a central role in various retinal degenerative diseases, but knowledge is limited regarding the pathways responsible for adult RPE stress responses in vivo. RPE mitochondrial dysfunction has been implicated in the pathogenesis of several forms of retinal degeneration. Here we have shown that postnatal ablation of RPE mitochondrial oxidative phosphorylation in mice triggers gradual epithelium dedifferentiation, typified by reduction of RPE-characteristic proteins and cellular hypertrophy. The electrical response of the retina to light decreased and photoreceptors eventually degenerated. Abnormal RPE cell behavior was associated with increased glycolysis and activation of, and dependence upon, the hepatocyte growth factor/met proto-oncogene pathway. RPE dedifferentiation and hypertrophy arose through stimulation of the AKT/mammalian target of rapamycin (AKT/mTOR) pathway. Administration of an oxidant to wild-type mice also caused RPE dedifferentiation and mTOR activation. Importantly, treatment with the mTOR inhibitor rapamycin blunted key aspects of dedifferentiation and preserved photoreceptor function for both insults. These results reveal an in vivo response of the mature RPE to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function. Our findings provide a rationale for mTOR pathway inhibition as a therapeutic strategy for retinal degenerative diseases involving RPE stress. IntroductionThe retinal pigment epithelium (RPE) is a polarized, cuboidal epithelial cell layer situated in the outer retina between the photoreceptors and choroidal vasculature. The RPE supplies an estimated 60% of the glucose consumed by the neural retina (1) and performs a variety of other functions crucial for retinal homeostasis, including delivery of amino acids and docosahexaenoic acid for photoreceptor protein and membrane synthesis; transport, storage, and enzymatic conversion of retinoids essential for phototransduction; regulation of fluid and ion balance in the subretinal space; maintenance of the blood retinal barrier; secretion of growth factors; and phagocytosis of shed photoreceptor outer segment membranes (2). The RPE is a postmitotic tissue, so RPE cells must carry out these functions for the life of an individual.The retinal degenerative consequences of mutations in RPEexpressed genes illustrate the importance of the RPE for photoreceptor viability in humans. Mutations that impair production of the chromophore 11-cis retinal cause Leber congenital amaurosis, retinitis pigmentosa (RP), and allied disorders (3). Disruption of RPE phagocytosis causes RP and rod/cone dystrophy (4, 5). Mutations that affect ion channel function cause disease of the specialized retinal region necessary for high-acuity vision (the macula) (6) as well as RP (7), while mutations in genes encoding the RPE-secreted proteins TIMP3 (8) and EFEMP1 (9) cause lateronset macular disease.

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“…The advent of genetic linkage and next-generation sequencing (NGS) technologies has led to significant insights into the role of mitochondrial mutations in driving disease processes [3,4]. Mitochondrial disorders can be subdivided into three classes: (i) primary mitochondrial disorders caused by mutations in mitochondrial genes; (ii) disorders with mutations in nuclear genes involved in mitochondrial function; and (iii) secondary disorders that arise from the accumulation of mitochondrial damage over time frequently involving neurodegenerative pathologies [5][6][7][8]. Tissues such as retina, brain, and muscle, which have enormous energy requirements, are particularly vulnerable to variations in mitochondrial function.…”

Section: Mitochondrial Dysfunction In Human Disordersmentioning

confidence: 99%

“…Approximately 50% of mitochondrial disorders have an ocular phenotype [9]. In addition to dominant optic atrophy (DOA) [10] and LHON (Box 1 [11]), mitochondrial dysfunction has been linked to multifactorial diseases, including age-related macular degeneration (AMD) [7,12] and diabetic retinopathies [12], as well as complex disorders involving multiple tissues, including the eye, such as neuropathy, ataxia and retinitis pigmentosa (NARP) and Kearns-Sayre syndrome (KSS) [13,14].…”

Section: Mitochondrial Dysfunction In Human Disordersmentioning

confidence: 99%

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

et al. 2013

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Mitochondrial DNA Damage as a Potential Mechanism for Age-Related Macular Degeneration

Abstract: Collectively, the data indicate that mtDNA is preferentially damaged with AMD progression. These results suggest a potential link between mt dysfunction due to increased mtDNA lesions and AMD.

Cited by 215 publications

References 44 publications

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

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