Retinal pigment epithelium, age-related macular degeneration and neurotrophic keratouveitis

Bianchi, Enrica; Scarinci, Fabio; Ripandelli, Guido; Fehér, János; Pacella, Elena; Magliulo, Giuseppe; Gabrieli, C. Balacco; Plateroti, Rocco; Plateroti, Pasquale; Mignini, Fiorenzo; Artico, Marco

doi:10.3892/ijmm.2012.1164

Cited by 34 publications

(25 citation statements)

References 92 publications

(95 reference statements)

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“…In the murine RPE, metabolic or oxidative stress resulted in the formation of large mitochondria produced by activation of the P13/AKT/mTor signaling pathway 47 . From our data, a decrease in mitochondrial size with age appears to be the normal progression in WT zebrafish, which has also been observed in human RPE cells 48,49 . To explore whether the abnormal growth in the obe td15 retina may be related to alterations in the mitochondrial dynamics, we investigated fis1 and opa1 expression as indicators of fission and fusion, respectively.…”

Section: Discussionsupporting

confidence: 82%

Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy

Toms¹,

Burgoyne²,

Tracey‐White³

et al. 2019

Sci Rep

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Mutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD). We examined the retina of kcnj13 mutant zebrafish ( obelix td15 , c.502T > C p.[Phe168Leu]) to provide new insights into the pathophysiology underlying these conditions. Detailed phenotyping of obelix td15 fish revealed a late onset retinal degeneration at 12 months. Electron microscopy of the obelix td15 retinal pigment epithelium (RPE) uncovered reduced phagosome clearance and increased mitochondrial number and size prior any signs of retinal degeneration. Melanosome distribution was also affected in dark-adapted 12-month obelix td15 fish. At 6 and 12 months, ATP levels were found to be reduced along with increased expression of glial fibrillary acidic protein and heat shock protein 60. Quantitative RT-PCR of polg2 , fis1 , opa1 , sod1/2 and bcl2a from isolated retina showed expression changes consistent with altered mitochondrial activity and retinal stress. We propose that the retinal disease in this model is primarily a failure of phagosome physiology with a secondary mitochondrial dysfunction. Our findings suggest that alterations in the RPE and photoreceptor cellular organelles may contribute to KCNJ13 -related retinal degeneration and provide a therapeutic target.

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Section: Discussionsupporting

confidence: 82%

Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy

Toms¹,

Burgoyne²,

Tracey‐White³

et al. 2019

Sci Rep

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“…Quantitative analysis confirmed the significantly increased presence of autophagic structures in PD cells (Figure 6G ; p < 0.01, Unpaired t- test). Furthermore, in addition to typical autophagosomes and autophagolysosomes (Figures 6C,F ; black arrows, black arrowhead showing high magnification of an autophagolysosome) a marked increase in very dense structures, potentially compatible with lysosomes containing undegraded residues, was seen broadly in PD cells (Figures 6D,E,I ; white arrows; Bianchi et al, 2013 ; Biswal et al, 2016 ). Given the autofluorescent nature of lipofuscin, flow cytometry was used to analyze autofluorescence levels in the fibroblasts.…”

Section: Resultsmentioning

confidence: 86%

Parkinson's Disease Skin Fibroblasts Display Signature Alterations in Growth, Redox Homeostasis, Mitochondrial Function, and Autophagy

et al. 2018

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The discovery of biomarkers for Parkinson's disease (PD) is challenging due to the heterogeneous nature of this disorder, and a poor correlation between the underlying pathology and the clinically expressed phenotype. An ideal biomarker would inform on PD-relevant pathological changes via an easily assayed biological characteristic, which reliably tracks clinical symptoms. Human dermal (skin) fibroblasts are accessible peripheral cells that constitute a patient-specific system, which potentially recapitulates the PD chronological and epigenetic aging history. Here, we compared primary skin fibroblasts obtained from individuals diagnosed with late-onset sporadic PD, and healthy age-matched controls. These fibroblasts were studied from fundamental viewpoints of growth and morphology, as well as redox, mitochondrial, and autophagic function. It was observed that fibroblasts from PD subjects had higher growth rates, and appeared distinctly different in terms of morphology and spatial organization in culture, compared to control cells. It was also found that the PD fibroblasts exhibited significantly compromised mitochondrial structure and function when assessed via morphological and oxidative phosphorylation assays. Additionally, a striking increase in baseline macroautophagy levels was seen in cells from PD subjects. Exposure of the skin fibroblasts to physiologically relevant stress, specifically ultraviolet irradiation (UVA), further exaggerated the autophagic dysfunction in the PD cells. Moreover, the PD fibroblasts accumulated higher levels of reactive oxygen species (ROS) coupled with lower cell viability upon UVA treatment. In essence, these studies highlight primary skin fibroblasts as a patient-relevant model that captures fundamental PD molecular mechanisms, and supports their potential utility to develop diagnostic and prognostic biomarkers for the disease.

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“…In addition to glycolysis, mitochondrial function is also essential for proper photoreceptor function, as deletion of the mitochondrial pyruvate carrier (MPC1) in the neuroretina results in retinal degeneration 42 . Several findings have also implicated metabolic dysregulation in the pathogenesis of AMD 43–45 . In this disease, RPE dysfunction is considered a primary event, and studies have shown that RPE stability and its ability to support retinal function is reduced when it is forced to rely on glycolysis 46 .…”

Section: Discussionmentioning

confidence: 99%

AMP-activated-protein kinase (AMPK) is an essential sensor and metabolic regulator of retinal neurons and their integrated metabolism with RPE

Brown

Keuthan

et al. 2020

Preprint

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15The retina has one of the highest energy demands in the human body, and proper 16 regulation of metabolism among the cell types of the retina is required for functional vision. 17Recent studies have reported that retinal metabolism is disrupted during retinal degeneration 18 and aging, while therapies designed to enhance metabolism can slow or prevent degeneration. 19Here, we show that multiple metabolic pathways, including those regulated by a key ATP sensor 20 and regulator of metabolism, AMP-activated-kinase (AMPK), were dysregulated in a model of 21 inherited retinal degeneration. In order to assess the direct role of AMPK in regulating retinal 22 metabolism, we used mice with retina-specific knockout of AMPK activity. Conditional loss of 23 AMPK resulted in impaired visual function at an early age, with slow photoreceptor loss 24 observed in older mice. Moreover, we found that loss of AMPK resulted in decreased metabolic 25 flux from glucose, decreased mitochondrial DNA copy number, decreased mitochondrial-related 26 gene expression, and alterations in mitochondrial morphology in the photoreceptors, all of which 27 preceded degeneration. Surprisingly, metabolic changes from the loss of AMPK in retinal 28 neurons also resulted in secondary degeneration of retinal pigment epithelial (RPE) cells. 29Together, these data show that AMPK signaling is important for maintaining metabolic 30 homeostasis of the retina and support the hypothesis that photoreceptors and RPE have a 31 shared metabolic ecosystem that is controlled, in part, by AMPK. 32 33 Main 34 The central nervous system, including the retina, is often cited as having one of the 35 highest energy demands in the body, with pathways that require utilization of ATP, glucose, 36 lactate, fatty acids, glutathione (GSH), and NADPH for proper neuronal function and protection 37 against retinal degeneration 1-4 . As much as half of the metabolites and metabolic activity in the 38 retina are located in the light-sensitive photoreceptors 5,6 . ATP is heavily consumed by NaK-39 ATPases in photoreceptors to maintain the ion gradient within the cells, and a considerable 40 amount of energy is dedicated to supporting phototransduction in response to light 1,2 . While 41 disruption of metabolism has been associated with retinal degeneration, manipulations that 42 restore energy homeostasis by enhancing glycolysis or mitochondrial activity can preserve 43 retinal function and promote photoreceptor survival 7-12 . 44 However, little is known about how metabolic activity is regulated in the retina. The 5' 45 adenosine monophosphate-activated protein kinase (AMPK) pathway is a logical control 46 mechanism for high metabolic activity in cells. AMPK is an evolutionarily conserved 47 EY016459, the Foundation Fighting Blindness, and an unrestricted grant from Research to 388 Prevent Blindness. The authors wish to acknowledge the contributions of Lena Phu for her 389 assistance in genotyping, qRT-PCR, and measuring ONL thicknesses. The authors also wish to 390 acknowledge the...

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Retinal pigment epithelium, age-related macular degeneration and neurotrophic keratouveitis

Cited by 34 publications

References 92 publications

Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy

Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy

Parkinson's Disease Skin Fibroblasts Display Signature Alterations in Growth, Redox Homeostasis, Mitochondrial Function, and Autophagy

AMP-activated-protein kinase (AMPK) is an essential sensor and metabolic regulator of retinal neurons and their integrated metabolism with RPE

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