Accumulation of A2-E in mitochondrial membranes of cultured RPE cells

Schütt, F.; Bergmann, Marion; Holz, Frank G.; Dithmar, Stefan; Völcker, Hans-Eberhard; Kopitz, Jürgen

doi:10.1007/s00417-006-0376-5

Cited by 18 publications

(15 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We and others have previously used microscopy to demonstrate that A2E primarily accumulates in lysosomes of RPE cells in culture (15,17,36,37). Schutt and colleagues (38) recently used biochemical analysis to confirm that A2E efficiently distributes to RPE lysosomes during initial experimental load and that A2E remains in these organelles for extended periods of time unless cells receive more and more A2E in sequential additions. We found no evidence for mitochondrial localization of A2E after our standard one time 6-h load with A2E that results in cellular concentrations within the normal range of aged human RPE (17,36).…”

Section: Discussionmentioning

confidence: 99%

The Age Lipid A2E and Mitochondrial Dysfunction Synergistically Impair Phagocytosis by Retinal Pigment Epithelial Cells

Vives-Bauzà

Anand

Shirazi

et al. 2008

Journal of Biological Chemistry

140

110

View full text Add to dashboard Cite

Accumulation of indigestible lipofuscin and decreased mitochondrial energy production are characteristic age-related changes of post-mitotic retinal pigment epithelial (RPE) cells in the human eye. To test whether these two forms of age-related impairment have interdependent effects, we quantified the ATPdependent phagocytic function of RPE cells loaded or not with the lipofuscin component A2E and inhibiting or not mitochondrial ATP synthesis either pharmacologically or genetically. We found that physiological levels of lysosomal A2E reduced mitochondrial membrane potential and inhibited oxidative phosphorylation (OXPHOS) of RPE cells. Furthermore, in media with physiological concentrations of glucose or pyruvate, A2E significantly inhibited phagocytosis. Antioxidants reversed these effects of A2E, suggesting that A2E damage is mediated by oxidative processes. Because mitochondrial mutations accumulate with aging, we generated novel genetic cellular models of RPE carrying mitochondrial DNA point mutations causing either moderate or severe mitochondrial dysfunction. Exploring these mutant RPE cells we found that, by itself, only the severe but not the moderate OXPHOS defect reduces phagocytosis. However, sub-toxic levels of lysosomal A2E are sufficient to reduce phagocytic activity of RPE with moderate OXPHOS defect and cause cell death of RPE with severe OXPHOS defect. Taken together, RPE cells rely on OXPHOS for phagocytosis when the carbon energy source is limited. Our results demonstrate that A2E accumulation exacerbates the effects of moderate mitochondrial dysfunction. They suggest that synergy of sub-toxic lysosomal and mitochondrial changes in RPE cells with age may cause RPE dysfunction that is known to contribute to human retinal diseases like agerelated macular degeneration. Retinal pigment epithelial (RPE)5 cells form a polarized monolayer epithelium between the photoreceptors of the neurosensory retina and the choroidal capillary bed. Daily phagocytosis of outer segment (OS) tips shed by adjacent photoreceptors is a vital task of the RPE (recently reviewed by Strauss (1)). RPE cells are post-mitotic and face each ϳ30 photoreceptor outer segments in the human eye, all of which shed their distal tip containing stacked membrane disks once a day. Diurnal phagocytosis and digestion of thousands of OS disks for life renders RPE cells the most active phagocytes in the body. Photoreceptor function strictly depends on efficient RPE phagocytosis of spent OS. Complete failure of RPE cells to engulf OS causes rapid photoreceptor degeneration in the Royal College of Surgeons rat (2-4). Impaired RPE phagocytosis also contributes to human retinal disease such as retinitis pigmentosa and, likely, age-related macular degeneration (5, 6).The continuous nature of outer segment renewal implies that any delay in OS removal by aged or damaged RPE will gradually cause OS components to accumulate. RPE cells are at risk for oxidative damage due to their location in the highly oxygenated environment of the outer retina and th...

show abstract

Section: Discussionmentioning

confidence: 99%

The Age Lipid A2E and Mitochondrial Dysfunction Synergistically Impair Phagocytosis by Retinal Pigment Epithelial Cells

Vives-Bauzà

Anand

Shirazi

et al. 2008

Journal of Biological Chemistry

140

110

View full text Add to dashboard Cite

show abstract

Section: Lysosomal Membrane Permeabilization (Lmp)mentioning

confidence: 99%

“…Toxicity of lipofuscin could also involve other less-studied mechanisms, including mitochondrial poisoning, as it has been shown that lysosomal A2E progressively leaks into the mitochondrial compartment [100], where it destabilizes the membrane [101] and inhibits oxidative phosphorylation [102], derail of cholesterol traicking [103], activation of Retinoid Acid Receptor (RAR)-dependent VEGF secretion in RPE [104,105], and inhibition of RPE-65 isomerohydrolase activity, which limits the RPE supply of 11-cis retinal [106]. In summary, although numerous mechanisms of toxicity elicited by pathologic accumulation of LBs in RPE lysosomes have been proposed, no viable therapeutic options have resulted yet from targeting them.…”

Section: Lysosomal Membrane Permeabilization (Lmp)mentioning

confidence: 99%

“…cannot cross 0.10 micron pore size ilters with molecular weight cutof of 300,000 Da. This retention was due to size exclusion as A2E passed through 3 micron ilters of the same material ( Figure 5).Toxicity of lipofuscin could also involve other less-studied mechanisms, including mitochondrial poisoning, as it has been shown that lysosomal A2E progressively leaks into the mitochondrial compartment [100] …”

mentioning

confidence: 99%

See 1 more Smart Citation

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

Nociari¹,

Kiss²,

Rodríguez-Boulan³

2017

Lysosomes - Associated Diseases and Methods to Study Their Function

View full text Add to dashboard Cite

Photoreceptors undergo a constant renewal of their light sensitive outer segments (POSs). In the renewal process, 10% of the POS mass is daily phagocytized by the adjacent retinal pigment epithelium (RPE). POS contain vast amounts of 11-cis retinal and alltrans-retinal, two highly reactive vitamin A aldehydes that spontaneously dimerize into lipid bisretinoids (LBs) and accumulate into RPE lysosomes during phagocytosis. As LBs are refractory to lysosomal hydrolases and RPE cells do not divide, this accumulation is irreversible and results in the formation of lipofuscin granules. Lipofuscin accumulation is toxic for RPE cells through a variety of light-dependent and light-independent mechanisms. Beyond a threshold, RPE cells die resulting in secondary loss of overlying photoreceptors. Currently, there are no efective treatments for retinal disorders associated with genetic or age-associated LB accumulation, such as Stargardt disease and age-related macular degeneration (AMD). Thus, there is a great need for medical interventions. Here, we discuss the current understanding of lipofuscin's pathogenicity and the status of diferent strategies under development to promote LB elimination from RPE lysosomes.Keywords: lipofuscin, Stargardt, age-related macular degeneration (AMD), bisretinoids, retinal pigment epithelium (RPE), cyclodextrins, cellular clearance, TFEB, lysosome IntroductionTo understand the origin and consequences of the lysosomal accumulation of lipofuscin in the eye, a basic knowledge of retinal function and organization is required.© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The retinal pigment epithelium (RPE) in vertebrate's eyesLight entering the eye gets refracted by the cornea and lens on the neural retina, where photoreceptors (PR) convert photons into a cascade of chemical and electrical events that propagate to second-order (horizontal, bipolar, and amacrine cells) and third-order (ganglion cells) retinal neurons, which distribute this information to various visual centers of the brain through the ibers of the optic nerve. The bodies of PR cells, rods and cones, display three sectors (Figure 1): the outer segment, illed with stacks of disks densely packed with light-sensitive photopigment; the inner segment, illed with genetic, biosynthetic, and metabolic organelles Lysosomes -Associated Diseases and Methods to Study Their Function 4(nucleus, endoplasmic reticulum, Golgi complex, ribosomes, mitochondria); and the synaptic terminal that connects with bipolar neurons of the retina. In vertebrates, the retina is inverted in the sense that light passes through secondary and tertiary neuronal layers in the inner retina before reaching the rods and cones in the outer retina (Figure 1). Photoreceptors are metabolically very active cells that req...

show abstract

“…Diese Aktivitäten stellen eine hohe Belastung dar, die durch metabolische Abbauprodukte wie z. B. freie Radikale oder oxidierte Lipide, Beeinträchtigungen erfahren können, welche die Funktionsfähigkeit des Komplexes langfristig herabsetzen [2].…”

unclassified

Genetisches Risiko bei der altersabhängigen Makuladegeneration

et al. 2015

View full text Add to dashboard Cite

Age-related macular degeneration (AMD) is a frequent cause of blindness influenced by environmental and genetic risk factors. While current knowledge on AMD genetics and its use in diagnostic testing is readily present in press and electronic media, risk quantification is still a challenge when communicating testing results. Here we ask whether and how this information is perceived by the public, specifically in light of the lack of preventive and therapeutic measures of this devastating disease.

show abstract

Accumulation of A2-E in mitochondrial membranes of cultured RPE cells

Cited by 18 publications

References 35 publications

The Age Lipid A2E and Mitochondrial Dysfunction Synergistically Impair Phagocytosis by Retinal Pigment Epithelial Cells

The Age Lipid A2E and Mitochondrial Dysfunction Synergistically Impair Phagocytosis by Retinal Pigment Epithelial Cells

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

Genetisches Risiko bei der altersabhängigen Makuladegeneration

Contact Info

Product

Resources

About