A vicious cycle of bisretinoid formation and oxidation relevant to recessive Stargardt disease

Kim, Hye Jin; Ueda, Keiko; Zhang, Kevin; Montenegro, Diego; Dunaief, Joshua L.; Sparrow, Janet R.

doi:10.1016/j.jbc.2021.100259

Cited by 17 publications

(31 citation statements)

References 63 publications

(104 reference statements)

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“…Surprisingly, a large range of different radicals are formed during phagocytosis of the outer segments, with superoxide, hydroxyl radicals, hydrogen peroxide (H2O2), and the hazardous Fenton-type reaction occuring inside the phagosomes [24]. Radicals [25] can degrade bisretinoids [14, 26] and therefore some bisretinoid removal may take place during phagocytosis. However, phagosomal degradation is not able to digest all components completely particularly when there is an overload with bisretinoids as in Abca4 -/- mice.…”

Section: Discussionmentioning

confidence: 99%

Melanosomes degrade lipofuscin and precursors that are derived from photoreceptor membrane turnover in the retinal pigment epithelium—an explanation for the origin of the melanolipofuscin granule

Lyu¹,

Tschulakow²,

Schraermeyer³

2022

Preprint

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The accumulation of the age pigment lipofuscin within the retinal pigment epithelium (RPE) is one the most remarkable changes observed in association with age-related macular degeneration (AMD) and Stargardt disease. Both aging and pathological processes lead to the accumulation of melanolipofuscin (MLF) granules, which have been reported to reflect the onset of AMD more accurately than lipofuscin. The underlying mechanism by which MLF forms is still not understood. We investigate the potential role that melanin plays in the degradation of lipofuscin and MLF in pigmented Abca4-/- mice following treatment with several NO generating drugs. Abca4-/- mice are generally used as models for lipofuscin-related eye diseases. We also induced melanogenesis in albino Abca4-/- mice via the over-expression of tyrosinase, the key enzyme involved in melanogenesis. We compared the ultrastructure of lipofuscinogensis in the RPE of pigmented and albino Abca4-/- mice. Fluorescence microscopy was employed for the quantification of lipofuscin. We found high amounts of unique thin (3-4 nm) lamellar membranes (TLMs) that were left over from the degradation of photoreceptor disc membranes by high-resolution electron microscopy. Accumulated TLMs were significantly more frequent in the RPE cells of the albinos than the pigmented mice, indicating that melanin plays a role in removing TLMs. The intravitreal injection of several NO generating drugs was found to reduce the amount of autofluorescent lipofuscin in the cytoplasm of RPE cells, particularly the MLF granules of pigmented Abca4-/- mice. No effect was observed in terms of lipofuscin removal in NO-exposed albino Abca4-/- mice. However, transfection with tyrosinase led to a reduction in the lipofuscin levels of artificially pigmented RPE cells in albino Abca4-/- mice following the formation of melanin. The results show for the first time that melanin plays an important, if not a key, role in the degradation of lipofuscin in RPE cells.

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Section: Discussionmentioning

confidence: 99%

Melanosomes degrade lipofuscin and precursors that are derived from photoreceptor membrane turnover in the retinal pigment epithelium—an explanation for the origin of the melanolipofuscin granule

Lyu¹,

Tschulakow²,

Schraermeyer³

2022

Preprint

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“…This effect can be due to the initial oxidation of bisretinoids or other compounds resulting in the formation of oxidation products emitting fluorescence at about 530 nm. Further oxidation of these products can lead to their photodegradation accompanied by fluorescence decrease as suggested in recent reviews [53,68,90].…”

Section: Decrease In Long-wavelength Fluorescence During Photooxidation Of Lipofuscin and An Increase In Blue/cyan Or Green To Orange Flumentioning

confidence: 92%

Photodegradation of Lipofuscin in Suspension and in ARPE-19 cells and the Similarity of Fluorescence of the Photodegradation Product with Oxidized Docosahexaenoate

Różanowska¹,

Rozanowski²

2021

Preprint

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Retinal lipofuscin accumulates with age in the retinal pigment epithelium (RPE) where its fluorescence properties are used to assess the retinal health. It was observed that there is a decrease in lipofuscin fluorescence above the age of 75 years and in early stages of age-related macular degeneration (AMD). The purpose of this study was to investigate the response of lipofuscin isolated from human RPE, and lipofuscin-laden-cells to visible light, and determine whether an abundant component of lipofuscin, docosahexaenoate (DHA) can contribute to lipofuscin fluorescence upon oxidation. Exposure of lipofuscin to visible leads to a decrease of its long-wavelength fluorescence at about 610 nm with concomitant growth of the short-wavelength fluorescence. The emission spectrum of photodegraded lipofuscin exhibits similarity with that of oxidized DHA. Exposure to light of lipofuscin-laden cells leads to loss of lipofuscin granules from cells, while retaining cell viability. The spectral changes of fluorescence in lipofuscin-laden cells resemble those seen during photodegradation of isolated lipofuscin. Our results demonstrate that fluorescence emission spectra together with quantitation of intensity of long-wavelength fluorescence can serve as a marker useful for lipofuscin quantification and for monitoring its oxidation, thereby useful for screening the retina for increased oxidative damage and early AMD-related changes.

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“…Just as with photomediated oxidation [ 55 , 56 ], the conjugated systems of double bonds within bisretinoid structures can be oxidized as a consequence of iron-mediated hydroxyl radical production [ 76 ]. The latter mechanism explains the reduction in HPLC-(high-performance liquid chromatography) quantified bisretinoid levels in liver-specific hepcidin (Hepc)-knockout ( LS-Hepc −/− ) mice; these mice present with elevated iron in their blood and increased free (labile) iron levels in their retinal and RPE cells [ 77 , 78 ]. Similarly, the excessive iron in the RPE cells of mice deficient in ceruloplasmin (Cp) and hephaestin (Heph) ( Cp −/− ; Heph −/− mice) [ 79 ] is associated with toxic bisretinoid photo-oxidation and degradation [ 76 ].…”

Section: Iron-assisted Oxidation Of Bisretinoidsmentioning

confidence: 99%

“…Under these conditions, it was surmised that light in the presence of the photosensitizer A2E potentiated the Fenton reaction due to reduction of Fe 3+ to Fe 2+ (one electron transfer) by superoxides (O 2 •− ) [ 46 , 76 , 83 , 84 ] ( Figure 6 ). Synergy between the Fenton reaction, photosensitization of bisretinoids, and redox conversion of the Fe 2+ and Fe 3+ oxidation states is significant to the retina since, unlike most tissues, the retina is exposed to visible light [ 77 ].…”

Section: Iron-assisted Oxidation Of Bisretinoidsmentioning

confidence: 99%

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Bisretinoids of the Retina: Photo-Oxidation, Iron-Catalyzed Oxidation, and Disease Consequences

et al. 2021

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The retina and, in particular, retinal pigment epithelial cells are unusual for being encumbered by exposure to visible light, while being oxygen-rich, and also amassing photoreactive molecules. These fluorophores (bisretinoids) are generated as a byproduct of the activity of vitamin A aldehyde—the chromophore necessary for vision. Bisretinoids form in photoreceptor cells due to random reactions of two molecules of vitamin A aldehyde with phosphatidylethanolamine; bisretinoids are subsequently transferred to retinal pigment epithelial (RPE) cells, where they accumulate in the lysosomal compartment with age. Bisretinoids can generate reactive oxygen species by both energy and electron transfer, and they become photo-oxidized and photolyzed in the process. While these fluorescent molecules are accrued by RPE cells of all healthy eyes, they are also implicated in retinal disease.

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A vicious cycle of bisretinoid formation and oxidation relevant to recessive Stargardt disease

Cited by 17 publications

References 63 publications

Melanosomes degrade lipofuscin and precursors that are derived from photoreceptor membrane turnover in the retinal pigment epithelium—an explanation for the origin of the melanolipofuscin granule

Melanosomes degrade lipofuscin and precursors that are derived from photoreceptor membrane turnover in the retinal pigment epithelium—an explanation for the origin of the melanolipofuscin granule

Photodegradation of Lipofuscin in Suspension and in ARPE-19 cells and the Similarity of Fluorescence of the Photodegradation Product with Oxidized Docosahexaenoate

Bisretinoids of the Retina: Photo-Oxidation, Iron-Catalyzed Oxidation, and Disease Consequences

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