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The bisretinoids of retinal pigment epithelium
Open accessAbstract
The retina exhibits an inherent autofluorescence that is imaged ophthalmoscopically as fundus autofluorescence. In clinical settings, fundus autofluorescence examination aids in the diagnosis and follow-up of many retinal disorders. Fundus autofluorescence originates from the complex mixture of bisretinoid fluorophores that are amassed by retinal pigment epithelial (RPE) cells as lipofuscin. Unlike the lipofuscin found in other cell-types, this material does not form as a result of oxidative stress. Rather, the formation is attributable to non-enzymatic reactions of vitamin A aldehyde in photoreceptor cells; transfer to RPE occurs upon phagocytosis of photoreceptor outer segments. These fluorescent pigments accumulate even in healthy photoreceptor cells and are generated as a consequence of the light capturing function of the cells. Nevertheless, the formation of this material is accelerated in some retinal disorders including recessive Stargardt disease and ELOVL4-related retinal degeneration. As such, these bisretinoid side-products are implicated in the disease processes that threaten vision. In this article, we review our current understanding of the composition of RPE lipofuscin, the structural characteristics of the various bisretinoids, their related spectroscopic features and the biosynthetic pathways by which they form. We will revisit factors known to influence the extent of the accumulation and therapeutic strategies being used to limit bisretinoid formation. Given their origin from vitamin A aldehyde, an isomer of the visual pigment chromophore, it is not surprising that the bisretinoids of retina are light sensitive molecules. Accordingly, we will discuss recent findings that implicate the photodegradation of bisretinoid in the etiology of age-related macular degeneration.
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“Dysfunction of such processes as phagocytosis, lysosomal degradation, and removal of waste products by the RPE can lead to severe retinopathies, including age-related macular degeneration (AMD).”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [270]
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“As A2E can not be further metabolized and as RPE cells are postmitotic, A2E and related bisretinoids accumulate in the RPE in the form of lipofuscin deposits.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [74]
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“Although abundant lipofuscin accumulation is involved in the aetiology of certain retinal diseases (e.g., AMD, Best disease and ABCA4-retinopathy), it accumulates at a lower level also with age in the RPE of healthy eyes [9,72,73,74,75].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [74]
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“Lipofuscin is an autofluorescent cellular waste product that compromises the function and viability of RPE cells and ultimately results in photoreceptor degeneration and a loss of vision [54,69,73,74,75].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [74]
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“In the membranes of outer photoreceptor segments are nonenzymatically formed toxic bisretinoids. Upon phagocytosis, these bisretinoids are in the acidic environment of RPE phagolysosomes converted to bisretinoid pyridinium compound A2E and related bisretinoids [54,69,70,71,72,73,74].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [74]
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“Several potentially toxic byproducts are condensation compounds derived from all-trans-retinal.”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [270]
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“They also increase with age because they are delivered from photoreceptors (at least the first steps of condensation reaction occur in ROS) by daily phagocytosis.”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [270]
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“Second, bis-retinoids constitute the major extractable component of lipofuscin (Kim et al., 2007; Sparrow et al., 2012).”
From New insights into retinoid metabolism and cycling within the retina (2013) · cites this paper as Sparrow et al., 2012
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Metadata
- Authors
- Sparrow, J. R., Gregory-Roberts, E., Yamamoto, K., Blonska, A., Ghosh, S. K., Ueda, K., & Zhou, J.
- Affiliations
- Columbia University Irving Medical Center (US)
- Columbia University (US)
- Corresponding author
- Sparrow, Janet R.
- Venue
- Progress in Retinal and Eye Research
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 31
- Issue
- 2
- Pages
- 121-135
- ISSN
- 1350-9462 (ISSN-L)
- PMC
- PMC3288746
- OpenAlex
- W2019731198
- Cited by
- 392
- References
- 140
- Citations by year
- 2026: 19 · 2025: 26 · 2024: 26 · 2023: 24 · 2022: 23 · 2021: 34 · 2020: 35 · 2019: 33 · 2018: 29 · 2017: 28 · 2016: 25 · 2015: 31 · 2014: 30 · 2013: 21 · 2012: 8
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Progress in Retinal and Eye Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (R01EY012951, EY 12951, P30EY019007)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- bisretinoids, retinal pigment epithelium, lipofuscin, fundus autofluorescence, vitamin A aldehyde, photoreceptor outer segment phagocytosis, Stargardt disease, age-related macular degeneration, photodegradation, retinal degeneration
- MeSH terms
- Animals, Cattle, Fluorescence, Humans, Lipofuscin, Macular Degeneration, Retinaldehyde, Retinoids, Spectrometry, Fluorescence, Molecular Structure, Mice, Rats, Retinal Pigment Epithelium
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