Removal of RPE lipofuscin results in rescue from retinal degeneration in a mouse model of advanced Stargardt disease: Role of reactive oxygen species

Fang, Yuan; Taubitz, Tatjana; Tschulakow, Alexander; Heiduschka, Peter; Szewczyk, Grzegorz; Burnet, Michael; Peters, Tobias; Biesemeier, Antje; Sarna, Tadeusz; Schraermeyer, Ulrich; Julien-Schraermeyer, Sylvie

doi:10.1016/j.freeradbiomed.2022.02.025

Cited by 11 publications

(12 citation statements)

References 49 publications

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“…Melanin could enhance these radical reactions by its bound transition metals substituting as an electron donor for making A2E • or its semiquinones serving as H donors to make A2EH +• . Riboflavin and Remofuscin also donate their light-excited electron to O 2 to make O 2 •– ( 13 , 17 ) and so could initiate similar reactions, perhaps near their target due to their melanin binding.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacologically, the lipofuscin component can be degraded following intravitreal injection with generators of oxygen radicals such as superoxide (O 2 •- ), peroxyl (OO•), and hydroperoxyl (HOO•), in both monkeys and Abca4 -/- mice. Examples include Remofuscin plus ambient or blue light ( 13 , 14 ), riboflavin ( 15 – 17 ), and peroxidase ( 18 , 19 ). The oxygen radical generator Visudyne plus red light, originally used to destroy pathological blood vessels in wet AMD, also efficiently removes the lipofuscin component from MLF granules in Abca4 -/- mice ( 20 ).…”

mentioning

confidence: 99%

“…Blue light itself, when absorbed by lipofuscin, generates superoxide and degrades the lipofuscin, but with toxic effect ( 21 , 22 ). Remofuscin treatment not only removes lipofuscin from the RPE of monkeys and aged primary human RPE cells but also rescues existing retinal degeneration in an advanced Stargardt mouse model ( 13 , 14 ).…”

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confidence: 99%

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Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration

Lyu¹,

Tschulakow²,

Wang³

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Age-related macular degeneration, Stargardt disease, and their Abca4 -/- mouse model are characterized by accelerated accumulation of the pigment lipofuscin, derived from photoreceptor disc turnover in the retinal pigment epithelium (RPE); lipofuscin accumulation and retinal degeneration both occur earlier in albino mice. Intravitreal injection of superoxide (O 2 •– ) generators reverses lipofuscin accumulation and rescues retinal pathology, but neither the target nor mechanism is known. Here we show that RPE contains thin multi-lamellar membranes (TLMs) resembling photoreceptor discs, which associate with melanolipofuscin granules in pigmented mice but in albinos are 10-fold more abundant and reside in vacuoles. Genetically over-expressing tyrosinase in albinos generates melanosomes and decreases TLM-related lipofuscin. Intravitreal injection of generators of O 2 •– or nitric oxide ( • NO) decreases TLM-related lipofuscin in melanolipofuscin granules of pigmented mice by ~50% in 2 d, but not in albinos. Prompted by evidence that O 2 •– plus • NO creates a dioxetane on melanin that excites its electrons to a high-energy state (termed “chemiexcitation”), we show that exciting electrons directly using a synthetic dioxetane reverses TLM-related lipofuscin even in albinos; quenching the excited-electron energy blocks this reversal. Melanin chemiexcitation assists in safe photoreceptor disc turnover.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration

Lyu¹,

Tschulakow²,

Wang³

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…Strikingly, the lipofuscin component of melanolipofuscin can be degraded following intravitreal injection with generators of O 2 ÁÀ or Á NO, in both monkeys and Abca4 À/À mice, with some even rescuing retinal degeneration in an advanced Stargardt mouse model. The radical generators used include drugs, riboflavin, and light (169)(170)(171)(172)(173)(174). Lipofuscin removal from cultured human RPE was blocked by a radical scavenger (172).…”

Section: A Roster Of Candidate Degenerative Diseasesmentioning

confidence: 99%

Chemiexcitation: Mammalian Photochemistry in the Dark^†

Brash

Gonçalves

2023

Photochem & Photobiology

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Light is one way to excite an electron in biology. Another is chemiexcitation, birthing a reaction product in an electronically excited state rather than exciting from the ground state. Chemiexcited molecules, as in bioluminescence, can release more energy than ATP. Excited states also allow bond rearrangements forbidden in ground states. Molecules with low-lying unoccupied orbitals, abundant in biology, are particularly susceptible. In mammals, chemiexcitation was discovered to transfer energy from excited melanin, neurotransmitters, or hormones to DNA, creating the lethal and carcinogenic cyclobutane pyrimidine dimer. That process was initiated by nitric oxide and superoxide, radicals triggered by ultraviolet light or inflammation. Several poorly understood chronic diseases share two properties: inflammation generates those radicals across the tissue, and cells that die are those containing melanin or neuromelanin. Chemiexcitation may therefore be a pathogenic event in noise-and drug-induced deafness, Parkinson's disease, and Alzheimer's; it may prevent macular degeneration early in life but turn pathogenic later. Beneficial evolutionary selection for excitable biomolecules may thus have conferred an Achilles heel. This review of recent findings on chemiexcitation in mammalian cells also describes the underlying physics, biochemistry, and potential pathogenesis, with the goal of making this interdisciplinary phenomenon accessible to researchers within each field.

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“…It has been recognized very early in the studies on light-induced injury to the retina that RPE is the primary target for the threshold injury induced by light of 441 nm and longer wavelengths applied to the macaque retina [228]. More recent studies on macaques demonstrated that exposure of the retina to 460, 488, 544, 568, and 594 nm laser light can lead to bleaching of RPE fluorescence and, at higher retinal radiant exposures, varying from about 30 to 300 J/cm 2 for the shortest and longest wavelengths, respectively, to the disruption of the RPE mosaic, suggesting that photoreactivity of lipofuscin could contribute to the RPE injury [229][230][231][232].…”

Section: Effects Of Rpe Lipofuscin On the Function And Viability Of R...mentioning

confidence: 99%

Lipofuscin, Its Origin, Properties, and Contribution to Retinal Fluorescence as a Potential Biomarker of Oxidative Damage to the Retina

Różanowska¹

2023

Preprint

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Lipofuscin accumulates with age as intracellular fluorescent granules originating from incomplete lysosomal digestion of phagocytosed and autophagocytosed material. The purpose of this review is to provide an update on the current understanding of the role of oxidative stress and/or lysosomal dysfunction in lipofuscin accumulation and its consequences, particularly for retinal pigment epithelium (RPE). Next, the fluorescence of lipofuscin, spectral changes induced by oxidation, and its contribution to retinal fluorescence are discussed. This is followed by reviewing recent developments in fluorescence imaging of the retina, and the current evidence on the prognostic value of retinal fluorescence for the progression of age-related macular degeneration (AMD), the major blinding disease affecting elderly people in developed countries. The evidence of lipofuscin oxidation in vivo, and the evidence of increased oxidative damage in AMD retina ex vivo lead to the conclusion that imaging of spectral characteristics of lipofuscin fluorescence may serve as a useful biomarker of oxidative damage which can be helpful in assessing the efficacy of potential antioxidant therapies in retinal degenerations associated with accumulation of lipofuscin and increased oxidative stress. Finally, amendments to currently used fluorescence imaging instruments are suggested, to be more sensitive and specific for imaging spectral char-acteristics of lipofuscin fluorescence.

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Removal of RPE lipofuscin results in rescue from retinal degeneration in a mouse model of advanced Stargardt disease: Role of reactive oxygen species

Cited by 11 publications

References 49 publications

Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration

Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration

Chemiexcitation: Mammalian Photochemistry in the Dark^†

Lipofuscin, Its Origin, Properties, and Contribution to Retinal Fluorescence as a Potential Biomarker of Oxidative Damage to the Retina

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Removal of RPE lipofuscin results in rescue from retinal degeneration in a mouse model of advanced Stargardt disease: Role of reactive oxygen species

Cited by 11 publications

References 49 publications

Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration

Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration

Chemiexcitation: Mammalian Photochemistry in the Dark†

Lipofuscin, Its Origin, Properties, and Contribution to Retinal Fluorescence as a Potential Biomarker of Oxidative Damage to the Retina

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Chemiexcitation: Mammalian Photochemistry in the Dark^†