Abstract
Lipofuscin granules (LGs) are accumulated in the retinal pigment epithelium (RPE) cells. The progressive LG accumulation can somehow lead to pathology and accelerate the aging process. The review examines composition, spectral properties and photoactivity of LGs isolated from the human cadaver eyes. By use of atomic force microscopy and near-field microscopy, we have revealed the fluorescent heterogeneity of LGs. We have discovered the generation of reactive oxygen species by LGs, and found that LGs and melanolipofuscin granules are capable of photoinduced oxidation of lipids. It was shown that A2E, as the main fluorophore (bisretinoid) of LGs, is much less active as an oxidation photosensitizer than other fluorophores (bisretinoids) of LGs. Photooxidized products of bisretinoids pose a much greater danger to the cell than non-oxidized one. Our studies of the fluorescent properties of LGs and their fluorophores (bisretinoids) showed for the first time that their spectral characteristics change (shift to the short-wavelength region) in pathology and after exposure to ionizing radiation. By recording the fluorescence spectra and fluorescence decay kinetics of oxidized products of LG fluorophores, it is possible to improve the methods of early diagnosis of degenerative diseases. Lipofuscin (“aging pigment”) is not an inert “slag”. The photoactivity of LGs can pose a significant danger to the RPE cells. Fluorescence characteristics of LGs are a tool to detect early stages of degeneration in the retina and RPE.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abokyi S, To C-H, Lam TT, Tse DY (2020) Central role of oxidative stress in age-related macular degeneration: evidence from a review of the molecular mechanisms and animal models. Oxid Med Cell Longev 2020:7901270. https://doi.org/10.1155/2020/7901270
Andersen KM, Sauer L, Gensure RH, Hammer M, Bernstein PS (2018) Characterization of retinitis pigmentosa using fluorescence lifetime imaging ophthalmoscopy (FLIO). Transl Vision Sci Technol 7(3):20. https://doi.org/10.1167/tvst.7.3.20
Avalle LB, Dillon J, Tari S, Gaillard ER (2005) A new approach to measuring the action spectrum for singlet oxygen pro-duction by human retinal lipofuscin. Photochem Photobiol 81:1347–1350. https://doi.org/10.1562/2005-05-17-RN-531
Azzam EI, Jay-Gerin JP, Pain D (2012) Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett 327:48–60. https://doi.org/10.1016/j.canlet.2011.12.012
Bazan HEP, Bozan NG, Feeney-Burns L, Berman ER (1990) Lipids in human lipofuscin-enriched subcellular fractions of two age populations. Comparison with rod outer segments and neural retina. Invest Ophthalmol vis Sci 31:1433–1443
Beatty S, Koh H, Phil M, Henson D, Boulton M (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45:115–134. https://doi.org/10.1155/2020/7901270
Belli M, Indovina L (2020) The response of living organisms to low radiation environment and its implications in radiation protection. Front Public Health 8:601711. https://doi.org/10.3389/fpubh.2020.601711
Ben-Shabat S, Itagaki Y, Jockusch S, Sparrow JR, Turro NJ, Nakanishi K (2002) Formation of a nona-oxirane from A2E, a lipofuscin fluorophore related to macular degeneration, and evidence of singlet oxygen involvement. Angew Chem Int Ed Engl 41:814–817. https://doi.org/10.1002/1521-3773(20020301)41:5%3c814::aid-anie814%3e3.0.co;2-2
Bhosale P, Serban B, Bernstein PS (2009) Retinal carotenoids can attenuate formation of A2E in the retinal pigment epithelium. Arch Biochem Biophys 483(2):175–181. https://doi.org/10.1016/j.abb.2008.09.012
Blasiak J, Glowacki S, Kauppinen A, Kaarniranta K (2013) Mitochondrial and nuclear DNA damage and repair in age-related macular degeneration. Int J Mol Sci 14:2996–3010. https://doi.org/10.3390/ijms14022996
Boulton M, Docchio F, Dayhaw-Barker P, Ramponi R, Cubeddu R (1990) Age-related changes in the morphology, absorption and fluorescence of melanosomes and lipofuscin granules of the retinal pigment epithelium. Vision Res 30:1291–1303. https://doi.org/10.1016/0042-6989(90)90003-4
Boulton M, Dontsov A, Jarvis-Evans J, Ostrovsky M, Svistunenko D (1993) Lipofuscin is a photoinducible free radical generator. J Photochem Photobiol B Biol 19:201–204. https://doi.org/10.1016/1011-1344(93)87085-2
Boulton M, Rozanowska M, Rozanowski B, Wess T (2004) The photoreactivity of ocular lipofuscin. Photochem Photobiol Sci 3(8):759–764. https://doi.org/10.1039/B400108G
Broniec A, Pawlak A, Sarna T, Wielgus A, Roberts JE, Land EJ, Truscott TG, Edge R, Navaratnam S (2005) Spectroscopic properties and reactivity of free radical forms of A2E. Free Radic Biol Med 38:1037–1046. https://doi.org/10.1016/j.freeradbiomed.2004.12.023
Brunk UT, Wihlmark U, Wrigstad A, Roberg K, Nilsson SE (1995) Accumulation of lipofuscin within retinal pigment epithelial cells results in enhanced sensitivity to photo-oxidation. Gerontology 41:201–212. https://doi.org/10.1159/000213743
Bynoe LA, Del Priore LV, Hornbeck R (1998) Photosensitization of retinal pigment epithelium by protoporphyrin IX. Graefes Arch Clin Exp Ophthalmol 236(3):230–233. https://doi.org/10.1007/s004170050069
Cantrell A, McGarvey DJ, Roberts J, Sarna T, Truscott TG (2001) Photochemical studies of A2-E. J Photochem Photobiol, B 64(2–3):162–165. https://doi.org/10.1016/S1011-1344(01)00224-X
Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, Sakaguchi H, Kamei M, Hasan A, Yan L, Rayborn ME, Salomon RG, Hollyfield JG (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA 99:14682–14687. https://doi.org/10.1073/pnas.222551899
Clancy CMR, Krogmeier JR, Pawlak A, Rozanowska M, Sarna T, Dunn RC, Simon J (2000) Atomic force microscopy and near-field scanning optical microscopy measurements of single human retinal lipofuscin granules. J Phys Chem B 104:12098–12100. https://doi.org/10.1021/jp0030544
Datta S, Cano M, Ebrahimi K, Wang L, Handa JT (2017) The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res 60:201–218. https://doi.org/10.1016/j.preteyeres.2017.03.002
Davies S, Elliott MH, Floor E, Truscott TG, Zareba M, Sarna T, Shamsi FA, Boulton ME (2001) Photocytotoxicity of lipofuscin in human retinal pigment epithelial cells. Free Radic Biol Med 31(2):256–265. https://doi.org/10.1016/S0891-5849(01)00582-2
De S, Sakmar TP (2002) Interaction of A2E with model membranes. Implications to the pathogenesis of age-related macular degeneration. J Gen Physiol 120:147–157. https://doi.org/10.1085/jgp.20028566
Delori FC, Goger DG, Dorey CK (2001) Age-related accumulation and spatial distribution of lipofuscin in RPE of normal subjects. Invest Ophthalmol vis Sci 42:1855–1866
Dontsov AE, Glickman RD, Ostrovsky MA (1999) Retinal pigment epithelium pigment granules stimulate the photo-oxidation of unsaturated fatty acids. Free Radic Biol Med 26:1436–1446. https://doi.org/10.1016/S0891-5849(99)00003-9
Dontsov AE, Koromyslova AD, Sakina NL (2013) Lipofuscin component A2E does not reduce antioxidant activity of DOPA-melanin. Bull Exp Biol Med 154(5):624–627. https://doi.org/10.1007/s10517-013-2015-6
Dontsov A, Koromyslova A, Ostrovsky M, Sakina N (2016) Lipofuscins prepared by modification of photoreceptor cells via glycation or lipid peroxidation show the similar phototoxicity. World J Exp Med 6(4):63–71. https://doi.org/10.5493/wjem.v6.i4.63
Dontsov AE, Sakina NL, Bilinska B, Krzyzanowski L, Feldman TB, Ostrovsky MA (2005) Comparison of photosensitizing effect of lipofuscin granules from retinal pigment epithelium of human donor eyes and their fluorophore A2E. Dokl Biochem Biophys 405:458–460. https://doi.org/10.1007/s10628-005-0139-y
Dontsov AE, Sakina NL, Golubkov AM, Ostrovsky MA (2009) Light-induced release of A2E photooxidation toxic products from lipofuscin granules of human retinal pigment epithelium. Dokl Biochem Biophys 425:98–101. https://doi.org/10.1134/S1607672909020112
Dontsov AE, Sakina NL, Ostrovsky MA (2012) Comparative study of the dark and light induced toxicity of lipofuscin granules from human retinal pigment epithelium and their chromophore A2E on the cardiolipin liposome model. Rus Cheml Bull Intl Ed 61:442–448. https://doi.org/10.1007/s11172-012-0061-2
Dontsov AE, Sakina NL, Ostrovsky MA (2017) Loss of melanin by eye retinal pigment epithelium cells is associated with its oxidative destruction in melanolipofuscin granules. Biochemistry (mosc) 82:916–924. https://doi.org/10.1134/S0006297917080065
Dontsov A, Yakovleva M, Trofimova N, Sakina N, Gulin A, Aybush A, Gostev F, Vasin A, Feldman T, Ostrovsky M (2022) Water-soluble products of photooxidative destruction of the bisretinoid A2E cause proteins modification in the dark. Int J Mol Sci 23:1534. https://doi.org/10.3390/ijms23031534
Dysli C, Schürch K, Pascal E, Wolf S, Zinkernagel MS (2018) Fundus autofluorescence lifetime patterns in retinitis pigmentosa. Invest Ophthalmol vis Sci 59:1769–1778. https://doi.org/10.1167/iovs.17-23336
Dysli C, Wolf S, Hatz K, Zinkernagel MS (2016) Fluorescence lifetime imaging in Stargardt disease: potential marker for disease progression. Invest Ophthalmol vis Sci 57:832–841. https://doi.org/10.1167/iovs.15-18033
Eldred GE, Katz ML (1988) Fluorophores of the human retinal pigment epithelium: separation and spectral characterization. Exp Eye Res 47:71–86. https://doi.org/10.1016/0014-4835(88)90025-5
Eldred GE, Lasky MR (1993) Retinal age pigments generated by self-assembling lysosomotropic detergents. Nature 361(6414):724–726. https://doi.org/10.1038/361724a0
Feeney L (1973) The phagosomal system of the pigment epithelium: a key to retinal disease. Invest Ophthalmol vis Sci 12:635–638
Feeney-Burns L, Burns RP, Gao C-L (1990) Age-related macular changes in humans over 90 years old. Am J Ophthalmol 109:265–278. https://doi.org/10.1016/S0002-9394(14)74549-0
Feeney-Burns L, Hilderbrand ES, Eldridge S (1984) Aging human RPE: morphometric analysis of macular, equatorial, and peripheral cells. Invest Ophthalmol vis Sci 25:195–200
Feldman TB, Yakovleva MA, Arbukhanova PM, Borzenok SA, Kononikhin AS, Popov IA, Nikolaev EN, Ostrovsky MA (2015) Changes in spectral properties and composition of lipofuscin fluorophores from human retinal pigment epithelium with age and pathology. Anal Bioanal Chem 407:1075–1088. https://doi.org/10.1007/s00216-014-8353-z
Feldman TB, Yakovleva MA, Larichev AV, Arbukhanova PM, Ash R, Borzenok SA, Kuzmin VA, Ostrovsky MA (2018) Spectral analysis of fundus autofluorescence pattern as a tool to detect early stages of degeneration in the retina and retinal pigment epithelium. Eye 32:1440–1448. https://doi.org/10.1038/s41433-018-0109-0
Fernandes AF, Zhou J, Zhang X, Bian Q, Sparrow J, Taylor A, Pereira P, Shang F (2008) Oxidative inactivation of the proteasome in retinal pigment epithelial cells. A potential link between oxidative stress and upregulation of interleukin-8. J Biol Chem 283(30):20745–20753. https://doi.org/10.1074/jbc.M800268200
Ferrington DA, Sinha D, Kaarniranta K (2016) Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration. Prog Retin Eye Res 51:69–89. https://doi.org/10.1016/j.preteyeres.2015.09.002
Gaillard ER, Avalle LB, Keller LM, Wang Z, Reszka KJ, Dillon JP (2004) A mechanistic study of the photooxidation of A2E, a component of human retinal lipofuscin. Exp Eye Res 79(3):313–319. https://doi.org/10.1016/j.exer.2004.05.005
Golestaneh N, Chu Y, Xiao Y-Y, Stoleru GL, Theos AC (2018) Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration. Cell Death Dis 8(1):e2537. https://doi.org/10.1038/cddis.2016.453
Haralampus-Grynaviski NM, Lamb LE, Clancy CM, Skumatz C, Burke JM, Sarna T, Simon JD (2003) Spectroscopic and morphological studies of human retinal lipofuscin granules. Proc Natl Acad Sci U S A 100(6):3179–3184. https://doi.org/10.1073/pnas.0630280100
Holz FG, Pauleikhoff D, Klein R, Bird AC (2004) Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol 137:504–510. https://doi.org/10.1016/j.ajo.2003.11.026
Holz FG, Schmitz-Valckenberg S, Spaide RF, Bird AC (2007) Atlas of fundus autofluorescence imaging. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-71994-6
Holz FG, Schutt F, Kopitz J, Eldred GE, Kruse FE, Volcker HE, Cantz M (1999) Inhibition of lysosomal degradative functions in RPE cells by a retinoid component of lipofuscin. Invest Ophthalmol vis Sci 40(3):737–743
Hyttinen JMT, Viiri J, Kaarniranta K, Błasiak J (2018) Mitochondrial quality control in AMD: does mitophagy play a pivotal role? Cell Mol Life Sci 75:2991–3008. https://doi.org/10.1007/s00018-018-2843-7
Jentsch S, Schweitzer D, Schmidtke KU, Peters S, Dawczynski J, Bar KJ, Hammer M (2014) Retinal fluorescence lifetime imaging ophthalmoscopy measures depend on the severity of Alzheimer’s disease. Acta Ophthalmol 93:e241–e247. https://doi.org/10.1111/aos.12609
Jung T, Bader N, Grune T (2007) Lipofuscin: formation, distribution, and metabolic consequences. Ann NY Acad Sci 1119:97–111. https://doi.org/10.1196/annals.1404.008
Katz M (2002) Potential role of retinal pigment epithelial lipofuscin accumulation in age-related macular degeneration. Arch Gerontol Geriatric 34:359–370. https://doi.org/10.1016/S0167-4943(02)00012-2
Kennedy CJ, Rakoczy PE, Constable IJ (1995) Lipofuscin of the retinal pigment epithelium: a review. Eye 9:763–771. https://doi.org/10.1038/eye.1995.192
Kim SR, Jang YP, Jockusch S, Fishkin NE, Turro NJ, Sparrow JR (2007) The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model. Proc Natl Acad Sci USA 104:19273–19278. https://doi.org/10.1073/pnas.0708714104
Kim HJ, Montenegro D, Zhao J, Sparrow JR (2021) Bisretinoids of the retina: photo-oxidation, iron-catalyzed oxidation, and disease consequences. Antioxidants 10(9):1382. https://doi.org/10.3390/antiox10091382
Kinnunen K, Petrovski G, Moe MC, Berta A, Kaarniranta K (2012) Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration. Acta Ophthalmol 90:299–309. https://doi.org/10.1111/j.1755-3768.2011.02179.x
Kobashigawa S, Suzuki K, Yamashita S (2011) Ionizing radiation accelerates Drp1-dependent mitochondrial fission, which involves delayed mitochondrial reactive oxygen species production in normal human fibroblast-like cells. Biochem Biophys Res Commun 414:795–800. https://doi.org/10.1016/j.bbrc.2011.10.006
Kohen R, Nyska A (2002) Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30:620–650. https://doi.org/10.1080/01926230290166724
Lakkaraju A, Finnemann SC, Rodriguez-Boulan E (2007) The lipofuscin fluorophore A2E perturbs cholesterol metabolismin retinal pigment epithelial cells. Proc Natl Acad Sci USA 104(26):11026–11031. https://doi.org/10.1073/pnas.0702504104
Lamb LE, Simon JD (2004) A2E: a component of ocular lipofuscin. Photochem Photobiol 79:127–136. https://doi.org/10.1111/j.1751-1097.2004.tb00002.x
Lin J-A, Wu C-H, Lu C-C, Hsia S-M, Yen G-C (2016) Glycative stress from advanced glycation end products (AGEs) and dicarbonyls: an emerging biological factor in cancer onset and progression. Mol Nutr Food Res 60:1850–1864. https://doi.org/10.1002/mnfr.201500759
Lu L, Gu X, Hong L, Laird J, Jaffe K, Choi J, Crabb J, Salomon RG (2009) Synthesis and structural characterization of carboxyethylpyrrole-modified proteins: mediators of age-related macular degeneration. Bioorg Med Chem 17(21):7548–7561. https://doi.org/10.1016/j.bmc.2009.09.009
Maeda A, Maeda T, Golczak M, Chou S, Desai A, Hoppel CL, Matsuyama S, Palczewski K (2009) Involvement of all-trans-retinal in acute light-induced retinopathy of mice. J Biol Chem 284:15173–15183. https://doi.org/10.1074/jbc.M900322200
Mahendra CK, Tan LTH, Pusparajah P, Htar TT, Chuah L, Lee VS, Low LE, Tang SY, Chan K-G, Goh BH (2020) Detrimental effects of UVB on retinal pigment epithelial cells and its role in age-related macular degeneration. Oxid Med Cell Longev 2020:1904178. https://doi.org/10.1155/2020/1904178
Marmorstein AD, Marmorstein LY, Sakaguchi H, Hollyfield JG (2002) Spectral profiling of autofluorescence associated with lipofuscin, bruch’s membrane, and sub-RPE deposits in normal and AMD eyes. Invest Ophthalmol vis Sci 43:2435
Mitter SK, Song C, Qi X, Mao H, Rao H, Akin D, Lewin A, Grant M, Dunn W Jr, Ding J, Bowes Rickman C, Boulton M (2014) Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 10(11):1989–2005. https://doi.org/10.4161/auto.36184
Moreno-García A, Kun A, Calero O, Medina M, Calero M (2018) An overview of the role of lipofuscin in age-related neurodegeneration. Front Neurosci 12:464. https://doi.org/10.3389/fnins.2018.00464
Murdaugh LS, Avalle LB, Mandal S, Dill AE, Dillon J, Simon JD, Gaillard ER (2010) Compositional studies of human RPE lipofuscin. J Mass Spectrom 45:1139–1147. https://doi.org/10.1002/jms.1795
Murdaugh LS, Mandal S, Dill AE, Dillon J, Simon D, Gaillard ER (2011) Compositional studies of human RPE lipofuscin: mechanisms of molecular modifications. J Mass Spectrom 46:90–95. https://doi.org/10.1002/jms.1865
Ng KP, Gugiu B, Renganathan K, Davies MW, Gu X, Crabb JS, Kim SR, Różanowska MB, Bonilha VL, Rayborn ME, Salomon RG, Sparrow JR, Boulton ME, Hollyfield JG, Crabb JW (2008) Retinal pigment epithelium lipofuscin proteomics. Mol Cell Proteomics 7:1397–1405. https://doi.org/10.1074/mcp.M700525-MCP200
Nilsson SE, Sundelin SP, Wihlmark U, Brunk UT (2003) Aging of cultured retinal pigment epithelial cells: oxidative reactions, lipofuscin formation and blue light damage. Doc Ophthalmol 106(1):13–16. https://doi.org/10.1023/a:1022419606629
Nowak JZ (2013) Oxidative stress, polyunsaturated fatty acids-derived oxidation products and bisretinoids as potential inducers of CNS diseases: focus on age-related macular degeneration. Pharmacol Rep 65(2):288–304. https://doi.org/10.1016/s1734-1140(13)71005-3
Olchawa MM, Szewczyk GM, Zadlo AC, Krzysztynska-Kuleta OI, Sarna TJ (2021) The effect of aging and antioxidants on photoreactivity and phototoxicity of human melanosomes: an in vitro study. Pigment Cell Melanoma Res 34:670–682. https://doi.org/10.1111/pcmr.12914
Ostrovsky MA, Dontsov AE, Sakina NL, Boulton M, Jarvis-Evans J (1992) The ability of lipofuscin granules of the retinal pigment epithelium of the human eye a photosensitized peroxidation lipid by the action of visible light. Sensor Systems 6:51–54
Ostrovsky MA, Dontsov AE (2019) Vertebrate eye melanosomes and invertebrate eye ommochromes as antioxidant cell organelles. Biology Bulletin 46:105–116
Ostrovsky MA, Sakina NL, Dontsov AE (1987) An antioxidative role of ocular screening pigments. Vision Res 27:893–899. https://doi.org/10.1016/0042-6989(87)90005-8
Ostrovsky MA, Zak PP, Dontsov AE (2018) Vertebrate eye melanosomes and invertebrate eye ommochromes as screening cell organelles. Biology Bulletin 45:570–579. https://doi.org/10.1134/S1062359018060109
Parish CA, Hashimoto M, Nakanishi K, Dillon J, Sparrow J (1998) Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. Proc Natl Acad Sci USA 95(25):14609–14613. https://doi.org/10.1073/pnas.95.25.14609
Pawlak A, Rozanowska M, Zareba M, Lamb LE, Simon JD, Sarna T (2002) Action spectra for the photo consumption of oxygen by human ocular lipofuscin and lipofuscin extracts. Arch Biochem Biophys 403(1):59–62. https://doi.org/10.1016/S0003-9861(02)00260-6
Pawlak A, Wrona M, Rozanowska M, Zareba M, Lamb LE, Roberts JE, Simon JD, Sarna T (2003) Comparison of the aerobic photoreactivity of A2E with its precursor retinal. Photochem Photobiol 77:253–258. https://doi.org/10.1562/0031-8655(2003)077%3c0253:cotapo%3e2.0.co;2
Petrukhin AN, Astaf’ev AA, Zolotavin PN, Fel’dman TB, Dontsov AE, Sarkisov OM, Ostrovsky MA. (2005) Heterogeneity of structure and fluorescence of single lipofuscin granule from retinal pigment epithelium of human donor eyes: study with the use of atomic force microscopy and near-field microscopy. Dokl Biochem Biophys 405:445–449. https://doi.org/10.1007/s10628-005-0136-1
Ragauskaite L, Heckathorn RC, Gaillard ER (2001) Environmental effects on the photochemistry of A2-E, a component of human retinal lipofuscin. Photochem Photobiol 74(3):483–488. https://doi.org/10.1562/0031-8655(2001)074%3c0483:eeotpo%3e2.0.co;2
Roberts JE, Kukieczak BM, Hu DN, Miller DS, Bilski P, Sik RH, Motten AG, Chignell CF (2002) The role of A2E in prevention or enhancement of light damage in human retinal pigment epithelial cells. Photochem Photobiol 75(2):184–190. https://doi.org/10.1562/0031-8655(2002)075%3c0184:troaip%3e2.0.co;2
Rowan S, Bejarano E, Taylor A (2018) Mechanistic targeting of advanced glycation end-products in age-related diseases. BBA Mol Basis Dis 1864:3631–3643. https://doi.org/10.1016/j.bbadis.2018.08.036
Rozanowska M, Jarvis-Evans J, Korytowski W, Boulton ME, Burke JM, Sarna T (1995) Blue light-induced reactivity of retinal age pigment. In vitro generation of oxygen-reactive species. J Biol Chem 270:18825–18830. https://doi.org/10.1074/jbc.270.32.18825
Rozanowska M, Korytowski W, Rozanowski B, Skumatz C, Boulton ME, Burke JM, Sarna T (2002) Photoreactivity of aged human RPE melanosomes: a comparison with lipofuscin. Invest Ophthalmol vis Sci 43(7):2088–2096
Rozanowska M, Pawlak A, Rozanowski B, Skumatz C, Zareba M, Boulton ME, Burke JM, Sarna T, Simon JD (2004) Age-related changes in the photoreactivity of retinal lipofuscin granules: role of chloroform-insoluble components. Invest Ophthalmol vis Sci 45(4):1052–1060. https://doi.org/10.1167/iovs.03-0277
Rózanowska MB, Rózanowski B (2022) Photodegradation of lipofuscin in suspension and in ARPE-19 cells and the similarity of fluorescence of the photodegradation product with oxidized docosahexaenoate. Int J Mol Sci 23:922. https://doi.org/10.3390/ijms23020922
Różanowska M, Sarna T (2005) Light-induced damage to the retina: role of rhodopsin chromophore revisited. Photochem Photobiol 81:1305–1330. https://doi.org/10.1562/2004-11-13-IR-371
Rozanowska M, Wessels J, Boulton M, Burke JM, Rodgers MAJ, Truscott TG, Sarna T (1998) Blue light-induced singlet oxygen generation by retinal lipofuscin in non-polar media. Free Radic Biol Med 24:1107–1112. https://doi.org/10.1016/S0891-5849(97)00395-X
Ruan Y, Jiang S, Gericke A (2021) Age-related macular degeneration: role of oxidative stress and blood vessels. Int J Mol Sci 22:1296. https://doi.org/10.3390/ijms22031296
Sadda SR, Borrelli E, Fan W, Ebraheem A, Marion KM, Harrington M, Kwon S (2019) A pilot study of fluorescence lifetime imaging ophthalmoscopy in preclinical Alzheimer’s disease. Eye 33:1271–1279. https://doi.org/10.1038/s41433-019-0406-2
Sakai N, Decatur J, Nakanishi K, Eldred GE (1996) Ocular age pigment “A2E”: an unprecedented pyridinium bisretinoid. J Am Chem Soc 118:1559–1560. https://doi.org/10.1021/ja953480g
Sakina NL, Koromyslova AD, Dontsov AE, Ostrovsky MA (2013) RPE melanosomes bind A2E fluorophore of lipofuscin granules and products of its photooxidation. Ross Fiziol Zh Im I M Sechenova 99(5):642–653
Sarna T (1992) New trends in photobiology: properties and function of the ocular melanin—a photobiophysical view. J Photochem Photobiol, B 12:215–258. https://doi.org/10.1016/1011-1344(92)85027-R
Sarna T, Burke JM, Korytowski W, Rózanowska M, Skumatz CM, Zareba A, Zareba M (2003) Loss of melanin from human RPE with aging: possible role of melanin photooxidation. Exp Eye Res 76:89–98. https://doi.org/10.1016/s0014-4835(02)00247-6
Sauer L, Andersen KM, Dysli C, Zinkernagel MS, Bernstein PS, Hammer M (2018a) Review of clinical approaches in fluorescence lifetime imaging ophthalmoscopy. J Biomed Opt 23:091415. https://doi.org/10.1117/1.JBO.23.9.091415
Sauer L, Gensure RH, Andersen KM, Kreilkamp L, Hageman GS, Hammer M, Bernstein PS (2018b) Patterns of fundus autofluorescence lifetimes in eyes of individuals with nonexudative age-related macular degeneration. Invest Ophthalmol Vis Sci 59:AMD65. https://doi.org/10.1167/iovs.17-23764
Sauer L, Gensure RH, Hammer M, Bernstein PS (2018c) Fluorescence lifetime imaging ophthalmoscopy: a novel way to assess macular telangiectasia type 2. Ophthalmol Retina 2:587–598. https://doi.org/10.1016/j.oret.2017.10.008
Schmidt SY, Peisch RD (1986) Melanin concentration in normal human retinal pigment epithelium. Regional variation and age-related reduction. Invest Ophthalmol vis Sci 27:1063–1067
Schleicher ED, Bierhaus A, Haring HU, Nawroth PP, Lehmann R (2001) Chemistry and pathobiology of advanced glycation end products. Contrib Nephrol 131:1–9. https://doi.org/10.1159/000060056
Schmitz-Valckenberg S, Holz FG, Fitzke FW (2007) Perspectives in imaging technologies. In: Holz FG, Schmitz-Valckenberg S, Spaide RF, Bird AC (ed) Atlas of fundus autofluorescence imaging. Berlin: Springer pp. 331–338. https://doi.org/10.1007/978-3-540-71994-6
Schutt F, Bergmann M, Holz FG, Dithmar S, Volcker HE, Kopitz J (2007) Accumulation of A2-E in mitochondrial membranes of cultured RPE cells. Graefes Arch Clin Exp Ophthalmol 245(3):391–398. https://doi.org/10.1007/s00417-006-0376-5
Schutt F, Bergmann M, Holz FG, Kopitz J (2003) Proteins modified by malondialdehyde,4-hydroxynonenal, or advanced glycation end products in lipofuscin of human retinal pigment epithelium. Invest Ophthalmol vis Sci 44:3663–3668. https://doi.org/10.1167/iovs.03-0172
Schutt F, Davies S, Kopitz J, Boulton M, Holz FG (2000a) A retinoid constituent of lipofuscin, A2E, is a photosensitizer in human retinal pigment epithelial cells. Ophthalmologe 97:682–687. https://doi.org/10.1007/s003470070037
Schutt F, Davies S, Kopitz J, Holz FG, Boulton ME (2000b) Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Invest Ophthalmol vis Sci 41(8):2303–2308
Schweitzer D, Deutsch L, Klemm M, Jentsch S, Hammer M, Peters S, Haueisen J, Muller UA, Dawczynski J (2015) Fluorescence lifetime imaging ophthalmoscopy in type 2 diabetic patients who have no signs of diabetic retinopathy J Biomed Opt 20:061106. https://doi.org/10.1117/1.JBO.20.6.061106
Schweitzer D, Quick S, Schenke S, Klemm M, Gehlert S, Hammer M, Jentsch S, Fischer J (2009) Comparison of parameters of time-resolved autofluorescence between healthy subjects and patients suffering from early AMD. Ophthalmology 106:714–722. https://doi.org/10.1007/s00347-009-1975-4
Schweitzer D, Schenke S, Hammer M, Schweitzer F, Jentsch S, Birckner E, Becker W, Bergmann A (2007) Towards metabolic mapping of the human retina. Microsc Res Tech 70:410–419. https://doi.org/10.1002/jemt.20427
Shamsi FA, Boulton M (2001) Inhibition of RPE lysosomal and antioxidant activity by the age pigment lipofuscin. Invest Ophthalmol vis Sci 42(12):3041–3046
Sokolov VS, Sokolenko EA, Sokolov AV, Dontsov AE, Chizmadzhev YuA, Ostrovsky MA (2007) Interaction of pyridinium bis-retinoid (A2E) with bilayer lipid membranes. J Photochem and Photobiol b: Biology 86:177–185. https://doi.org/10.1016/j.jphotobiol.2006.09.006
Sparrow JR, Boulton ME (2005) RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res 80:595–606. https://doi.org/10.1016/j.exer.2005.01.007
Sparrow JR, Gregory-Roberts E, Yamamoto K, Blonska A, Ghosh SK, Ueda K, Zhou J (2012) The bisretinoids of retinal pigment epithelium. Prog Retin Eye Res 31:121–135. https://doi.org/10.1016/j.preteyeres.2011.12.001
Sparrow JR, Kim SR, Cuervo AM, Bandhyopadhyayand U (2008) A2E, a pigment of RPE lipofuscin, is generated from the precursor, A2PE by a lysosomal enzyme activity. Adv Exp Med Biol 613:393–398. https://doi.org/10.1007/978-0-387-74904-4_46
Sparrow JR, Nakanishi K, Parish CA (2000) The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigment epithelial cells. Invest Ophthalmol vis Sci 41:1981–1990
Sparrow JR, Parish CA, Hashimoto M, Nakanishi K (1999) A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture. Invest Ophthalmol vis Sci 40:2988–2995 (PMID: 10549662)
Sparrow JR, Wu Y, Kim CY, Zhou J (2010a) Phospholipid meets all-trans retinal: the making of RPE bisretinoids. J Lipid Res 51:247–261. https://doi.org/10.1194/jlr.R000687
Sparrow JR, Wu Y, Nagasaki T, Yoon KD, Yamamoto K, Zhou J (2010b) Fundus autofluorescence and the bisretinoids of retina. Photochem Photobiol Sci 9:1480–1489. https://doi.org/10.1039/C0PP00207K
Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85:845–881. https://doi.org/10.1152/physrev.00021.2004
Suter M, Reme C, Grimm C, Wenzel A, Jaattela M, Esser P, Kociok N, Leist M, Richter C (2000) Age-related macular degeneration The lipofusion component N retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells. J Biol Chem 275(50):3L9625-39630. https://doi.org/10.1074/jbc.M007049200
Thao MT, Renfus DJ, Dillon J, Gaillard ER (2014) A2E mediated photochemical modification to fibronectin and its implications to age related changes in Bruch’s membrane. Photochem Photobiol 90:329–334. https://doi.org/10.1111/php.12200
Totan Y, Yağci R, Bardak Y, Ozyurt H, Kendir F, Yilmaz G, Sahin S, Sahin Tiğ U (2009) Oxidative macromolecular damage in age-related macular degeneration. Curr Eye Res 34(12):1089–1093. https://doi.org/10.3109/02713680903353772
Von Ruckmann A, Fitzke FW, Bird AC (1997) In vivo fundus autofluorescence in macular dystrophies. Arch Ophthalmol 115:609–615. https://doi.org/10.1001/archopht.1997.01100150611006
Wang Z, Dillon J, Gaillard ER (2006a) Antioxidant properties of melanin in retinal pigment epithelial cells. Photochem Photobiol 82:474–479. https://doi.org/10.1562/2005-10-21-RA-725
Wang Z, Keller LMM, Dillon J, Gaillard ER (2006b) Oxidation of A2E results in the formation of highly reactive aldehydes and ketones. Photochem Photobiol 82:1251–1257. https://doi.org/10.1562/2006-04-01-RA-864
Warburton S, Southwick K, Hardman RM, Secrest AM, Grow RK, Xin H, Woolley AT, Burton GF, Thulin CD (2005) Examining the proteins of functional retinal lipofuscin using proteomic analysis as a guide for understanding its origin. Mol vis 11:1122–1134
Wassell J, Davies S, Bardsley W, Boulton M (1999) The photoreactivity of the retinal age pigment lipofuscin. J Biol Chem 274(34):23828–23832. https://doi.org/10.1074/jbc.274.34.23828
Wielgus AR, Chignell CF, Ceger P, Roberts JE (2010) Comparison of A2E cytotoxicity and phototoxicity with all-trans-retinal in human retinal pigment epithelial cells. Photochem Photobiol 86(4):781–791. https://doi.org/10.1111/j.1751-1097.2010.00750.x
Wiktor A, Sarna M, Wnuk D, Sarna T (2018) Lipofuscin-mediated photodynamic stress induces adverse changes in nanomechanical properties of retinal pigment epithelium cells. Sci Rep 8:17929. https://doi.org/10.1038/s41598-018-36322-2
Wing G, Blanchard G, Weiter J (1978) The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Invest Ophthalmol vis Sci 17:601–607
Wolf G (2003) Lipofuscin and macular degeneration. Nutr Rev 61:342–346. https://doi.org/10.1301/nr.2003.oct.342-346
Wu Y, Yanase E, Feng X, Siegel MM, Sparrow JR (2010) Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration. Proc Natl Acad Sci USA 107:7275–7280. https://doi.org/10.1073/pnas.0913112107
Yacout SM, McIlwain KL, Mirza SP, Gaillard ER (2019) Characterization of retinal pigment epithelial melanin and degraded synthetic melanin using mass spectrometry and in vitro biochemical diagnostics. Photochem Photobiol 95:183–191. https://doi.org/10.1111/php.12934
Yakovleva M, Dontsov A, Trofimova N, Sakina N, Kononikhin A, Aybush A, Gulin A, Feldman T, Ostrovsky M (2022a) Lipofuscin granule bisretinoid oxidation in the human retinal pigment epithelium forms cytotoxic carbonyls. Int J Mol Sci 23:222. https://doi.org/10.3390/ijms23010222(a)
Yakovleva MA, Feldman TB, Lyakhova KN, Utina DM, Kolesnikova IA, Vinogradova YV, Molokanov AG, Ostrovsky MA (2022b) Ionized radiation-mediated retinoid oxidation in the retina and retinal pigment epithelium of the murine eye. Radiat Res 197:270–279. https://doi.org/10.1667/RADE-21-00069.1(b)
Yakovleva MA, Gulin AA, Feldman TB, Bel’skich YC, Arbukhanova PM, Astaf’ev AA, Nadtochenko VA, Borzenok SA, Ostrovsky MA, (2016) Time-of-flight secondary ion mass spectrometry to assess spatial distribution of A2E and its oxidized forms within lipofuscin granules isolated from human retinal pigment epithelium. Anal Bioanal Chem 408:7521–7528. https://doi.org/10.1007/s00216-016-9854-8
Yakovleva MA, Sakina NL, Kononikhin AS, Feldman TB, Nikolaev EN, Dontsov AE, Ostrovsky MA (2006) Detection and study of the products of photooxidation of N-Retinylidene-N-retinylethanolamine (A2E), the fluorophore of lipofuscin granules from retinal pigment epithelium of human donor eyes. Dokl Biochem Biophys 409:223–225. https://doi.org/10.1134/S1607672906040089
Ye F, Kaneko H, Hayashi Y, Takayama K, Hwang SJ, Nishizawa Y, Kimoto R, Nagasaka Y, Tsunekawa T, Matsuura T, Yasukawa T, Kondo T, Terasaki H (2016) Malondialdehyde induces autophagy dysfunction and VEGF secretion in the retinal pigment epithelium in age-related macular degeneration. Free Radic Biol Med 94:121–134. https://doi.org/10.1016/j.freeradbiomed.2016.02.027
Yin D (1996) Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. Free Rad Biol Med 21:871–888. https://doi.org/10.1016/0891-5849(96)00175-X
Yoon KD, Yamamoto K, Ueda K, Zhou J, Sparrow JR (2012) A novel source of methylglyoxal and glyoxal in retina: implications for age-related macular degeneration. PLoS ONE 7:e41309. https://doi.org/10.1371/journal.pone.0041309
Young RW (1967) The renewal of the photoreceptor cell outer segments. J Cell Biol 33:61–72. https://doi.org/10.1083/jcb.33.1.61
Zareba M, Szewczyk G, Sarna T, Hong L, Simon JD, Henry MM, Burke JM (2006) Effects of photodegradation on the physical and antioxidant properties of melanosomes isolated from retinal pigment epithelium. Photochem Photobiol 82:1024–1029. https://doi.org/10.1562/2006-03-08-RA-836
Zhang X, Zhou J, Fernandes AF, Sparrow JR, Pereira P, Taylor A, Shang F (2008) The proteasome: a target of oxidative damage in cultured human retina pigment epithelial cells. Invest Ophthalmol vis Sci 49(8):3622–3630. https://doi.org/10.1167/iovs.07-1559
Zhou J, Ueda K, Zhao J, Sparrow JR (2015) Correlations between photodegradation of bisretinoid constituents of retina and dicarbonyl adduct deposition. J Bio Chem 290:27215–27227. https://doi.org/10.1074/jbc.M115.680363
Funding
This work was supported by the Russian Science Foundation (grant number 22–24-00549).
Author information
Authors and Affiliations
Contributions
All authors had the idea for the article and performed the literature search and data analysis; T.B. Feldman, A.E. Dontsov and M.A. Ostrovsky drafted the work. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Feldman, T.B., Dontsov, A.E., Yakovleva, M.A. et al. Photobiology of lipofuscin granules in the retinal pigment epithelium cells of the eye: norm, pathology, age. Biophys Rev 14, 1051–1065 (2022). https://doi.org/10.1007/s12551-022-00989-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12551-022-00989-9