Bisretinoids: More than Meets the Eye

Bisretinoid fluorophores are the major constituents of the lipofuscin of retinal pigment epithelium (RPE) that accumulates with age and contributes to retina disease. Knowledge of the burden placed on the RPE cell by the accumulation of these phototoxic retinaldehyde-adducts depends on the identification and quantitation of the various bisretinoid species that constitute this family of fluorophores. Here we report a previously unidentified fluorescent bisretinoid by UPLC coupled to photodiode array detection, fluorescence, and electrospray ionization mass spectrometry (UPLC-PDA-FLR-ESI-MS) (Kim HJ, Sparrow JR, J Lipid Res 59:1620-1629, 2018). This novel bisretinoid is 1-octadecyl-2-lyso-sn-glycero A2PE (alkyl ether lysoA2PE). The structural assignment was based on molecular weight (m/z 998), UV-visible absorbance maxima (340, 440 nm), and retention time (73 minutes) and was corroborated by biomimetic synthesis using all-trans-retinal and glycerophosphoethanolamine analogues as starting materials. In mechanistic studies, A2PE was hydrolyzed by PLA, and plasmalogen lysoA2PE was cleaved under acidic conditions. Unprecedented UPLC detection of the bisretinoid alkyl ether lysoA2PE in human RPE but not in neural retina indicates that the phospholipase A activity that generates the latter bisretinoid resides in RPE.