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Introduction
Condensation products of all-trans-retinal accumulate with age as lipofuscin in retinal pigment epithelium (RPE) cells of the eye and are closely associated with the pathology of autosomal recessive Stargardt’s disease (STGD1) and dry age-related macular degeneration (AMD) [1, 2, 3, 4–5]. STGD1 is a juvenile macular degeneration caused by mutations in the retina-specific ATP-binding cassette (ABC) transporter 4 (Abca4) gene [6]. There is already evidence suggesting that the gene Abca4 serves as a contributing risk factor for dry AMD [7, 8–9]. Moreover, previous reports indicate that the photoreceptor-specific all-trans-retinol dehydrogenase 8 (Rdh8) is an assistant susceptibility gene for STGD1 and dry AMD, and its knockout accelerates retinal atrophy in Abca4 mutant mice [10, 11]. Mice with a knockout of Abca4 and Rdh8 genes (Abca4−/−Rdh8−/− mice) reproduce primary features of STGD1 and dry AMD, including the deterioration of photoreceptors and the RPE as well as the accumulation of all-trans-retinal condensation products [11]. N-retinylidene-N-retinylethanolamine (A2E) is a product of all-trans-retinal condensation reactions, and it is incriminated as a major component of RPE lipofuscin [12]. Compared with wild-type mice, Abca4−/−Rdh8−/− mice exhibit a much greater accumulation of A2E in the eye with age [11, 13]. Several lines of investigation show that A2E that accumulates beyond a critical level in RPE cells mediates the detergent-like effect on cell membranes, alkalinization of lysosomes, and detachment of proapoptotic proteins from mitochondria, as well as the induction of autophagy [4, 14, 15, 16–17]. A2E is a compound that is highly sensitive to 430 nm blue light [18, 19]. Upon irradiation with blue light, A2E elicits the death of RPE cells via triggering DNA damage, oxidative stress, and complement activation [20, 21–22]. Marie and colleagues have posited that exposure to blue light at a wavelength of 430 nm is implicated in the highest levels of reactive oxygen species (ROS) and mitochondrial dysfunction in A2E-loaded RPE cells [23].
Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by the accumulation of lipid peroxides to a lethal level [24]. It is morphologically, functionally, and biochemically distinct from other forms of cell death, such as apoptosis, necrosis, and autophagy [25]. Although A2E...