The retina, together with the brain and testis, is highly enriched in omega-3 (n-3) long chain and very long chain polyunsaturated fatty acids (LC-PUFAs (C18-C22), VLC-PUFAs (≥C24)) (Yeboah, Lobanova, Brush, & Agbaga, 2021). The most abundant n-3 PUFA is docosahexaenoic acid (DHA, C22:6n-3). Over the years, the health benefits of DHA have been extensively studied, showing that it is essential throughout all stages of life, from fetal development to prevention of cardiovascular and cognitive diseases in elderly (J. Li, Pora, Dong, & Hasjim, 2021). It is generally accepted that this extraordinary lipid is pivotal for retinal functioning, but there are still many uncertainties and controversies concerning its acquirement in the retina and its specific roles.

The retina is the light sensitive layer in the eye and is roughly subdivided into the neural retina and the retinal pigment epithelium (RPE), which intensively interact to regulate vision (Hildebrand & Fielder, 2011; Masland, 2001). The neural retina consists of several specialized cell types including the photoreceptors, which are the light sensitive neurons of the retina as they convert photons into a nerve signal, through a process called phototransduction. The two types of photoreceptors, rods and cones, share the same principle of phototransduction, but they exhibit important differences in function and spatial distribution. In the human retina, rods outnumber the cones by approximately 20-fold and are predominantly localized to the periphery where they are responsible for night vision. Cones on the other hand, are localized to the central macula and regulate day vision (Hildebrand & Fielder, 2011; Masland, 2001). In the mouse retina, rods represent 97.2% and cones 2.8% of the photoreceptors and are intermingled (Jeon, Strettoi, & Masland, 1998). Each photoreceptor consists of an outer segment, inner segment, connecting cilium, nucleus, inner fiber, and synaptic terminal (Molday & Moritz, 2015). The photoreceptor outer segment (POS) is a modified sensory cilium, filled with densely packed lipid-rich disc membranes, carrying the visual pigments. The inner and outer segments are connected by a narrow connecting cilium (Baehr et al., 2019). The organelles are located in the inner segments, where synthesis of components that populate the POS occurs. The inner fiber is the axon of the photoreceptor that transmits the light signal via the synaptic terminal to interneurons, which further relay with retinal ganglion cells to the brain (Hildebrand & Fielder, 2011; Masland, 2001).

The RPE is a monolayer of postmitotic, hexagonally shaped, dark pigmented cells that are connected through tight junctions (Strauss, 2005). Their main task is to maintain photoreceptor health by exerting several functions. Firstly, RPE cells act as important distributors of nutrients and waste products. In addition, they absorb scattered light via the melanosomes (Strauss, 2005). Furthermore, RPE cells assist in the visual cycle, as photoreceptors are unable to re-isomerize all-trans-retinol, which is formed during the phototransduction, back to 11-cis-retinal (a vitamin A derived chromophore) (Lakkaraju et al., 2020; Strauss, 2005). Another important function of RPE cells is the phagocytosis of damaged POS (Kevany & Palczewski, 2010; Lakkaraju et al., 2020). Photoreceptors are exposed to intense levels of light each day, leading to accumulation of photo-damaged proteins and lipids. To maintain excitability of photoreceptors, daily a part of these POS is shed by the photoreceptors, ingested and processed by the RPE. The lipid components are either degraded, converted to derivatives or recycled back to the photoreceptors. Of note, in the human retina, each RPE cell supports approximately 45 photoreceptors and it takes about 10 days to replace an entire outer segment (Strauss, 2005).

In this review, we first discuss the synthesis, distribution and roles of DHA and VLC-PUFAs in the retina. Next, we summarize the retinal pathologies in patients and mouse models in which retinal DHA levels are reduced due to either a defined genetic cause or a more general pathology (age-related macular degeneration (AMD), diabetic retinopathy (DR) or retinitis pigmentosa (RP)). We also pay attention to the impact on the RPE. Finally, the potential contribution of deregulated lipids to retinopathy will be scrutinized and possible therapeutic options will be discussed.