Docosahexaenoic acid preserves visual function by maintaining correct disc morphology in retinal photoreceptor cells

Abstract

Docosahexaenoic acid (DHA) has essential roles in photoreceptor cells in the retina and is therefore crucial to healthy vision. Although the influence of dietary DHA on visual acuity is well known and the retina has an abundance of DHA-containing phospholipids (PL-DHA), the mechanisms associated with DHA's effects on visual function are unknown. We previously identified lysophosphatidic acid acyltransferase 3 (LPAAT3) as a PL-DHA biosynthetic enzyme. Here, using comprehensive phospholipid analyses and imaging mass spectroscopy, we found that LPAAT3 is expressed in the inner segment of photoreceptor cells and that PL-DHA disappears from the outer segment in the LPAAT3-knock-out mice. Dynamic light-scattering analysis of liposomes and molecular dynamics simulations revealed that the physical characteristics of DHA reduced membrane-bending rigidity. Following loss of PL-DHA, LPAAT3-knock-out mice exhibited abnormalities in the retinal layers, such as incomplete elongation of the outer segment and decreased thickness of the outer nuclear layers and impaired visual function, as well as disordered disc morphology in photoreceptor cells. Our results indicate that PL-DHA contributes to visual function by maintaining the disc shape in photoreceptor cells and that this is a function of DHA in the retina. This study thus provides the reason why DHA is required for visual acuity and may help inform approaches for overcoming retinal disorders associated with DHA deficiency or dysfunction.

Metabolism and functions of docosahexaenoic acid‐containing membrane glycerophospholipids

“…In addition, a recent study comparing in vitro LPLAT activities and tissue PC compositions also suggested that levels of DHA‐containing GPLs may be primarily regulated by LPAAT activities functioning in the Kennedy pathway rather than other LPLATs functioning in the Lands’ cycle . Recently, we also reported that in LPAAT3 KO mice DHA‐containing GPLs were greatly decreased , consistent with the idea that DHA‐containing GPLs are primarily produced through the Kennedy pathway.…”

“…Mislocalization of rhodopsin in the perinuclear region was seen in both Mfsd2a and LPAAT3 KO mice (Fig. A) . As DHA‐containing GPLs may also promote membrane fusion and fission, another possible function for DHA‐containing GPLs in photoreceptor cells might be to promote trafficking of rhodopsin from endoplasmic reticulum to the plasma membrane via the Golgi apparatus (Fig.…”

“…The enzyme responsible for DHA incorporation into retinal GPLs was reported recently by our group. LPAAT3 KO mice showed a specific and almost complete lack of DHA‐containing GPLs in the retina, while AA‐containing GPLs were dramatically increased . LPAAT3 KO mice showed retinal degeneration with abnormal morphology/organization of photoreceptor OS disks, indicating the critical requirement of DHA in retina and suggesting that increased AA‐containing GPLs cannot rescue the functions of DHA‐containing species.…”

“…It has long been known that retinal membrane contains a high amount of DHA . In the retina, DHA‐containing GPLs are abundant in outer segment (OS) disks of rod photoreceptor cells . OS disk is a unique organelle specialized in phototransduction.…”

“…Omega‐3 PUFAs have important functions on human health, and recent studies have clarified some of the molecular mechanisms underlying the effects of DHA in various tissues. Several important molecules involved in the incorporation of DHA into cells and production of DHA‐containing GPLs have been identified, including LPAAT3, Mfsd2a, and AdipoR1 . However, very basic questions still remain as to how DHA is incorporation is regulated and the precise functions of DHA in membrane GPLs.…”