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other·ophthalmology, retina, preclinical research, biomedical research·PMC10406976

PNPLA2 mobilizes retinyl esters from retinosomes and promotes the generation of 11- cis -retinal in the visual cycle

Cell reports · 6 authors, 5 centres

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TL;DR

This preclinical study used Pnpla2 knockout mice to investigate the enzyme's role in the visual cycle. The central result is that PNPLA2 mobilizes retinyl esters from retinosomes in the retinal pigment epithelium, and its absence impairs dark adaptation and visual function.

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The study investigated the function of PNPLA2 in the visual cycle using Pnpla2 global knockout mice compared to wild-type littermates. Researchers demonstrated that PNPLA2 is expressed in the retinal pigment epithelium (RPE) and colocalizes with lipid droplets. The absence of PNPLA2 led to a significant accumulation of lipid droplets in RPE cells, increased retinyl ester levels, and delayed dark adaptation, as evidenced by declined electroretinography (ERG) responses and slower regeneration of 11-cis-retinal. In vitro experiments confirmed PNPLA2 acts as a retinyl ester hydrolase, and its overexpression enhanced the production of 11-cis-retinol by RPE65. The findings suggest PNPLA2 mobilizes retinyl esters from retinosomes to provide substrate for RPE65 in the endoplasmic reticulum. A key limitation is that the global knockout model may confound results due to PNPLA2's potential role in the neural retina, which remains unknown.

STUDY TYPE

other

SPECIALTY

ophthalmology

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AI pipeline

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ORIGINAL PAPER

PMC10406976

PNPLA2 mobilizes retinyl esters from retinosomes and promotes the generation of 11- cis -retinal in the visual cycle

Cell reports

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ABSTRACT

SUMMARY Retinosomes are intracellular lipid bodies found in the retinal pigment epithelium (RPE). They contain retinyl esters (REs) and are thought to be involved in visual chromophore regeneration during dark adaptation and in case of chromophore depletion. However, key enzymes in chromophore regeneration, retinoid isomerase (RPE65), and lecithin:retinol acyltransferase (LRAT) are located in the endoplasmic reticulum (ER). The mechanism and the enzyme responsible for mobilizing REs from retinosomes remained unknown. Our study demonstrates that patatin-like phospholipase domain containing 2 (PNPLA2) mobilizes all- trans -REs from retinosomes. The absence of PNPLA2 in mouse eyes leads to a significant accumulation of lipid droplets in RPE cells, declined electroretinography (ERG) response, and delayed dark adaptation compared with those of WT control mouse. Our work suggests a function of PNPLA2 as an RE hydrolase in the RPE, mobilizing REs from lipid bodies and functioning as an essential component of the visual cycle.

CITATION EXPORT

Miwa Hara, Wenjing Wu, Volha V. Malechka et al.. PNPLA2 mobilizes retinyl esters from retinosomes and promotes the generation of 11-cis-retinal in the visual cycle. Cell reports. (2023). https://doi.org/10.1016/j.celrep.2023.112091

AUTHORS

6 · 5 CENTRES

Miwa Hara, Wenjing Wu, Volha V. Malechka, Yusuke Takahashi, Jian-Xing Ma, Gennadiy Moiseyev

1Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
2Department of Biochemistry, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
3Present address: Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
4These authors contributed equally
5Lead contact