Acyl-CoA synthetase 6 controls rod photoreceptor function and survival by shaping the phospholipid composition of retinal membranes
The retina is light-sensitive neuronal tissue in the back of the eye. The phospholipid composition of the retina is unique and highly enriched in polyunsaturated fatty acids, including docosahexaenoic fatty acid (DHA). While it is generally accepted that a high DHA content is important for vision, surprisingly little is known about the mechanisms of DHA enrichment in the retina. Furthermore, the biological processes controlled by DHA in the eye remain poorly defined as well. Here, we combined genetic manipulations with lipidomic analysis in mice to demonstrate that acyl-CoA synthetase 6 (Acsl6) serves as a regulator of the unique composition of retinal membranes. Inactivation of Acsl6 reduced the levels of DHA-containing phospholipids, led to progressive loss of light-sensitive rod photoreceptor neurons, attenuated the light responses of these cells, and evoked distinct transcriptional response in the retina involving the Srebf1/2 (sterol regulatory element binding transcription factors 1/2) pathway. This study identifies one of the major enzymes responsible for DHA enrichment in the retinal membranes and introduces a model allowing an evaluation of rod functioning and pathology caused by impaired DHA incorporation/retention in the retina.
Authors
- John D. Ash
- Екатерина С. Лобанова (ORCID: https://orcid.org/0000-0002-8309-7199)
- Vadim Y. Arshavsky (ORCID: https://orcid.org/0000-0001-8394-3650)
- Frank M. Dyka (ORCID: https://orcid.org/0000-0001-7973-7125)
- Frans Vinberg (ORCID: https://orcid.org/0000-0003-3439-4979)
- Haitao Liu (ORCID: https://orcid.org/0000-0002-3757-779X)
- Martin‐Paul Agbaga (ORCID: https://orcid.org/0000-0002-1920-915X)
- William J. Spencer (ORCID: https://orcid.org/0000-0001-9301-3828)
- Jianhai Du (ORCID: https://orcid.org/0000-0002-2019-8128)
- Jessica M. Ellis (ORCID: https://orcid.org/0000-0003-3803-8461)
- Richard S. Brush (ORCID: https://orcid.org/0000-0002-8527-5315)
- Stella Finkelstein
- Yixiao Wang (ORCID: https://orcid.org/0000-0001-6049-1962)
- Hao Ying (ORCID: https://orcid.org/0000-0003-0824-9348)
- Silke Becker (ORCID: https://orcid.org/0000-0003-4674-6011)
- Mark Eminhizer
Institutions
- West Virginia University (US)
- University of Pittsburgh (US)
- Duke University (US)
- East Carolina University (US)
- SUNY Upstate Medical University (US)
- University of Utah (US)
- University of Florida (US)
- Dean McGee Eye Institute (US)
- University of Oklahoma Health Sciences Center (US)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1038/s42003-024-06691-8
- Citations
- 2
- Primary Topic
- Retinal Development and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- Research to Prevent Blindness
- University of Pittsburgh
- University of Oklahoma
- Diabetes Research Connection
- National Institutes of Health
- School of Medicine
- National Eye Institute