Lipidomic and transcriptomic remodeling underlies early retinal pathogenesis in dry age-related macular degeneration
5 affiliations
- 1Department of Ophthalmology, Margaret M. Dyson Vision Research Institute, Weill Cornell Medicine, New York, NY USA
- 2Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA USA
- 3The Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD USA
- 4Department of Radiology, Weill Cornell Medicine, Brain Health Imaging Institute, New York, NY USA
- 5Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY USA
Abstract
Dry age-related macular degeneration (AMD) is initiated by retinal pigment epithelium (RPE) dysfunction, yet early metabolic mechanisms linking RPE injury to photoreceptor dysfunction remain unclear. Using a physiologically relevant mouse model, we performed cell-type–resolved lipidomic and transcriptomic profiling with ultrastructural analyses. RPE-specific loss of Chloride Intracellular Channel 4 (CLIC4) induced coordinated lipid remodeling and transcriptional rewiring compromising RPE–photoreceptor lipid homeostasis. Both RPE and neural retina exhibited shifts toward very-long-chain unsaturated phospholipids and ceramides, while mutant RPE also accumulated saturated very-long-chain ceramides and cholesterol, particularly in females, favoring drusen deposition. Strikingly, RPE and rods mounted divergent responses: RPE activated compensatory mechanisms, whereas rods exhibited transcriptomic and ultrastructural evidence of bioenergetic suppression, mitochondrial structural abnormalities, and mitochondria-derived oxidative damage, establishing a feed-forward stress cycle extending beyond canonical rod-RPE carbon-energy coupling. These findings underscore rod mitochondrial structural integrity as a potential early biomarker, positioning disrupted lipid recycling as a targetable axis in dry AMD pathogenesis.
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BibTeX
@article{roy2026lipidomic,
title = {{Lipidomic and transcriptomic remodeling underlies early retinal pathogenesis in dry age-related macular degeneration}},
author = {Neeta Roy and Jen-Zen Chuang and Ting-Huan Chen and Ye Sun and Danielle E. Allen and Marie-Audrey I. Kautzmann and Surjyadipta Bhattacharjee and Maxwell Ping Lee and Laura Beth J. McIntire and Nicolas G. Bazan and Ching-Hwa Sung},
journal = {Cell Death \& Disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09147-5},
url = {https://doi.org/10.1038/s41419-026-09147-5},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Lipidomic and transcriptomic remodeling underlies early retinal pathogenesis in dry age-related macular degeneration
AU - Neeta Roy
AU - Jen-Zen Chuang
AU - Ting-Huan Chen
AU - Ye Sun
AU - Danielle E. Allen
AU - Marie-Audrey I. Kautzmann
AU - Surjyadipta Bhattacharjee
AU - Maxwell Ping Lee
AU - Laura Beth J. McIntire
AU - Nicolas G. Bazan
AU - Ching-Hwa Sung
PY - 2026
DA - 2026/08/07
JO - Cell Death & Disease
DO - 10.1038/s41419-026-09147-5
UR - https://doi.org/10.1038/s41419-026-09147-5
AB - Dry age-related macular degeneration (AMD) is initiated by retinal pigment epithelium (RPE) dysfunction, yet early metabolic mechanisms linking RPE injury to photoreceptor dysfunction remain unclear. Using a physiologically relevant mouse model, we performed cell-type–resolved lipidomic and transcriptomic profiling with ultrastructural analyses. RPE-specific loss of Chloride Intracellular Channel 4 (CLIC4) induced coordinated lipid remodeling and transcriptional rewiring compromising RPE–photoreceptor lipid homeostasis. Both RPE and neural retina exhibited shifts toward very-long-chain unsaturated phospholipids and ceramides, while mutant RPE also accumulated saturated very-long-chain ceramides and cholesterol, particularly in females, favoring drusen deposition. Strikingly, RPE and rods mounted divergent responses: RPE activated compensatory mechanisms, whereas rods exhibited transcriptomic and ultrastructural evidence of bioenergetic suppression, mitochondrial structural abnormalities, and mitochondria-derived oxidative damage, establishing a feed-forward stress cycle extending beyond canonical rod-RPE carbon-energy coupling. These findings underscore rod mitochondrial structural integrity as a potential early biomarker, positioning disrupted lipid recycling as a targetable axis in dry AMD pathogenesis.
SN - 2041-4889
ER -