Jun 2026· Nature Communications· Vol 17· 0 citations· 63 references
Medicine
TL;DR
It is shown that the NAD+ precursor NMN protects against retinal degeneration by improving mitochondrial function in MERTK-associated models, offering potential therapeutic insights.
Abstract
Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease leading to blindness. RP is characterized by progressive loss of photoreceptors and retinal pigment epithelium (RPE), leading to retinal degeneration. The mechanisms that initiate RP and drive retinal vulnerability are poorly understood, and new strategies for preventing and treating RP are urgently needed. Although mitochondrial dysfunction initiates many neurodegenerative diseases, the contribution of mitochondrial dysfunction to RP is unclear. Single-cell RNA sequencing, transmission electron microscopy, and enzyme-linked immunosorbent assays revealed that photoreceptor and RPE cells have abnormal mitochondria in rats with RP. Nicotinamide adenine dinucleotide (NAD+) metabolism decreased in rats with RP, increasing the vulnerability to disease-related insults. Similar experimental results were observed in a Mer tyrosine kinase receptor (MERTK)-associated RP primary human RPE cell model. Electroretinography, immunofluorescence, and fundus photography revealed that oral administration of the NAD+ precursor nicotinamide mononucleotide (NMN) protected rats with RP from retinal degeneration. Single-cell RNA sequencing, siRNA targeting, and Adeno-associated virus applications demonstrated that NMN elicits therapeutic effects via the glyceraldehyde-phosphate dehydrogenase-mitochondria pathway. These results indicate that mitochondrial abnormalities may be drivers of RP, and NMN elicits therapeutic effects on RP. Retinitis pigmentosa leads to blindness due to photoreceptor loss. Here, the authors show that the NAD+ precursor NMN protects against retinal degeneration by improving mitochondrial function in MERTK-associated models, offering potential therapeutic insights.
Retinitis Pigmentosa (RP) is an inherited retinal degenerative disease that affects 1 in 4000 individuals worldwide and can lead to complete blindness. Early stages of RP involve death of rod photoreceptors via apoptosis, causing loss of peripheral and night vision, which is followed by death of cone photoreceptors, leading to loss of central and daytime vision. Mutations in over 300 genes cause RP. Many of these genes encode retina-specific proteins; however, some encode globally expressed proteins, such as pre-mRNA splicing factors. This study is focused on mutations in the SNRNP200 gene encoding a core pre-mRNA splicing factor. The pathological mechanisms of SNRNP200-associated RP are not well understood and treatments are limited. An approach to study pathogenic mechanisms is to utilize model organisms. Therefore, we developed Drosophila models in which RP-causing mutations were introduced into the Drosophila melanogaster orthologue Snrnp200. In addition, we used RNAi to knock-down Snrnp200 in the developing eye. Depletion of Snrnp200 caused an adult rough eye phenotype due to apoptosis of cells in the retina. When human RP-causing mutations were modeled in Drosophila Snrnp200, they resulted in abnormal retinal electrophysiology and defective patterning of photoreceptors. Further analysis of the photoreceptors revealed mitochondrial defects and altered expression of genes related to redox homeostasis. Consistent with these changes, treatment with the antioxidant N-acetylcysteine (NAC) partially suppressed the photoreceptor defects. Taken together, these findings established a new genetic model for studies of splicing-factor associated RP that recapitulates aspects of the human disease and suggests that antioxidants might serve as a treatment for individuals with SNRNP200-associated RP.
Sara K. Mayer, Quinton H Christensen, Hailey McCoy-Munger et al.· Human Molecular Genetics· 0 citations
Retinitis pigmentosa (RP) is a hereditary retinal degeneration disorder often caused by mutations in the rhodopsin gene, leading to photoreceptor death and vision loss. While structural misfolding of rhodopsin is a known contributor to disease pathology, the mechanisms of its cellular and in particular metabolic consequences are poorly understood. To study the direct effects of rhodopsin misfolding and structural rescue on cellular metabolism, we used the P23A mutant and its N2C/D282C stabilized counterpart as a structural tool to assess how differences in folding stability relate to measurable changes at the metabolite level. The engineered cysteine pair allows the formation of a disulfide bond restoring structural integrity and reinforcing the stable seven-transmembrane bundle. We used untargeted Gas Chromatography-Mass Spectrometry (GC-MS) metabolomics analysis conducted in inducible rhodopsin-expressing cell lines, providing a broad and general profiling of metabolic pathway alterations in response to the expression of RP mutants and their structurally rescued counterparts. Principal component analysis, hierarchical clustering, and K-means clustering revealed distinct metabolic signatures associated with each rhodopsin-expressing cell line, demonstrating a highly significant effect of genotype on global metabolite composition (F = 71.679; R2 = 0.93724; p = 0.001). Pairwise comparisons and background-subtracted analyses identified consistent alterations in arginine and proline metabolism, glutathione metabolism, and the TCA cycle, nucleotide, amino acid metabolism, redox regulation, and mitochondrial function in cells expressing misfolded P23A. Pathway enrichment highlighted key metabolites in the respective pathways as candidate biomarkers for the rhodopsin P23A mutation. As this study employs a non-retinal cell system, the observed metabolic changes reflect conserved responses to rhodopsin misfolding and proteostatic stress in the ER rather than a direct model of rod cell degeneration. Our findings support the hypothesis that there is a biochemical link, most likely the UPR, between rhodopsin folding/misfolding status and metabolic homeostasis and suggest that targeted metabolic modulation may offer a complementary therapeutic avenue for treating RP.
M. Murthy, Hannah Staggs-Sandy, Paniz Jasbi et al.· The FASEB Journal· 0 citations
Results identify Cryaa as a critical regulator of ER stress and demonstrate that its reduction promotes UPR activation and subsequent photoreceptor apoptosis in the rd9 model, revealing a key role for Cryaa in XLRP pathology and may provide a novel therapeutic perspective for this disease.
Mingzhu Yang, Ruiqi Qiu, S. Yao et al.· Cell Death & Disease· 0 citations
Photoreceptors work in a biologically demanding compartment of the eye. They consume large amounts of energy, receive continuous light and oxygen, and renew outer-segment membranes enriched in polyunsaturated lipids. These conditions are necessary for vision, but they also make the outer retina poorly tolerant to persistent mitochondrial dysfunction and oxidative stress. Photobiomodulation (PBM), mainly based on red and near-infrared light, has been investigated as a way to support retinal cells that are functionally impaired but not yet irreversibly lost. The field has also acquired new clinical relevance after the 2024 De Novo marketing authorization by the United States Food and Drug Administration (FDA) of the Valeda Light Delivery System for dry age-related macular degeneration (AMD). This narrative review examines the mitochondrial, redox, inflammatory, and neurovascular mechanisms proposed for PBM, and discusses preclinical and clinical evidence across nonexudative AMD, inherited retinal degeneration, diabetic retinal disease, and light-induced damage. Current findings are encouraging, but devices, doses, schedules, endpoints, and sponsorship patterns differ substantially among studies. PBM therefore deserves further investigation, especially in early or intermediate disease, but its clinical use should remain linked to tested protocols, rigorous safety monitoring, and biomarkers of residual retinal functional reserve.
M. Toro, Alessandro Avitabile, Roberta Amato et al.· Antioxidants· 0 citations
Heterogeneous degeneration of the retinal pigment epithelium (RPE) leads to irreversible blindness in diseases associated with macular atrophy. However, the underlying mechanisms of regional RPE degeneration remain poorly understood. To address this gap, this study identifies a peripheral RPE subpopulation through spatial, transcriptomic, and functional analyses, thereby contributing to the understanding of the heterogeneity of degenerative RPE cells. Specifically, omics analyses in human and macaque RPE reveal a peripheral RPE cell population with high SERPINE3 expression, while SERPINE3-GFP knock-in mice show comparable expression patterns. In addition, SMART-seq2 analysis further distinguishes transcriptomic profiles between GFP-positive and GFP-negative RPE cells. Under oxidative stress, SERPINE3 expression increases, and GFP-positive cells exhibit improved survival and reentry into the cell cycle. Notably, genetic studies indicate that SERPINE3 is essential for the oxidative stress resistance of GFP-positive cells. Moreover, loss of SERPINE3 results in regional RPE degeneration and increased microglial accumulation in aged mice. Mechanistically, proteinase screening and co-immunoprecipitation indicate that SERPINE3 targets Caspase-1. Importantly, delivery of SERPINE3 via AAV-Serpine3 partially reduces RPE degeneration in an oxidative damage model. These findings advance the understanding of RPE heterogeneous degeneration and highlight SERPINE3 as a protective factor with therapeutic potential for macular atrophy.
Huirong Li, Takerra K. Johnson-Stephenson, Vincent P. Kunze et al.· Journal of Clinical Investig...· 0 citations
Retinal degeneration (RD) is a group of retinopathies characterized by progressive photoreceptor death and chronic neuroinflammation. Quercetin (QUE) is a natural flavonol with potent anti-inflammatory and free-radical scavenging properties. However, its protective effects against RD remain poorly characterized. This study aims to investigate the therapeutic potential of QUE on RD.In vitro and in vivo models of sodium iodate (NaIO3)-induced oxidative damage were used to evaluate the effects of QUE in RD. NaIO3 was used to induce oxidative damage in 661W cells. QUE was added to the cell cultures, and cell viability and oxidative markers were assessed. In vivo, QUE was delivered into the vitreous cavity of NaIO3-induced RD mice, followed by morphological analysis, visual function evaluation, behavioral testing, and Western blot detection.QUE protected 661W cells from NaIO3-induced oxidative damage by reducing intracellular reactive oxygen species, restoring mitochondrial membrane potential, and alleviating mitochondrial membrane pore disruption. In vivo, intravitreal QUE injection preserved retinal structure, reduced lesion area, elevated electroretinogram P-wave amplitude, and improved behavioral performance. QUE administration was accompanied by alleviated oxidative stress, inhibited glial activation, reduced pro-inflammatory cytokines, and elevated p-PI3K and p-AKT expression in RD. Neuroinflammation and oxidative stress are involved in RD pathology. These findings provide preliminary evidence that QUE exerts protective effects on photoreceptors in NaIO₃-induced RD. No causal relationship between PI3K/AKT activation and the retinal protection of QUE was established in this study.