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Dysfunctional retinal metabolism has been shown to contribute to retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR) and inherited retinal degeneration (IRD). Data indicates that metabolism in the retina is complex and involves intricate interactions between cell types, including the exchange of metabolites between photoreceptors and retinal pigment epithelium (RPE) cells. To understand these interactions on a single cell level, cell-type specific expression of genetically encoded metabolic sensors can be used to reach a spatial and temporal resolution that is superior to other techniques. These sensors comprise a metabolite binding site and a fluorescent reporter protein. The binding of the metabolite leads to changes in the emission of the fluorophore which can be detected by specialized microscopy. The usage of such sensors together with other techniques in the normal and diseased retina will not only help to resolve metabolic interactions between cells and fluxes of metabolites but also enhance our understanding of pathophysiological changes in the retina., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The outer retina (OR) is highly energy demanding. Impaired energy metabolism combined with high demands are expected to cause energy insufficiencies that make the OR susceptible to complex blinding diseases such as age-related macular degeneration (AMD). Here, anatomical, physiological and quantitative molecular data were used to calculate the ATP expenditure of the main energy-consuming processes in three cell types of the OR for the night and two different periods during the day. The predicted energy demands in a rod dominated (perifovea) area are 1.69 x 1013 ATP/s/mm2 tissue in the night and 6.53 x 1012 ATP/s/mm2 tissue during the day with indoor light conditions. For a cone-dominated foveal area the predicted energy demands are 6.41 x 1012 ATP/s/mm2 tissue in the night and 6.75 x 1012 ATP/s/mm2 tissue with indoor light conditions during daytime. We propose the likely need for diurnal/circadian shifts in energy demands to efficiently stagger all energy consuming processes. Our data provide insights into vulnerabilities in the aging OR and suggest that diurnal constraints may be important when considering therapeutic interventions to optimize metabolism. [ABSTRACT FROM AUTHOR]

Background/Objectives: The interphotoreceptor matrix proteoglycans 1 and 2 (IMPG1 and IMPG2) are two interdependent proteoglycans of the interphotoreceptor matrix (IPM). Mutations in IMPG1 or IMPG2 are linked to retinal diseases such as retinitis pigmentosa (RP) and vitelliform macular dystrophy (VMD), yet the specific mutations responsible for each condition remain undefined. This study identifies mutations in IMPG1 and IMPG2 linked to either RP or VMD. It also provides an in-depth in silico analysis of these mutations' structural and functional impact on protein domains, alongside a detailed examination of the corresponding disease phenotypes. Methods: From a cohort of 480 patients with inherited retinal diseases (IRDs), we identified seven patients with mutations in IMPG1 or IMPG2. Multimodal imaging was performed to assess the clinical phenotypes, including fundus photography, fundus autofluorescence, fluorescein angiography, and spectral domain optical coherence tomography (SD-OCT). We provide structure modeling and analysis of each variant. Results: Our findings indicate a prevalence of 1.45% of IRD patients being affected by IMPG mutations; two were diagnosed with RP and five with VMD. One VMD patient carried a novel IMPG1 p.Asp423Glu mutation. Most patients exhibited heterozygous mutations, and one RP patient presented a compound heterozygous mutation in IMPG2. Conclusions: This work describes a novel mutation and expands our understanding of the specific IMPG protein domains implicated in RP and VMD. Furthermore, it establishes, for the first time, the prevalence of IMPG mutations in an IRD population. [ABSTRACT FROM AUTHOR]

Purpose of Review: Neurodegeneration is a common endpoint of various blinding retinal diseases. Yet, despite exciting advances in disease treatment, there continues to exist a critical need for the development of neuroprotective strategies to prevent retinal cell death. Here, we summarize the recent advances in neuroprotective strategies., Recent Findings: From laboratory deciphering of the mechanisms involved in disease, many novel neuroprotective strategies have emerged and are currently under investigation for the treatment of various retinal and ocular diseases such as inherited retinal degeneration, retinal detachment, diabetic retinopathy, age-related macular degeneration, macular telangiectasia type 2, and glaucoma. These strategies include gene therapies, Fas inhibition, and targeting inflammatory, metabolic and reduction-oxidation abnormalities. Interestingly, investigation of several treatments across different diseases suggests shared neuroprotection mechanisms that can be targeted regardless of the particular disease., Summary: Retinal neuroprotection can improve treatment of different retinal diseases. Fortunately, the current landscape, with a plethora of novel neuroprotective therapies, portends a better future for patients., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

The retinal pigment epithelium (RPE) is a polarized monolayer of cells that provides essential functions to the light-sensitive photoreceptors in the retina. Many of the cell biological processes involving the RPE, including those underlying disease mechanisms, can be studied using in vitro culture systems. For such models to be informative, the RPE cultures must be well-differentiated and fully mature, exhibiting the key characteristics of their native counterparts. In this mini review, we emphasize this requirement to use fully differentiated RPE cultures by discussing structural, functional, and metabolic aspects of the RPE., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The retina is one of the most metabolically active tissues in the human body and has its own complex metabolic environment as the different cell types in this tissue are interconnected to maintain a healthy retinal homeostasis. Any disturbances in the homeostatic balance may have a severe impact on retinal function affecting vision. About 341 genes are listed in the RetNet database as being causative for monogenic inherited retinal diseases. By intersecting this list with the Mammalian Metabolic Enzyme Database, we identified 28 metabolic genes that can result in diseases such as retinitis pigmentosa, Leber congenital amaurosis, or optic atrophy when mutated. Alongside inherited retinal diseases, metabolism also plays a prominent role in acquired retinal diseases. Metabolomics studies have been performed on patients with age-related macular degeneration, diabetic retinopathy, and glaucoma revealing dysregulated metabolic pathways, such as lipid, amino acid, and purine metabolism, in the onset of disease. Although there are distinct pathophysiological differences between inherited and acquired retinal disorders, diving deeper into the role of metabolism and how metabolic dysfunction may overlap with different pathologies, could give us indications on how to design approaches to normalize the homeostatic balance in the retina as treatment options to protect vision., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The underlying mechanisms associated with age-related changes in the morphology and function of retinal pigmented epithelial (RPE) cells are poorly understood. The aging RPE progresses through several structural changes including loss of melanin granules, accumulation of lipofuscin, and cytoskeletal changes, among others. Extracellular to it, there is also thickening of Bruch's membrane and changes in the integrity of the choroid. Recent studies have revealed that aging also affects the metabolic ecosystem of the RPE. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species generation, and increased number of mitochondrial mutations relative to baseline. These changes are also found in age-related macular degeneration (AMD), a late-onset vision-impairing disease, in which the RPE is particularly vulnerable. The orphan nuclear receptor NR4A1/NUR77 is an early response gene and regulator of various cellular processes during development, aging, and disease. Previously we observed decreased levels of Nur77/NUR77 in both mouse and human RPE as a function of age. Current knowledge of the function of this receptor in the RPE is limited. Herein, we discuss the putative roles of NUR77 in the RPE during aging and disease., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Photoreceptors are the most glycolytically active cells in the body. Vital to glucose homeostasis is the metabolic relationship between the photoreceptors and the retinal pigment epithelium (RPE). The photoreceptors and RPE are in metabolic symbiosis, wherein the RPE takes up glucose from circulation and passes it on to the photoreceptors to fuel glycolysis. In turn, the photoreceptors produce energy substrates that are taken up by the RPE to support their metabolism. One of the main roles of the RPE is to phagocytose "used" photoreceptor outer segments (POS), a process that occurs to mitigate damage accrued by light. This mini-review explores the role that POS phagocytosis has in supporting the metabolic ecosystem linking photoreceptors and the RPE., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Age-related macular degeneration (AMD) is a leading cause of visual impairment affecting nearly 200 million people worldwide, and this number is expected to increase in the coming decades. The role of the retinal pigment epithelium (RPE) in AMD pathogenesis has been extensively studied. However, the contribution of photoreceptor (PR) dysfunction to AMD pathogenesis remains understudied and is a critical gap in our knowledge. The RPE and PRs are coupled to promote and enhance their respective survival and function, and this delicate relationship becomes disrupted in AMD. Furthermore, PR metabolic demands are postulated to contribute to AMD pathogenesis, their dysfunction is associated with both the early and end stages of AMD, and their death is central to the vision loss patient's experience in AMD. Here, we review clinical and basic science data indicating that PRs are likely more than a bystander in AMD and play a significant role in AMD pathogenesis., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)