Biology subjects

Alabdallat, D.

Publications and source records attributed to Alabdallat, D..

3 recordsLinked to original sources

bioRxiv2026

Aging Differentially Remodels the Retina and RPE/Choroid Proteome and Metabolism

Purpose: The neural retina and retinal pigment epithelium/choroid (RPE/Cho) are metabolically coupled. Metabolic dysfunction of the RPE/Cho contributes to photoreceptor death in age-related macular degeneration (AMD). This study aimed to determine how aging, a major risk factor for AMD, alters the proteome and metabolic pathways in the retina and RPE/Cho. Methods: We performed quantitative proteomics on neural retina and RPE/Cho from young (8-week) and old (73-week) C57BL/6J mice. The differentially expressed proteins between old and young, as well as between the retina and RPE/Cho, were visualized using volcano plots and heatmaps, and functional analyses were assessed by Gene Ontology enrichment tools. Results: Aging altered the expression of 85 retinal proteins and 272 RPE/Cho, with 16 shared between tissues. In the aged retina, proteins associated with NADP(H) metabolism, neurodegeneration, and immunity were mostly upregulated, while proteins in lipid metabolism, transcription, and epigenetic regulation decreased. In the aged RPE/Cho, all 21 significantly altered lysosomal enzymes and transport proteins increased, together with complement components, and photoreceptor outer segment proteins. These changes accompanied increases in proteins associated with lipid metabolism and protection against lipid peroxidation, while several glutathione metabolism enzymes decreased. Seven shared proteins involved in lipid and NADP(H) metabolism, changed in opposite directions between retina and RPE/Cho. Comparison of the retinal and RPE/Cho proteomes identified 3073 differentially abundant proteins, of which 2452 maintained tissue-specific differences across both age groups, while approximately 17% showed age-dependent shifts in tissue enrichment. These shifts involved proteins associated with metabolism, extracellular matrix, visual function, lysosomal pathways, and innate immunity. Within the metabolic proteome, several glycolytic and fatty acid oxidation proteins showed greater relative enrichment in RPE/Cho with age, whereas glucose transporters and mitochondrial complexes shifted toward the retina. Conclusions: Overall, these findings show that aging differentially remodels the retina and RPE/Cho proteome, accompanied by altered metabolic specialization between the two tissues.

biochemistry↗

bioRxiv2026

Metabolic signatures of cone-dominant and cone-degenerating retinas

Cone photoreceptors are essential for daylight vision, and their degeneration has more profound visual consequences than rod loss in retinal degenerative diseases. Metabolic dysfunction is closely associated with cone degeneration, however the relatively small population of cones in mice and humans have limited our understanding of cone-specific metabolism. Here, we leveraged cone-dominant and cone-degeneration mouse models including Nrl-/-, Cnga3-/-, and high-dose Triiodothyronine (T3) treatment to investigate cone-specific metabolism and their metabolic impacts on the retinal pigment epithelium (RPE). Across models, cone-dominant retinas consistently showed lower pyruvate abundance alongside increases in glutathione, purines, pentose phosphate pathway intermediates, and one-carbon metabolites. Increases in several key amino acids were also associated with higher cone abundance, such as proline, arginine, alanine, valine, leucine, and hypotaurine. Strikingly, aminoadipate, an intermediate in lysine catabolism, was the most robustly changed metabolite in the retina, showing highly consistent increases across models. Relative cone increases were also associated with metabolic changes in the RPE/choroid. Like the retina, RPE/choroids showed consistent increases in aminoadipate, proline, and hypotaurine, as well as xanthosine and betaine, alongside decreases in uracil. Moreover, proteomic analysis of Nrl-/- mice showed decreases in many key metabolite transporters in the RPE/choroid, including carriers for glucose, lactate, aspartate, glutamate, serine, lysine, taurine, and proline. Collectively, these findings further our understanding of cone-specific metabolism and highlight potential cone-specific metabolic vulnerabilities in retinal degeneration.

biochemistry↗

bioRxiv2025

Absolute quantification of TCA cycle intermediates in mouse ocular tissues reveals distinct tissue- and sex-specific mitochondrial metabolism

ObjectiveMitochondrial tricarboxylic acid (TCA) cycle is central to energy production and redox balance in the eye, which must sustain high metabolic activity to support vision. Retinal neurons, the retinal pigment epithelium (RPE), cornea, and lens each have distinct physiological roles and metabolic demands, yet the absolute concentrations of key TCA intermediates and their variation by tissue, sex, and time of day are not well-defined. MethodsTargeted gas chromatography-mass spectrometry was employed to quantify the absolute concentrations of TCA cycle metabolites in mouse ocular tissues collected at 10 AM and 2 PM to capture diurnal variations. Key metabolite ratios were subsequently calculated to provide insight into TCA cycle dynamics across eye tissues. ResultsThe retina showed the highest concentrations of TCA metabolites among all ocular tissues, particularly succinate, citrate, and malate, consistent with its high energy demands. The RPE/choroid demonstrated well-balanced intermediates with the highest -ketoglutarate (-KG)/Isocitrate ratio, reflecting its efficient mitochondrial oxidation and reductive carboxylation. Corneal metabolism was featured by dominant malate, especially in females, suggesting a metabolic adaptation for redox regulation and oxidative stress defense. The lens had uniformly low metabolite levels except for succinate, indicating minimal mitochondrial activity under physiologically low oxygen conditions. Notably, both the cornea and lens showed significant sex-dependent and diurnal variations in TCA cycle intermediates. ConclusionThis study demonstrates distinct tissue-specific mitochondrial metabolism in the eye, reflecting the unique functional and biochemical demands of each tissue. These metabolic signatures may underlie their susceptibility to mitochondrial dysfunction in various ocular diseases.

biochemistry↗