Biology subjects

Rizwan, S.

Publications and source records attributed to Rizwan, S..

4 recordsLinked to original sources

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↗

bioRxiv2024

Metabolic phenotyping of healthy and diseased human RPE cells

PurposeMetabolic defects in the retinal pigment epithelium (RPE) underlie many retinal degenerative diseases. This study aims to identify the nutrient requirements of healthy and diseased human RPE cells. MethodsWe profiled nutrient utilization of various human RPE cells, including differentiated and dedifferentiated fetal RPE (fRPE), induced pluripotent stem cell derived-RPE (iPSC RPE), Sorsby fundus dystrophy (SFD) patient-derived iPSC RPE, CRISPR-corrected isogenic SFD (cSFD) iPSC RPE, and ARPE-19 cell lines using Biolog Phenotype MicroArray Assays. ResultsDifferentiated fRPE cells and healthy iPSC RPE cells can utilize 51 and 48 nutrients respectively, including sugars, intermediates from glycolysis and tricarboxylic acid (TCA) cycle, fatty acids, ketone bodies, amino acids, and dipeptides. However, when fRPE cells lose their epithelial phenotype through dedifferentiation, nutrient utilization becomes restricted to 17 nutrients, primarily sugar and glutamine-related amino acids. SFD RPE cells can utilize 37 nutrients; however, compared to cSFD RPE and healthy iPSC RPE, they are unable to utilize lactate, some TCA cycle intermediates, and short-chain fatty acids. Nonetheless, they show increased utilization of branch-chain amino acids (BCAAs) and BCAA-containing dipeptides. Dedifferentiated ARPE-19 cells grown in traditional culture media cannot utilize lactate and ketone bodies. In contrast, nicotinamide supplementation promotes differentiation towards an epithelial phenotype, restoring the ability to use these nutrients. ConclusionsEpithelial phenotype confers metabolic flexibility to healthy RPE for utilizing various nutrients. SFD RPE cells have reduced metabolic flexibility, relying on the oxidation of BCAAs. Our findings highlight the potentially important roles of nutrient availability and utilization in RPE differentiation and diseases.

biochemistry↗

bioRxiv2020

Alternating handedness motifs in proteins classify structure and cofactor binding

Cofactor binding sites in proteins often are composed of favorable interactions of specific cofactors with the sidechains and/or backbone protein fold motifs. In many cases these motifs contain left-handed conformations which enable tight turns of the backbone that present backbone amide protons in direct interactions with cofactors termed cationic nests. Here, we defined alternating handedness of secondary structure as a search constraint within the PDB to systematically identify these cofactor binding nests. We identify unique alternating handedness structural motifs which are specific to the cofactors they bind. These motifs can guide the design of engineered folds that utilize specific cofactors and also enable us to gain a deeper insight into the evolution of the structure of cofactor binding sites.

bioinformatics↗

bioRxiv2019

Peculiar cases of a \"sleeping\" brain in alert cancer patients

Cognitive and constitutional symptomatology is common in cancer patients but the causes are not well understood. To investigate whether cancers cause these symptoms by changing cerebral metabolism, we measured the cerebral rate of glucose consumption (CMRglc) in patients diagnosed with a lung lesion.\n\nMethodsThe CMRglc was quantified in 20 patients undergoing 18F-FDG PET for lesion staging. The cognitive status was assessed by neuropsychological testing.\n\nResultsParadoxically, despite being alert three of the patients had CMRglc typical of people who are in deep sleep or anesthetized. All three had cancers, two died within 2 months of scanning. Remaining patients including four with early stage cancer had CMRglc within normal range.\n\nConclusionsWe speculate that the low CMRglc reflects a switch to an alternative energy source that is mediated by cancers remotely. Identifying the underlying mechanism and the alternative energy sources may help to understand how cancers can change body metabolism.

cancer biology↗