Lysosomes in retinal health and disease

Boya, Patricia; Kaarniranta, Kai; Handa, James T.; Sinha, Debasish

doi:10.1016/j.tins.2023.09.006

Cited by 4 publications

(1 citation statement)

References 132 publications

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“…In addition to direct transport of nutrients to the neural retina, RPE can recycle and generate nutrients via lysosomes and mitochondria to support retinal metabolism, thereby establishing a metabolic ecosystem between the outer retina and RPE 1,2,19 . The ability to utilize various nutrients is crucial for maintaining this metabolic ecosystem and disruption of this balance due to mitochondrial and/or lysosomal dysfunction in RPE can lead to retinal degeneration 3,4,20 . Healthy human RPE cells are known to be versatile in utilizing different nutrients, including glucose, galactose, lactate, fatty acids, succinate, proline, glutamine and other amino acids 11,19,[21][22][23][24] .…”

Section: Culture Media Composition Controls the Differentiation And N...mentioning

confidence: 99%

Metabolic phenotyping of healthy and diseased human RPE cells

Rizwan,

Toothman,

et al. 2024

Preprint

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(250 words) Purpose: Metabolic defects in retinal pigment epithelium (RPE) are underlying many retinal degenerative diseases. This study aims to identify the nutrient requirements of healthy and diseased human RPE cells. Methods: We profiled the utilization of 183 nutrients in human RPE cells: 1) differentiated and dedifferentiated fetal RPE (fRPE), 2) induced pluripotent stem cell derived-RPE (iPSC RPE), 3) Sorsby fundus dystrophy (SFD) patient-derived iPSC RPE and its CRISPR-corrected isogenic SFD (cSFD) iPSC RPE, and 5) ARPE-19 cell lines cultured under different conditions. Results: Differentiated 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 epithelial phenotype through dedifferentiated, they can only utilize 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. The dedifferentiated ARPE-19 cells in traditional culture media cannot utilize lactate and ketone bodies. In contrast, nicotinamide supplementation promotes differentiation into epithelial phenotype, restoring the ability to use these nutrients. Conclusions: Epithelial phenotype confers metabolic flexibility to the RPE for utilizing various nutrients. SFD RPE cells have reduced metabolic flexibility, relying on the oxidation of BCAAs. Our findings highlight the importance of nutrient availability and utilization in RPE differentiation and diseases.

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