iPSC-derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function

Eade, KT; Ansell, BRE; Giles, S; Fallon, R; Harkins-Perry, S; Nagasaki, T; Tzaridis, S; Wallace, M; Mills, EA; Farashi, S; Johnson, A; Sauer, L; Hart, B; Rubio, ED; Bahlo, M; Metallo, C; Allikmets, R; Gantner, ML; Bernstein, PS; Friedlander, M

Author(s): Eade, KT; Ansell, BRE; Giles, S; Fallon, R; Harkins-Perry, S; Nagasaki, T; Tzaridis, S; Wallace, M; Mills, EA; Farashi, S; Johnson, A; Sauer, L; Hart, B; Rubio, ED; Bahlo, M; Metallo, C; Allikmets, R; Gantner, ML; Bernstein, PS; Friedlander, M;
Details: Publication Year 2023-05-01,Volume 133,Issue #9,Page e163771
Journal Title: Journal of Clinical Investigation
Abstract: Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease-contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway.
Publisher: American Society for Clinical Investigation
Keywords: Humans; Induced Pluripotent Stem Cells/metabolism; Retinal Telangiectasis/metabolism/pathology; Diabetic Retinopathy/metabolism; Mitochondria/metabolism; Epithelial Cells/metabolism; Serine/metabolism; Mitochondria; Ophthalmology; Retinopathy; Stem cells; iPS cells
Research Division(s): Population Health And Immunity
PubMed ID: 37115691
Publisher's Version: https://doi.org/10.1172/jci163771
Open Access at Publisher's Site: https://doi.org/10.1172/JCI163771
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-05-03 10:17:25

Last Modified: 2023-05-03 10:17:54