iPSC–derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function
Kevin T. Eade, Brendan Robert E. Ansell, Sarah Giles, Regis Fallon, Sarah Harkins-Perry, Takayuki Nagasaki, Simone Tzaridis, Martina Wallace, Elizabeth A. Mills, Samaneh Farashi, Alec Johnson, Lydia Sauer, Barbara Hart, M. Elena Diaz-Rubio, Melanie Bahlo, Christian Metallo, Rando Allikmets, Marin L. Gantner, Paul S. Bernstein, Martin Friedlander
Kevin T. Eade, Brendan Robert E. Ansell, Sarah Giles, Regis Fallon, Sarah Harkins-Perry, Takayuki Nagasaki, Simone Tzaridis, Martina Wallace, Elizabeth A. Mills, Samaneh Farashi, Alec Johnson, Lydia Sauer, Barbara Hart, M. Elena Diaz-Rubio, Melanie Bahlo, Christian Metallo, Rando Allikmets, Marin L. Gantner, Paul S. Bernstein, Martin Friedlander
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Research Article Ophthalmology

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

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.

Authors

Kevin T. Eade, Brendan Robert E. Ansell, Sarah Giles, Regis Fallon, Sarah Harkins-Perry, Takayuki Nagasaki, Simone Tzaridis, Martina Wallace, Elizabeth A. Mills, Samaneh Farashi, Alec Johnson, Lydia Sauer, Barbara Hart, M. Elena Diaz-Rubio, Melanie Bahlo, Christian Metallo, Rando Allikmets, Marin L. Gantner, Paul S. Bernstein, Martin Friedlander

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Figure 1

Multimodal retinal images in 4 representative eyes from 4 probands illustrating different stages of disease severity in MacTel and a healthy control proband.

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Multimodal retinal images in 4 representative eyes from 4 probands illus...
Probands 12, 1, and 11 show characteristic findings of MacTel, including increased central blue light autofluorescence (BAF) signaling and vascular leakage on fundus fluorescein angiography (FFA). Findings associated with more advanced disease stages, including a disruption of outer retinal layers, retinal hyper-reflectivity (black arrowheads), and perivascular pigment plaques (white arrowheads) can be found in proband 1 and are most pronounced in proband 11. Note the unusually young age, age of onset, and advanced disease state for proband 11. CFP, color fundus photography; OCT, optical coherence tomography; YOB, year of birth. Black dotted lines indicate the position of the respective B scans on OCT.