Human iPSC-derived retinal pigmented epithelium from patients with Macular Telangiectasia show decreased mitochondrial function

Modelling cell-specific disease mechanisms using induced pluripotent stem cells (iPSCs) is a powerful tool for identifying the cell and molecular basis for such diseases. Macular Telangiectasia type 2 (MacTel) is a rare, late-onset, degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to such an approach. Large whole exome sequencing (WES) screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and genome-wide association studies have linked MacTel to decreased circulating levels of serine and glycine and elevated levels of toxic 1-deoxysphingolipids. However, disease-contributing factors in retinal tissue have yet to be identified. Here, we utilize retinal pigmented epithelium differentiated from iPSCs (iRPE) derived from donors with and without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE mimic the low serine and glycine levels observed in MacTel patient serum. Through RNAseq and gene set enrichment pathway analysis we determine that MacTel iRPE have an enrichment of cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress test we functionally validate that MacTel iRPE have a reduction in mitochondrial function which is independent of defects in serine biosynthesis and 1-deoxysphingolipids accumulation. Thus, we identify phenotypes that may contribute to alternative disease mechanisms beyond the known serine/sphingolipid pathway.