Pluripotent Stem Cells Reveal Poly-unsaturated Fatty Acids-provoked Mitochondrial Stress as a Central Node Potentiating Retinal Pigmented Epithelium Degeneration in Bietti’s Crystalline Dystrophy

Abstract Bietti’s crystalline retinal dystrophy (BCD) is an incurable disorder caused by CYP4V2 mutations. Patients with BCD present degeneration of retinal pigmented epithelial cells (RPE) and consequent blindness. The lack of appropriate disease models and patients’ RPE cells limits our understanding on the pathological mechanism of RPE degeneration. In this study, using CYP4V2 mutant pluripotent stem cells as disease models, we demonstrated that RPE cells with CYP4V2 mutations presented a disrupted fatty acid homeostasis, which were characterized with excessive accumulation of poly-unsaturated fatty acid (PUFA) including arachidonic acid (AA) and eicosapentaenoic acid (EPA). The PUFA-overload increased mitochondrial reactive oxygen species, impaired mitochondrial respiratory functions, and triggered mitochondrial stress-activated p53-independent apoptosis in CYP4V2 mutant RPE cells. Restoration of the mutant CYP4V2 using adeno-associated virus 2 (AAV2) can effectively reduce PUFA deposition, alleviate mitochondria oxidative stresses, and rescue RPE cell death in BCD RPE cells. Together, our results highlight a role of PUFA-induced mitochondrial damage as a central node to potentiate the RPE degeneration in BCD patients. The AAV2-mediated gene therapy may represent a feasible strategy for the treatment of BCD.