IRE1α-mediated endoplasmic reticulum stress response regulates oxidative damage in CYP4V2 deficient human retinal pigment epithelial cells.

BACKGROUND: Given the role of polyunsaturated fatty acid (PUFA) overload and mitochondrial dysfunction in retinal pigment epithelium (RPE) cells in causing retinal degeneration in Bietti crystalline dystrophy (BCD), we aimed to identify the pathways responsible for intracellular oxidative stress and mitochondrial damage in CYP4V2-deficient RPE cells. MATERIALS AND METHODS: Proteomic analysis of control and CYP4V2-knockdown (KD) ARPE-19 cells revealed that endoplasmic reticulum (ER) stress was the most enriched pathway. The effects of CYP4V2 deficiency on intracellular reactive oxygen species, mitochondrial integrity, and ATP production were assessed. RESULTS: Inositol-requiring enzyme 1 α (IRE1α) inhibitors suppressed upregulation of endoplasmic reticulum oxidoreductase 1 alpha (ERO1-Lα) protein expression, which contributed to ER-associated oxidative stress. Loss of mitochondrial transmembrane potential and reduced ATP production were mitigated with IRE1α inhibitor in CYP4V2-KD ARPE-19 cells. CONCLUSIONS: Our findings reveal a novel regulatory mechanism involving potential reduction in PUFA utilization, IRE1α signaling mediated ER oxidative stress, and mitochondrial dysfunction in BCD, potentially offering future therapeutic avenues.