Mitochondrial functional impairment in ARL3-mutation related rod-cone dystrophy

Mitochondria are vital for retinal cell function and survival, and there is growing evidence linking mitochondrial dysfunction to retinal degenerations. Although ARL3 mutations have been linked to multiple forms of retinal degeneration, the relationship between ARL3 and mitochondria remains unexplored. Herein, we investigated the effects of ARL3^T31A, ARL3^C118F, and ARL3^T31A/C118F mutations on mitochondrial function in fibroblasts obtained from patients with ARL3-related rod-cone dystrophy. Our findings revealed that these mutations led to a decrease in mitochondrial respiration, an increase in the accumulation mitochondrial reactive oxygen species (ROS), and induction of apoptosis in fibroblasts. Additionally, we conducted a comparative analysis of the effects of ARL3^T31A, ARL3^C118F, and ARL3^T31A/C118F proteins on mitochondria in ARPE-19 cells. Results showed that ARL3^T31A and ARL3^T31A/C118F not only affected mitochondrial function but also induced apoptosis in ARPE-19 cells. Conversely, ARL3^C118F primarily influenced cell apoptosis with minimal effects on mitochondrial function in ARPE-19 cells. Transcriptome analysis further suggested the involvement of respiratory electron transport, response to ROS, and apoptotic signaling pathways in ARL3^T31A/C118F cells. Our study demonstrated that ARL3-related mutations play a significant role in the diversity of mitochondrial function, providing novel insights into the functional analysis of ARL3-related mutations.