Mitochondrial functional impairment in <i>ARL3</i> ‐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 <i>ARL3</i> mutations have been linked to multiple forms of retinal degeneration, the relationship between ARL3 and mitochondria remains unexplored. Herein, we investigated the effects of <i>ARL3</i> ^<i>T31A</i> , <i>ARL3</i> ^<i>C118F</i> , and <i>ARL3</i> ^{<i>T31A/C118F</i>} 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 <i>ARL3</i>-related mutations play a significant role in the diversity of mitochondrial function, providing novel insights into the functional analysis of <i>ARL3</i>-related mutations.