Disrupted Energy Metabolism is Associated with Retinal Ganglion Cell Degeneration in Autosomal Dominant Optic Atrophy
This study investigated the impact of an Opa1 variant on mitochondrial function and retinal metabolism using a novel knock-in mouse model (Opa1V291D/+) that mirrored autosomal dominant optic atrophy (ADOA). The model recapitulated RGC-specific structural and functional deficits, highlighting mitochondrial dysfunction characterized by reduced Complex I activity, increased oxidative stress, and diminished ATP production. Spatial metabolomics revealed metabolic imbalances, with heightened glycolysis in the outer retina but an energy deficit in the inner retina, particularly affecting RGCs. Single-nucleus RNA sequencing (snRNA-seq) confirmed a selective downregulation of energy-production genes in RGCs, underscoring their susceptibility to energy deficits. These findings established a mechanistic link between disrupted energy metabolism and RGC degeneration in ADOA and provided a valuable platform for exploring therapeutic strategies targeting energy pathways to prevent vision loss. Overall design: To investigate transcriptomic changes underlying RGC degeneration in ADOA, we performed single-nucleus RNA sequencing (snRNA-seq) on retinal tissues from Opa1V291D/+ and WT mice at 360 days, enabling the identification of cell-type-specific gene expression alterations, particularly in energy metabolism pathways across different retinal cell populations.