Vitamin A treatment restores vision failures arising from Leber's hereditary optic neuropathy-linked mtDNA mutation.

Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying retinal cell-specific effects of LHON-linked mtDNA mutations remains poorly understood, and there has been no effective treatment or cure for this disorder. Using a mouse model bearing an LHON-linked ND6P25L mutation, we demonstrated that the mutation caused retinal cell-specific deficiencies, especially in retinal ganglion cells (RGCs), rods, and Müller cells. Single-cell RNA sequencing revealed cell-specific dysregulation of oxidative phosphorylation and visual signaling pathways in the mutant retina. Strikingly, ND6 mutation-induced dysfunctions caused abnormal vitamin A (VA) metabolism essential for visual function. VA supplementation remarkably alleviated retinal deficiencies, including reduced fundus lesion and retinal thickness and increased numbers of RGCs, photoreceptors, and Müller cell neurites. The restoration of visual functions with VA treatment were further evidenced by correcting dysregulations of phototransduction cascade and neurotransmitter transmission and restoring electrophysiological properties. Interestingly, VA supplementation markedly rescued the abnormal mitochondrial morphologies and functions in the mutant retina. These findings provide insight into retina-specific pathophysiology of mitochondrial retinopathy arising from VA deficiency and mitochondrial dysfunction induced by mtDNA mutation and a step toward therapeutic intervention for LHON and other mitochondrial retinopathies.