Nitric Oxide May Adversely Affect the Metabolism and Viability of Retinal Organoids Derived from Patients with Leber...

Leber hereditary optic neuropathy (LHON) is a bilateral optic neuropathy associated with mitochondrial DNA (mtDNA) mutations characterized by parapapillary telangiectasia during the acute phase. However, its precise mechanism remains unclear. This study evaluated the effects of nitric oxide (NO) on retinal organoids (ROs) generated from induced pluripotent stem cells derived from patients with LHON. Established induced pluripotent stem cells from three patients with the m.11778G>A mutation (patient group) and three healthy individuals (control group) were differentiated into ROs. Changes in cell death ratios, mtDNA copy number, and metabolite profiles in the ROs following exposure to sodium nitroprusside (SNP), which was an NO donor, were compared between the two groups. At baseline, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cell ratios did not differ significantly, whereas the mtDNA copy number was significantly higher in the patient group. SNP exposure significantly increased the proportion of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in the patient group but did not affect the mtDNA copy number. Relative concentrations of metabolites, including taurine and γ-aminobutyric acid, were initially reduced in the patient group, but increased following SNP exposure. These findings suggest that NO may promote retinal cell death and disrupt metabolite profiles in ROs derived from patients with LHON.