Takano Fumio, Kitamura Megumi, Ueda Kaori, Nakamura Makoto
Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Am J Pathol. 2025 Sep;195(9):1693-1706. doi: 10.1016/j.ajpath.2025.05.006. Epub 2025 Jun 9.
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.
Leber遗传性视神经病变（LHON）是一种与线粒体DNA（mtDNA）突变相关的双侧视神经病变，其急性期特征为视乳头周围毛细血管扩张。然而，其确切机制仍不清楚。本研究评估了一氧化氮（NO）对来自LHON患者诱导多能干细胞生成的视网膜类器官（ROs）的影响。将三名携带m.11778G>A突变的患者（患者组）和三名健康个体（对照组）建立的诱导多能干细胞分化为ROs。比较了两组在暴露于NO供体硝普钠（SNP）后ROs中细胞死亡比率、mtDNA拷贝数和代谢物谱的变化。在基线时，末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性细胞比率无显著差异，而患者组的mtDNA拷贝数显著更高。SNP暴露显著增加了患者组中末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性细胞的比例，但不影响mtDNA拷贝数。包括牛磺酸和γ-氨基丁酸在内的代谢物的相对浓度在患者组中最初降低，但在SNP暴露后增加。这些发现表明，NO可能促进LHON患者来源的ROs中的视网膜细胞死亡并扰乱代谢物谱。
