PDF(Pubmed)
Abstract：
Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous. This hampers idebenone reduction. In its oxidized form, idebenone inhibits complex I, decreasing respiratory function in cells. By retrospectively analyzing a large cohort of idebenone-treated LHON patients, classified by their response to therapy, we show that patients with homozygous or compound heterozygous NQO1 variants have the poorest therapy response, particularly if carrying the m.3460G>A/MT-ND1 LHON mutation. These results suggest consideration of patient NQO1 genotype and mitochondrial DNA mutation in the context of idebenone therapy.
摘要：
Idebenone,Leber遗传性视神经病变（LHON）的唯一批准的治疗方法，促进高达50％的患者的视觉功能恢复，但是我们既不能预测也不能理解无反应者。艾地苯醌被胞质NAD（P）H氧化还原酶I（NQO1）还原，并直接将电子传递到呼吸复合物III，绕过复杂的我在LHON影响。我们在这里表明，当纯合或复合杂合时，两个多态性变体会大大降低NQO1蛋白水平。这阻碍了艾地苯醌的减少。以其氧化形式，艾地苯醌抑制复合物I,降低细胞的呼吸功能。通过回顾性分析大量艾地苯醌治疗的LHON患者，按他们对治疗的反应分类，我们表明，纯合或复合杂合子NQO1变异的患者有最差的治疗反应，特别是如果携带m.3460G>A/MT-ND1LHON突变。这些结果表明在艾地苯醌治疗的背景下考虑患者NQO1基因型和线粒体DNA突变。
