Santhera Pharmaceuticals, Liestal, Switzerland.
PLoS One. 2011 Mar 31;6(3):e17963. doi: 10.1371/journal.pone.0017963.
Short-chain quinones are described as potent antioxidants and in the case of idebenone have already been under clinical investigation for the treatment of neuromuscular disorders. Due to their analogy to coenzyme Q10 (CoQ10), a long-chain quinone, they are widely regarded as a substitute for CoQ10. However, apart from their antioxidant function, this provides no clear rationale for their use in disorders with normal CoQ10 levels. Using recombinant NAD(P)H:quinone oxidoreductase (NQO) enzymes, we observed that contrary to CoQ10 short-chain quinones such as idebenone are good substrates for both NQO1 and NQO2. Furthermore, the reduction of short-chain quinones by NQOs enabled an antimycin A-sensitive transfer of electrons from cytosolic NAD(P)H to the mitochondrial respiratory chain in both human hepatoma cells (HepG2) and freshly isolated mouse hepatocytes. Consistent with the substrate selectivity of NQOs, both idebenone and CoQ1, but not CoQ10, partially restored cellular ATP levels under conditions of impaired complex I function. The observed cytosolic-mitochondrial shuttling of idebenone and CoQ1 was also associated with reduced lactate production by cybrid cells from mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) patients. Thus, the observed activities separate the effectiveness of short-chain quinones from the related long-chain CoQ10 and provide the rationale for the use of short-chain quinones such as idebenone for the treatment of mitochondrial disorders.
短链醌被描述为强效抗氧化剂，在依地醌的情况下，已经在神经肌肉疾病的治疗中进行了临床研究。由于它们与辅酶 Q10（CoQ10），一种长链醌类似，因此被广泛认为是 CoQ10 的替代品。然而，除了它们的抗氧化功能外，这并没有为其在 CoQ10 水平正常的疾病中的应用提供明确的理由。使用重组 NAD(P)H：醌氧化还原酶（NQO）酶，我们观察到与 CoQ10 相反，短链醌如依地醌是 NQO1 和 NQO2 的良好底物。此外，NQOs 还原短链醌使得在人肝癌细胞（HepG2）和新鲜分离的小鼠肝细胞中，从细胞质 NAD(P)H 向线粒体呼吸链转移电子对安密妥 A 敏感。与 NQOs 的底物选择性一致，依地醌和 CoQ1，但不是 CoQ10，在复合体 I 功能受损的情况下部分恢复细胞内的 ATP 水平。观察到的依地醌和 CoQ1 的细胞质-线粒体穿梭也与线粒体脑肌病、乳酸酸中毒和中风样发作（MELAS）患者的细胞杂种的乳酸生成减少有关。因此，观察到的活性将短链醌的有效性与相关的长链 CoQ10 区分开来，并为使用短链醌如依地醌治疗线粒体疾病提供了依据。
