NQO1-Dependent Redox Cycling of Idebenone: Effects on Cellular Redox Potential and Energy Levels

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.

短链醌类被描述为强效抗氧化剂，其中艾地苯醌（idebenone）已针对神经肌肉疾病的治疗开展临床研究。由于其与长链醌类辅酶Q10（CoQ10）结构类似，短链醌类被广泛视为CoQ10的替代物。然而，除抗氧化功能外，目前尚无明确理论依据支持其在CoQ10水平正常的疾病中应用。本研究利用重组NAD(P)H:醌氧化还原酶（NQO）开展实验，结果发现，与CoQ10不同，艾地苯醌等短链醌类是NQO1与NQO2的优质底物。此外，在人类肝癌细胞（HepG2）与新鲜分离的小鼠肝细胞中，NQO介导的短链醌类还原反应可使电子从胞质NAD(P)H经抗霉素A敏感通路传递至线粒体呼吸链。与NQO的底物选择性相符，艾地苯醌与CoQ1（而非CoQ10）可在复合物I功能受损的条件下，部分恢复细胞ATP水平。上述艾地苯醌与CoQ1的胞质-线粒体穿梭现象，同样与线粒体脑肌病伴高乳酸血症和卒中样发作（MELAS）患者的胞质杂种细胞乳酸生成减少相关。综上，本研究发现的活性将短链醌类的功效与相关长链CoQ10区分开来，为艾地苯醌等短链醌类用于线粒体疾病治疗提供了理论依据。