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

作者：Haefeli Roman H^*; Erb Michael; Gemperli Anja C; Robay Dimitri; Fruh Isabelle Courdier; Anklin Corinne; Dallmann Robert; Gueven Nuri

来源：PLos One, 2011, 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 Q(10) (CoQ(10)), a long-chain quinone, they are widely regarded as a substitute for CoQ(10). However, apart from their antioxidant function, this provides no clear rationale for their use in disorders with normal CoQ(10) levels. Using recombinant NAD(P)H:quinone oxidoreductase (NQO) enzymes, we observed that contrary to CoQ(10) 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 CoQ(1), but not CoQ(10), partially restored cellular ATP levels under conditions of impaired complex I function. The observed cytosolic-mitochondrial shuttling of idebenone and CoQ(1) 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 CoQ(10) and provide the rationale for the use of short-chain quinones such as idebenone for the treatment of mitochondrial disorders.

• 出版日期2011-3-31