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NQO1-Dependent Redox Cycling of Idebenone: effects on cellular Redox potential and energy levels
Citation
Haefeli, RH and Erb, M and Gemperli, AC and Robay, D and Courdier Fruh, I and Anklin, C and Dallmann, R and Guven, N, NQO1-Dependent Redox Cycling of Idebenone: effects on cellular Redox potential and energy levels, PLoS One, 6, (3) Article e17963. ISSN 1932-6203 (2011) [Refereed Article]
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Licenced under the Creative Commons Attribution 2.5 Generic (CC BY 2.5) http://creativecommons.org/licenses/by/2.5/
DOI: doi:10.1371/journal.pone.0017963
Abstract
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.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | drug development |
| Research Division: | Chemical Sciences |
| Research Group: | Medicinal and Biomolecular Chemistry |
| Research Field: | Medicinal and Biomolecular Chemistry not elsewhere classified |
| Objective Division: | Health |
| Objective Group: | Other Health |
| Objective Field: | Health not elsewhere classified |
| Author: | Guven, N (Dr Nuri Guven) |
| ID Code: | 79271 |
| Year Published: | 2011 |
| Web of Science® Times Cited: | 72 |
| Deposited By: | Pharmacy |
| Deposited On: | 2012-08-29 |
| Last Modified: | 2014-01-10 |
| Downloads: | 217 View Download Statistics |
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