Document Detail


NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels.
MedLine Citation:
PMID:  21483849     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Roman H Haefeli; Michael Erb; Anja C Gemperli; Dimitri Robay; Isabelle Courdier Fruh; Corinne Anklin; Robert Dallmann; Nuri Gueven
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-03-31
Journal Detail:
Title:  PloS one     Volume:  6     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2011  
Date Detail:
Created Date:  2011-04-12     Completed Date:  2011-08-25     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e17963     Citation Subset:  IM    
Affiliation:
Santhera Pharmaceuticals, Liestal, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Animals
Cell Line
Cell Line, Tumor
Cells, Cultured
Female
HEK293 Cells
Hep G2 Cells
Humans
Lactic Acid / metabolism
Male
Membrane Potential, Mitochondrial / drug effects
Mice
NAD / metabolism
NAD(P)H Dehydrogenase (Quinone) / genetics,  metabolism*
Oxidation-Reduction / drug effects
Quinones / metabolism
Rats
Rotenone / pharmacology
Ubiquinone / analogs & derivatives*,  metabolism,  pharmacology
Chemical
Reg. No./Substance:
0/Quinones; 1339-63-5/Ubiquinone; 50-21-5/Lactic Acid; 53-84-9/NAD; 56-65-5/Adenosine Triphosphate; 727-81-1/Ubiquinone Q1; 83-79-4/Rotenone; EC 1.6.5.2/NAD(P)H Dehydrogenase (Quinone); HB6PN45W4J/idebenone
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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