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Mitochondrial bioenergetic dysfunction is a component of nearly all neurodegenerative diseases. One strategy to overcome this dysfunction is to replace the loss of mitochondrial reducing equivalents using exogenous electron donors. The drug was recently approved in Europe for the treatment of Leber’s Hereditary Optic Neuropathy, a mitochondrial disease due to deficient Complex I activity. For efficacy, it is believed that idebenone requires enzymatic reduction to idebenol. Previously, quinone reduction activity was mostly attributed to NAD(P)H quinone oxidoreductases, particularly NQO1. In the brain, NQO1 is primarily expressed in astrocytes; we therefore hypothesized that astrocytes would display higher NAD(P)H-dependent idebenone reduction activity compared to other brain cell types. Using lysates derived from primary cells, we found that rat cortical astrocytes have the highest capacity for idebenone reduction, with little to no activity observed in rat cortical neurons or microglia. As expected, idebenone reduction in astrocytes was fully inhibited by the NQO1 inhibitor dicoumarol. Interestingly, we found a significant increase in idebenone reduction potential in lysates derived from microglia treated with the pro-inflammatory stimulus lipopolysaccharide (LPS) plus interferon-gamma (IFN-γ) for 18 hours. This activity was not sensitive to dicoumarol and was not observed in rat bone marrow-derived macrophages similarly stimulated with LPS/IFN-γ. Preliminary results suggest that it may be a multi-subunit flavoprotein. Identification of the enzyme responsible for this novel idebenone-reducing activity may lead to improved therapeutic strategies using idebenone as well as suggest other diseases wherein idebenone may have a beneficial effect. |
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