Idebenone is a hydrophilic short-chain
coenzyme (Co) Q analogue, which has been used as a potential bypass of defective complex I in both
Leber Hereditary Optic Neuropathy and OPA1-dependent
Dominant Optic Atrophy. Based on its potential
antioxidant effects, it has also been tested in degenerative disorders such as
Friedreich's ataxia, Huntington's and
Alzheimer's diseases.
Idebenone is rapidly modified but the biological effects of its metabolites have been characterized only partially. Here we have studied the effects of
quinones generated during in vivo metabolism of
idebenone with specific emphasis on 6-(9-carboxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (QS10). QS10 partially restored respiration in cells deficient of complex I or of CoQ without inducing the mitochondrial permeability transition, a detrimental effect of
idebenone that may offset its potential benefits [Giorgio et al. (2012) Biochim. Biophys. Acta 1817: 363-369]. Remarkably, respiration was largely
rotenone-insensitive in complex I deficient cells and
rotenone-sensitive in CoQ deficient cells. These findings indicate that, like
idebenone, QS10 can provide a bypass to defective complex I; and that, unlike
idebenone, QS10 can partially replace endogenous CoQ. In zebrafish (Danio rerio) treated with
rotenone, QS10 was more effective than
idebenone in allowing partial recovery of respiration (to 40% and 20% of the basal respiration of untreated embryos, respectively) and allowing zebrafish survival (80% surviving embryos at 60 h post-fertilization, a time point at which all
rotenone-treated embryos otherwise died). We conclude that QS10 is potentially more active than
idebenone in the treatment of diseases caused by complex I defects, and that it could also be used in CoQ deficiencies of genetic and acquired origin.