Idebenone and neuroprotection: antioxidant, pro-oxidant, or electron carrier?

Ubiquinone, commonly called coenzyme Q10 (CoQ), is a lipophilic electron carrier and endogenous antioxidant found in all cellular membranes. In the mitochondrial inner membrane it transfers electrons to complex III of the electron transport chain. The short chain CoQ analogue idebenone is in clinical trials for a number of diseases that exhibit a mitochondrial etiology. Nevertheless, evidence that idebenone ameliorates neurological symptoms in human disease is inconsistent. Although championed as an antioxidant, idebenone can also act as a pro-oxidant by forming an unstable semiquinone at complex I. The antioxidant function of idebenone is critically dependent on two-electron reduction to idebenol without the creation of unstable intermediates. Recently, cytoplasmic NAD(P)H: quinone oxidoreductase 1 (NQO1) was identified as a major enzyme catalyzing idebenone reduction. While reduction allows idebenone to act as an antioxidant, evidence also suggests that NQO1 enables idebenone to shuttle reducing equivalents from cytoplasmic NAD(P)H to mitochondrial complex III, bypassing any upstream damage to the electron transport chain. In this mini-review we discuss how idebenone can influence mitochondrial function within the context of cytoprotection. Importantly, in the brain NQO1 is expressed primarily by glia rather than neurons. As NQO1 is an inducible enzyme regulated by oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, optimizing NQO1 expression in appropriate cell types within a specific disease context may be key to delivering on idebenone's therapeutic potential.