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

Abstract

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.

New insights into the chemistry of Coenzyme Q-0: A voltammetric and spectroscopic study

“…Due to the indispensable function in the processes of oxidative phosphorylation, Coenzyme Q-10 (CoQ-10) and its derivatives are the most prominent members in the family of Q/HQ [4][5][6][7]. Although the number of studies related to the chemical and redox features of CoQ family members has increased tremendously in the last three decades [8][9][10][11][12][13][14][15][16][17][18], many key features are still not well understood. In our last two publications we have shown that Coenzyme Q-1 (CoQ-1) and CoQ-10 undergo structural changes in strong alkaline environment or in the presence of Cytochrome P450 enzymes [19,20].…”

Measurement of Respiratory Function Decline in Patients with Duchenne Muscular Dystrophy: A Conjoint Analysis

“…Side effects are more relevant at time of loss of ambulation (i.e., alteration of bone metabolism and risk of spontaneous fractures) [15]. This gap has been fixed by the introduction of a different molecule: idebenone, a short-chain benzoquinone characterized by potent antioxidant activity and with the ability to stimulate mitochondrial electron flux and cellular energy production [16,17]. It has been shown in multicenter clinical trials that idebenone is able to slow the decline of pulmonary function of DMD patients, with a consequent reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics [6,7,18,19].…”

Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis

“…Idebenone, is a synthetic analog of coenzyme Q10, an endogenous antioxidant found in all cellular membranes, and a constituent of the adenosine triphosphate-producing electron transport chain of mitochondria [84]. In addition to antioxidant properties, idebenone has been shown to exert anti-inflammatory effects in vitro [85].…”