Idebenone: A Multifaceted Compound for Antioxidant Activity and Mitochondrial Function

General Description

Idebenone is a benzoquinone compound that can act as an electron carrier and antioxidant in cells. While its direct antioxidant activity is still unclear, it has been shown to enhance endogenous antioxidant defense mechanisms and reduce the production of oxidative radicals. Idebenone also protects against mitochondrial dysfunction by activating fundamental pathways that confer a broad protective effect on mitochondrial function. It competitively inhibits complex I at higher concentrations while activating complex II-dependent respiration, and upregulates the glycerophosphate shunt in isolated mitochondria. Furthermore, idebenone activates a protective mechanism that persists beyond the time that the drug is present, indicating a potential long-term therapeutic effect. The NQO1 pathway is crucial for idebenone's activity, and upregulating this pathway may increase its therapeutic efficacy.

Figure 1. Idebenone

Chemical context

Idebenone is a benzoquinone that can accept and donate electrons, making it a potential antioxidant and electron carrier in cells. However, quinones can be reduced by a single electron, producing an unstable semiquinone that generates superoxide and is associated with toxicity. To prevent this, a two-electron reduction mechanism is used in cells, involving NAD (P)H quinone oxidoreductase 1 (NQO1) to generate the stable hydroquinone form of idebenone. The activated idebenone molecule can then donate electrons to detoxify radicals and aide ATP production in the mitochondrial respiratory chain. Reports have shown that idebenone toxicity or lack of efficacy is present in test systems with low or absent NQO1 status, highlighting the importance of this pathway for idebenone's activity. Additionally, NQO1 can be upregulated via the Keap/Nrf2/ARE pathway in response to stress, affecting the biological activity of idebenone. While idebenone can act as an antioxidant through this pathway, its direct antioxidant activity remains unclear. ¹

Antioxidant activity

The antioxidant activity of idebenone based on in vitro and in vivo studies. Idebenone is widely considered a potent antioxidant due to its ability to protect against oxidative stress in various test systems. However, the evidence for its direct antioxidant function is not conclusive. While idebenone contains a redox-active quinone moiety that can potentially donate electrons to detoxify radicals, few studies have successfully measured its direct antioxidant function. Cell-free studies requiring high concentrations of idebenone have shown some antioxidant effects, but others have not detected any antioxidant activity at all. In cell culture studies, extended preincubation times with idebenone were often used, despite its rapid penetration into cells within minutes. Protective effects against ROS-induced toxicity have been reported at nanomolar concentrations, which are achievable in vivo. Animal studies consistently reported antioxidant effects of idebenone, although only low nanomolar concentrations were detected in target tissues for short periods of time. The contradictory findings regarding the direct antioxidant activity of idebenone led researchers to propose an amplification process, where small quantities of the drug induce effects that are several magnitudes larger. Idebenone appears to increase the total endogenous tissue antioxidant capacity by upregulating the expression of various endogenous antioxidants. It also downregulates the production of superoxide radicals. Furthermore, idebenone has been found to activate the transcription factor Nrf2, which controls the expression of antioxidant genes. This suggests that idebenone enhances cells' ability to counteract oxidative stress by upregulating their physiological defense mechanisms. It is also suggested that combining idebenone with other Nrf2-dependent NQO1-inducers may increase its therapeutic efficacy. In summary, while the direct antioxidant activity of idebenone is not well-established, it is believed to enhance cells' antioxidant defense mechanisms and reduce the production of oxidative radicals. ²

Mitochondrial function

Idebenone is a synthetic analogue of coenzyme Q10 that has been reported to protect against mitochondrial dysfunction in various pathological conditions. While idebenone was initially thought to act as a CoQ10 analogue by directly influencing mitochondrial respiration, recent studies have shown that idebenone affects mitochondrial function differently to CoQ10. Idebenone competitively inhibits complex I at higher concentrations while activating complex II-dependent respiration. Additionally, idebenone upregulates the glycerophosphate shunt in isolated mitochondria. Interestingly, nanomolar concentrations of idebenone can alter mitochondrial function in vivo, possibly by altering gene expression. Moreover, transient exposure to idebenone activates a protective mechanism that persists beyond the time that the drug is present. However, the multitude of toxic stimuli that idebenone protects against suggests that a single mitochondrial target is unlikely. Instead, it seems more likely that idebenone activates one or several fundamental pathways that confer a broad protective effect on mitochondrial function. ²

Reference

1. Gueven N, Woolley K, Smith J. Border between natural product and drug: comparison of the related benzoquinones idebenone and coenzyme Q10. Redox Biol. 2015;4:289-295.

2. Gueven N, Ravishankar P, Eri R, Rybalka E. Idebenone: When an antioxidant is not an antioxidant. Redox Biol. 2021;38:101812.

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