University of Tasmania, Australia

Mitochondria are increasingly recognized as central players in the life and death of cells and especially of neurons. Within the brain, the retina ranks amongst the highest energy-consuming systems and the energy-dependence of neurons in the retina is particularly striking (Wong-Riley, 2010). Therefore, it is not surprising that multiple mitochondrial disorders with systemic defects in energy metabolism, often lead to visual impairment and ultimately blindness. Mitochondrial dysfunction can be caused by mutations of nuclear or mitochondrial genes, by exposure to toxic xenobiotics, insufficient oxygen supply and by elevated intraocular pressure. Consequently, strategies to ascertain mitochondrial integrity by modulating mitochondrial function using small molecules with a view to restore energy production and/or reduce levels of oxidative stress are a promising approach for the treatment of ophthalmological disorders regardless of the causative event.

Idebenone, is a potent antioxidant and effectively inhibits lipid peroxidation (Erb et al. 2012), thus protecting cell membranes and mitochondria from oxidative damage. Idebenone also interacts with the mitochondrial electron transport chain and modulates mitochondrial electron flux (Sugiyama et al. 1985) through a bypass of complex I that maintains cellular energy production, which was recently described by us and others (Haefeli et al. 2011; Erb et al. 2012, Giorgio et al. 2012). Idebenone is efficiently reduced in the cytoplasm to the hydroquinone form, which is able to transport electron equivalents from the cytoplasm to the mitochondria where they are directly fed into the respiratory chain at the level of complex III. This mechanism effectively restores cellular ATP levels under conditions of impaired mitochondrial function (Haefeli et al. 2011; Erb et al. 2012; Giorgio et al. 2011). These activities provide a strong rationale for using idebenone and related compounds in indications associated with mitochondrial dysfunction. We have demonstrated that idebenone is effective in restoring vision in a mouse model of visual dysfunction caused by mitochondrial impairment (Heitz et al. 2012). Proof-of concept that this therapeutic approach can be successful was demonstrated in a randomized clinical trial where idebenone was able to counteract vision loss in a genetic eye disorder caused by mitochondrial dysfunction (Kloppstock et al. 2011). Currently we are developing novel idebenone-like molecules for the treatment of major disorders affecting vision such as glaucoma, diabetic retinopathy and age-related macular degeneration.

_{Erb M, Hoffmann-Enger B, Deppe H, Soeberdt M, Haefeli RH, Feurer A, Gueven N (2012) Features of Idebenone and Related Short-Chain Quinones that Rescue ATP Levels under Conditions of Impaired Mitochondrial Complex I. PLoS ONE 7(4): e36153. doi:10.1371/journal.pone.0036153}

_{Giorgio V, Petronilli V, Ghelli A, Carelli V, Rugolo M, et al. (2011) The effects of idebenone on mitochondrial bioenergetics. Biochim Biophys Acta. 1817(2): 363–9}

_{Haefeli RH, Erb M, Gemperli AC, Robay D, Courdier Fruh I, Anklin C, Dallmann R, Gueven N. (2011) NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels. PLoS One 6(3):e17963}

_{Heitz F, Michael Erb M, Anklin C, Robay D, Pernet V, Gueven N. (2012) Idebenone protects against retinal damage and loss of vision in a mouse model of Leber’s hereditary optic neuropathy. PLoS ONE 7(9): e45182. doi:10.1371/journal.pone.0045182}

_{Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, et al. (2011) A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain 134(Pt 9): 2677–86}

_{Sugiyama Y, Fujita T, Matsumoto M, Okamoto K, Imada I (1985) Effects of idebenone (CV-2619) and its metabolites on respiratory activity and lipid peroxidation in brain mitochondria from rats and dogs. J Pharmacobio-Dyn 8: 1006–1017}

_{Wong-Riley MTT (2010) Energy metabolism of the visual system. Eye and Brain 2:99-116}

Contact: Nuri.Guven@utas.edu.au