Short-chain quinones have been investigated as therapeutic molecules due to their ability to modulate cellular redox reactions, mitochondrial electron transfer and oxidative stress, which are pathologically altered in many mitochondrial and neuromuscular disorders. Recently, we and others described that certain short-chain quinones are able to bypass a deficiency in complex I by shuttling electrons directly from the cytoplasm to complex III of the mitochondrial respiratory chain to produce ATP. Although this energy rescue activity is highly interesting for the therapy of disorders associated with complex I dysfunction, no structure-activity-relationship has been reported for short-chain quinones so far. Using a panel of 70 quinones, we observed that the capacity for this cellular energy rescue as well as their effect on lipid peroxidation was influenced more by the physicochemical properties (in particular logD) of the whole molecule than the quinone moiety itself. Thus, the observed correlations allow us to explain the differential biological activities and therapeutic potential of short-chain quinones for the therapy of disorders associated with mitochondrial complex I dysfunction and/or oxidative stress.
Monks TJ, Hanzlik RP, Cohen GM, Ross D, Graham DG (1992) Contemporary issues in toxicology. Toxicol Appl Pharmacol 112: 2–16.
[3]
Long DJ II, Jaiswal AK (2000) NRH:quinone oxidoreductase2 (NQO2). Chem Biol Interact 129: 99–112.
[4]
Colucci MA, Moody CJ, Gouch GD (2008) Natural and synthetic quinones and their reduction by the quinone reductase enzyme NQO1: from synthetic organic chemistry to compounds with anticancer potential. Org Biomol Chem 6(4): 637–56.
[5]
Boutin , JA Chatelain-Egger F, Vella F, Delagrangea P, Ferry G (2005) Quinone reductase 2 substrate specificity and inhibition pharmacology. Chem Biol Interact 151: 213–228.
[6]
Chan TS, Teng S, Wilson JX, Galati G, Khan S, et al. (2002) Coenzyme Q cytoprotective mechanisms for mitochondrial complex I cytopathies involves NAD(P)H: quinone oxidoreductase 1(NQO1). Free Radic Res 36: 421–7.
[7]
Dragan M, Dixon SJ, Jaworski E, Chan TS, O'Brien PJ, et al. (2006) Coenzyme Q(1) depletes NAD(P)H and impairs recycling of ascorbate in astrocytes. Brain Res 1078: 9–18.
[8]
Suno M, Akinobu N (1984) Inhibition of lipid peroxidation by a novel compound (CV-2619) in brain mitochondria and mode of action of the inhibition. Biochem Biophys Res Comm 125: 1046–1052.
[9]
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.
[10]
Suno M, Akinobu N (1989) Inhibition of lipid peroxidation by idebenone in brain mitochondria in the presence of succinate. Arch Gerontol Geriatr 8: 291–297.
[11]
Rauchovà H, Vrbacky M, Bergamini C, Fato R, Lenaz G, et al. (2006) Inhibition of glycerophosphate-dependent H2O2 generation in brown fat mitochondria by idebenone. Biochem Biophys Res Comm 339: 362–366.
[12]
Ranganathan S, Harmison GG, Meyertholen K, Pennuto M, Burnett BG, et al. (2009) Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum Mol Genet 18: 27–42.
[13]
Jauslin ML, Wirth T, Meier T, Schoumacher F (2002) A cellular model for Friedreich Ataxia reveals small-molecule glutathione peroxidase mimetics as novel treatment strategy. Human Mol. Genet 11: 3055.
[14]
Becker C, Bray-French K, Drewe J (2010) Pharmacokinetic evaluation of idebenone. Expert Opin Drug Metab Toxicol. 6(11): 1437–44.
[15]
Haginoya K, Miyabayashi S, Kikuchi M, Kojima A, Yamamoto K, et al. (2009) Efficacy of idebenone for respiratory failure in a patient with Leigh syndrome: a long-term follow-up study. J Neurol Sci 278: 112–4.
[16]
Ikejiri Y, Mori E, Ishii K, Nishimoto K, Yasuda M, et al. (1996) Idebenone improves cerebral mitochondrial oxidative metabolism in a patient with MELAS. Neurology 47: 583–5.
[17]
Napolitano A, Salvetti S, Vista M, et al. (2000) Long-term treatment with idebenone and riboflavin in a patient with MELAS. Neurol Sci 21: 981–2.
[18]
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.
[19]
Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, et al. (2011) Idebenone treatment in Leber's hereditary optic neuropathy. Brain 134(Pt 9): e188.
[20]
Tsuruo Y, Ishimura K, Tamura M, Kagawa S, Morita K (1994) Biochemical and histochemical studies of the effects of cerebral metabolism-improving drugs on NADPH diaphorase activity in mouse brain. Jpn J Pharmacol. 65(3): 285–8.
[21]
Haefeli RH, Erb M, Gemperli AC, Robay D, Courdier Fruh I, et al. (2011) NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels. PLoS One. 2011 Mar 31; 6(3): e17963.
[22]
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.
[23]
King MS, Sharpley MS, Hirst J (2009) Reduction of hydrophilic ubiquinones by the flavin in mitochondrial NADH:ubiquinone oxidoreductase (Complex I) and production of reactive oxygen species. Biochemistry. 48(9): 2053–62.
[24]
Genova ML, Pich MM, Biondi A, Bernacchia A, Falasca A, et al. (2003) Mitochondrial production of oxygen radical species and the role of Coenzyme Q as an antioxidant. Exp Biol Med (Maywood). 228(5): 506–13.
[25]
Ross D, Kepa JK, Winski SL, Beall HD, Anwar A, et al. (2000) NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact. 129: 77–97.
[26]
Pink JJ, Planchon SM, Tagliarino C, Varnes ME, Siegel D, et al. (2000) NAD(P)H:Quinone oxidoreductase activity is the principal determinant of β-lapachone cytotoxicity. J Biol Chem 275: 5416–5424.
[27]
Adikesavan AK, Barrios R, Jaiswal AK (2007) In vivo role of NAD(P)H:Quinone oxidoreductase 1 in metabolic activation of mitomycin C and bone marrow cytotoxicity. Cancer Res 67: 7966–7971.
[28]
Mordente A, Martorana GE, Minotti G, Giardina B (1998) Antioxidant properties of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecy？l)-1,4-benzoquinone(idebenone). Chem Res Toxicol. 11(1): 54–63.
[29]
Degli Esposti M, Ngo A, Ghelli A, Benelli B, Carelli B, et al. (1996) The interaction of Q analogs, particularly hydroxydecyl-benzoquinone (idebenone), with the respiratory complexes of heart mitochondria. Arch Biochem Biophys 330: 395–400.
[30]
Fato R, Bergamini C, Bortolus M, Maniero AL, Leoni S, et al. (2008) Differential effects of mitochondrial Complex I inhibitors on production of reactive oxygen species. Biochim Biophys Acta 1787: 384–92.
[31]
Rauchová H, Drahota Z, Bergamini Z, Fato R, Lenaz G (2008) Modification of respiratory-chain enzyme activities in brown adipose tissue mitochondria by idebenone (hydroxydecyl-ubiquinone). J Bioenerg Biomembr 40: 85–93.
[32]
King MS, Sharpley MS, Hirst J (2009) Reduction of hydrophilic ubiquinones by the flavin in mitochondrial NADH:ubiquinone oxidoreductase (Complex I) and production of reactive oxygen species. Biochemistry. 48(9): 2053–62.
[33]
Feurer A, Gueven N, Hoffmann-Enger B, Erb M, Deppe H, et al. (2012) Benzoquinone Derivatives as Modulators of Mitochondrial Function. WO/2012/ 022468:
[34]
Feurer A, Hoffmann-Enger B, Deppe H, Soeberdt M, Gueven N, et al. (2012) Novel Benzoquinone Derivatives and Use thereof as Modulators of Mitochondrial Function WO/2012/ 022467:
[35]
Courdier-Fruh I, Briguet A (2006) Utrophin is a calpain substrate in muscle cells. Muscle Nerve; 33(6): 753–9.
[36]
Ernster L (1967) DT-diaphorase. Methods Enzymol 10: 309–317.
