The Effects of Idebenone on Mitochondrial Bioenergetics

Overview

Journal Biochim Biophys Acta

Specialties Biochemistry
Biophysics

Date 2011 Nov 17

PMID 22086148

Citations 60

Authors

Valentina Giorgio

Valeria Petronilli

Anna Ghelli

Valerio Carelli

Michela Rugolo

Giorgio Lenaz

Paolo Bernardi

Affiliations

Soon will be listed here.

Abstract

We have studied the effects of idebenone on mitochondrial function in cybrids derived from one normal donor (HQB17) and one patient harboring the G3460A/MT-ND1 mutation of Leber's Hereditary Optic Neuropathy (RJ206); and in XTC.UC1 cells bearing a premature stop codon at amino acid 101 of MT-ND1 that hampers complex I assembly. Addition of idebenone to HQB17 cells caused mitochondrial depolarization and NADH depletion, which were inhibited by cyclosporin (Cs) A and decylubiquinone, suggesting an involvement of the permeability transition pore (PTP). On the other hand, addition of dithiothreitol together with idebenone did not cause PTP opening and allowed maintenance of the mitochondrial membrane potential even in the presence of rotenone. Addition of dithiothreitol plus idebenone, or of idebenol, to HQB17, RJ206 and XTC.UC1 cells sustained membrane potential in intact cells and ATP synthesis in permeabilized cells even in the presence of rotenone and malonate, and restored a good level of coupled respiration in complex I-deficient XTC.UC1 cells. These findings demonstrate that idebenol can feed electrons at complex III. If the quinone is maintained in the reduced state, a task that in some cell types appears to be performed by dicoumarol-sensitive NAD(P)H:quinone oxidoreductase 1 [Haefeli et al. (2011) PLoS One 6, e17963], electron transfer to complex III may allow reoxidation of NADH in complex I deficiencies.

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References

Barnils N, Mesa E, Munoz S, Ferrer-Artola A, Arruga J . [Response to idebenone and multivitamin therapy in Leber's hereditary optic neuropathy]. Arch Soc Esp Oftalmol. 2007; 82(6):377-80. DOI: 10.4321/s0365-66912007000600012. View

Di Lisa F, Menabo R, Canton M, Barile M, Bernardi P . Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J Biol Chem. 2000; 276(4):2571-5. DOI: 10.1074/jbc.M006825200. View

Mashima Y, Kigasawa K, Wakakura M, Oguchi Y . Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy?. J Neuroophthalmol. 2000; 20(3):166-70. DOI: 10.1097/00041327-200020030-00006. View

Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M . A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011; 134(Pt 9):2677-86. PMC: 3170530. DOI: 10.1093/brain/awr170. View

Briere J, Schlemmer D, Chretien D, Rustin P . Quinone analogues regulate mitochondrial substrate competitive oxidation. Biochem Biophys Res Commun. 2004; 316(4):1138-42. DOI: 10.1016/j.bbrc.2004.03.002. View

Ghelli A, Porcelli A, Zanna C, Vidoni S, Mattioli S, Barbieri A . The background of mitochondrial DNA haplogroup J increases the sensitivity of Leber's hereditary optic neuropathy cells to 2,5-hexanedione toxicity. PLoS One. 2009; 4(11):e7922. PMC: 2774515. DOI: 10.1371/journal.pone.0007922. View

Ikejiri Y, Mori E, Ishii K, Nishimoto K, Yasuda M, Sasaki M . Idebenone improves cerebral mitochondrial oxidative metabolism in a patient with MELAS. Neurology. 1996; 47(2):583-5. DOI: 10.1212/wnl.47.2.583. View

Lim C, Kalinowski D, Richardson D . Protection against hydrogen peroxide-mediated cytotoxicity in Friedreich's ataxia fibroblasts using novel iron chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone class. Mol Pharmacol. 2008; 74(1):225-35. DOI: 10.1124/mol.108.046847. View

Esposti M, Ngo A, Ghelli A, Benelli B, Carelli V, McLennan H . The interaction of Q analogs, particularly hydroxydecyl benzoquinone (idebenone), with the respiratory complexes of heart mitochondria. Arch Biochem Biophys. 1996; 330(2):395-400. DOI: 10.1006/abbi.1996.0267. View

10.

Geromel V, Darin N, Chretien D, Benit P, Delonlay P, Rotig A . Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab. 2002; 77(1-2):21-30. DOI: 10.1016/s1096-7192(02)00145-2. View

11.

Carelli V, La Morgia C, Valentino M, Rizzo G, Carbonelli M, De Negri A . Idebenone treatment in Leber's hereditary optic neuropathy. Brain. 2011; 134(Pt 9):e188. DOI: 10.1093/brain/awr180. View

12.

Ernster L, Dallner G . Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. 1995; 1271(1):195-204. DOI: 10.1016/0925-4439(95)00028-3. View

13.

Haginoya K, Miyabayashi S, Kikuchi M, Kojima A, Yamamoto K, Omura K . Efficacy of idebenone for respiratory failure in a patient with Leigh syndrome: a long-term follow-up study. J Neurol Sci. 2008; 278(1-2):112-4. DOI: 10.1016/j.jns.2008.11.008. View

14.

Walter L, Miyoshi H, Leverve X, Bernard P, Fontaine E . Regulation of the mitochondrial permeability transition pore by ubiquinone analogs. A progress report. Free Radic Res. 2002; 36(4):405-12. DOI: 10.1080/10715760290021252. View

15.

Haefeli R, Erb M, Gemperli A, Robay D, Courdier Fruh I, Anklin C . NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels. PLoS One. 2011; 6(3):e17963. PMC: 3069029. DOI: 10.1371/journal.pone.0017963. View

16.

Brown M, Voljavec A, Lott M, Macdonald I, Wallace D . Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases. FASEB J. 1992; 6(10):2791-9. DOI: 10.1096/fasebj.6.10.1634041. View

17.

Rasola A, Sciacovelli M, Pantic B, Bernardi P . Signal transduction to the permeability transition pore. FEBS Lett. 2010; 584(10):1989-96. PMC: 2866765. DOI: 10.1016/j.febslet.2010.02.022. View

18.

Dinkova-Kostova A, Talalay P . NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys. 2010; 501(1):116-23. PMC: 2930038. DOI: 10.1016/j.abb.2010.03.019. View

19.

Porcelli A, Angelin A, Ghelli A, Mariani E, Martinuzzi A, Carelli V . Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels. J Biol Chem. 2008; 284(4):2045-52. DOI: 10.1074/jbc.M807321200. View

20.

Baracca A, Sgarbi G, Solaini G, Lenaz G . Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F(0) during ATP synthesis. Biochim Biophys Acta. 2003; 1606(1-3):137-46. DOI: 10.1016/s0005-2728(03)00110-5. View