title: The effects of idebenone on mitochondrial bioenergetics.
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.
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Giorgio
authors.forename: Valeria
authors.initials: V
authors.lastname: Petronilli
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lenaz
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D004229:Dithiothreitol / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004734:Energy Metabolism / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D014451:Ubiquinone; D000255:Adenosine Triphosphate; C036619:idebenone; D004229:Dithiothreitol
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