title: Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies.
abstract: Synthesis of cationic plastoquinone derivatives (SkQs) containing positively charged phosphonium or rhodamine moieties connected to plastoquinone by decane or pentane linkers is described. It is shown that SkQs (i) easily penetrate through planar, mitochondrial, and outer cell membranes, (ii) at low (nanomolar) concentrations, posses strong antioxidant activity in aqueous solution, BLM, lipid micelles, liposomes, isolated mitochondria, and cells, (iii) at higher (micromolar) concentrations, show pronounced prooxidant activity, the "window" between anti- and prooxidant concentrations being very much larger than for MitoQ, a cationic ubiquinone derivative showing very much lower antioxidant activity and higher prooxidant activity, (iv) are reduced by the respiratory chain to SkQH2, the rate of oxidation of SkQH2 being lower than the rate of SkQ reduction, and (v) prevent oxidation of mitochondrial cardiolipin by OH*. In HeLa cells and human fibroblasts, SkQs operate as powerful inhibitors of the ROS-induced apoptosis and necrosis. For the two most active SkQs, namely SkQ1 and SkQR1, C(1/2) values for inhibition of the H2O2-induced apoptosis in fibroblasts appear to be as low as 1x10(-11) and 8x10(-13) M, respectively. SkQR1, a fluorescent representative of the SkQ family, specifically stains a single type of organelles in the living cell, i.e. energized mitochondria. Such specificity is explained by the fact that it is the mitochondrial matrix that is the only negatively-charged compartment inside the cell. Assuming that the Deltapsi values on the outer cell and inner mitochondrial membranes are about 60 and 180 mV, respectively, and taking into account distribution coefficient of SkQ1 between lipid and water (about 13,000 : 1), the SkQ1 concentration in the inner leaflet of the inner mitochondrial membrane should be 1.3x10(8) times higher than in the extracellular space. This explains the very high efficiency of such compounds in experiments on cell cultures. It is concluded that SkQs are rechargeable, mitochondria-targeted antioxidants of very high efficiency and specificity. Therefore, they might be used to effectively prevent ROS-induced oxidation of lipids and proteins in the inner mitochondrial membrane in vivo.
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Y N
authors.initials: YN
authors.lastname: Antonenko
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authors.lastname: Avetisyan
authors.forename: L E
authors.initials: LE
authors.lastname: Bakeeva
authors.forename: B V
authors.initials: BV
authors.lastname: Chernyak
authors.forename: V A
authors.initials: VA
authors.lastname: Chertkov
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authors.initials: LV
authors.lastname: Domnina
authors.forename: O Yu
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authors.lastname: Ivanova
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authors.initials: DS
authors.lastname: Izyumov
authors.forename: L S
authors.initials: LS
authors.lastname: Khailova
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authors.initials: SS
authors.lastname: Klishin
authors.forename: G A
authors.initials: GA
authors.lastname: Korshunova
authors.forename: K G
authors.initials: KG
authors.lastname: Lyamzaev
authors.forename: M S
authors.initials: MS
authors.lastname: Muntyan
authors.forename: O K
authors.initials: OK
authors.lastname: Nepryakhina
authors.forename: A A
authors.initials: AA
authors.lastname: Pashkovskaya
authors.forename: O Yu
authors.initials: OY
authors.lastname: Pletjushkina
authors.forename: A V
authors.initials: AV
authors.lastname: Pustovidko
authors.forename: V A
authors.initials: VA
authors.lastname: Roginsky
authors.forename: T I
authors.initials: TI
authors.lastname: Rokitskaya
authors.forename: E K
authors.initials: EK
authors.lastname: Ruuge
authors.forename: V B
authors.initials: VB
authors.lastname: Saprunova
authors.forename: I I
authors.initials: II
authors.lastname: Severina
authors.forename: R A
authors.initials: RA
authors.lastname: Simonyan
authors.forename: I V
authors.initials: IV
authors.lastname: Skulachev
authors.forename: M V
authors.initials: MV
authors.lastname: Skulachev
authors.forename: N V
authors.initials: NV
authors.lastname: Sumbatyan
authors.forename: I V
authors.initials: IV
authors.lastname: Sviryaeva
authors.forename: V N
authors.initials: VN
authors.lastname: Tashlitsky
authors.forename: J M
authors.initials: JM
authors.lastname: Vassiliev
authors.forename: M Yu
authors.initials: MY
authors.lastname: Vyssokikh
authors.forename: L S
authors.initials: LS
authors.lastname: Yaguzhinsky
authors.forename: A A
authors.initials: AA
authors.lastname: Zamyatnin
authors.forename: V P
authors.initials: VP
authors.lastname: Skulachev
mesh_terms: D000375:Aging; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis; D001692:Biological Transport; D002478:Cells, Cultured; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism; D009336:Necrosis; D010084:Oxidation-Reduction; D010971:Plastoquinone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D010971:Plastoquinone