title: Novel mitochondria-targeted compounds composed of natural constituents: conjugates of plant alkaloids berberine and palmatine with plastoquinone.
abstract: Novel mitochondria-targeted compounds composed entirely of natural constituents have been synthesized and tested in model lipid membranes, in isolated mitochondria, and in living human cells in culture. Berberine and palmatine, penetrating cations of plant origin, were conjugated by nonyloxycarbonylmethyl residue with the plant electron carrier and antioxidant plastoquinone. These conjugates (SkQBerb, SkQPalm) and their analogs lacking the plastoquinol moiety (C10Berb and C10Palm) penetrated across planar bilayer phospholipid membrane in their cationic forms and accumulated in isolated mitochondria or in mitochondria in living human cells in culture. Reduced forms of SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations. In isolated mitochondria and in living cells, the berberine and palmatine moieties were not reduced, so antioxidant activity belonged exclusively to the plastoquinol moiety. In human fibroblasts, nanomolar SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by exogenous hydrogen peroxide. At higher concentrations, conjugates of berberine and palmatine induced proton transport mediated by free fatty acids both in model and in mitochondrial membrane. In mitochondria this process was facilitated by the adenine nucleotide carrier. As an example of application of the novel mitochondria-targeted antioxidants SkQBerb and SkQPalm to studies of signal transduction, we discuss induction of cell cycle arrest, differentiation, and morphological normalization of some tumor cells. We suggest that production of oxygen radicals in mitochondria is necessary for growth factors-MAP-kinase signaling, which supports proliferation and transformed phenotype.
authors.affiliation: Belozersky Institute of Physico-Chemical Biology and Center of Mitoengineering, Lomonosov Moscow State University, 119991 Moscow, Russia. fxb@belozersky.msu.ru
authors.forename: B V
authors.initials: BV
authors.lastname: Chernyak
authors.forename: Y N
authors.initials: YN
authors.lastname: Antonenko
authors.forename: E R
authors.initials: ER
authors.lastname: Galimov
authors.forename: L V
authors.initials: LV
authors.lastname: Domnina
authors.forename: V B
authors.initials: VB
authors.lastname: Dugina
authors.forename: R A
authors.initials: RA
authors.lastname: Zvyagilskaya
authors.forename: O Yu
authors.initials: OY
authors.lastname: Ivanova
authors.forename: D S
authors.initials: DS
authors.lastname: Izyumov
authors.forename: K G
authors.initials: KG
authors.lastname: Lyamzaev
authors.forename: A V
authors.initials: AV
authors.lastname: Pustovidko
authors.forename: T I
authors.initials: TI
authors.lastname: Rokitskaya
authors.forename: A G
authors.initials: AG
authors.lastname: Rogov
authors.forename: I I
authors.initials: II
authors.lastname: Severina
authors.forename: R A
authors.initials: RA
authors.lastname: Simonyan
authors.forename: M V
authors.initials: MV
authors.lastname: Skulachev
authors.forename: V N
authors.initials: VN
authors.lastname: Tashlitsky
authors.forename: E V
authors.initials: EV
authors.lastname: Titova
authors.forename: T A
authors.initials: TA
authors.lastname: Trendeleva
authors.forename: G S
authors.initials: GS
authors.lastname: Shagieva
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001599:Berberine / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010971:Plastoquinone / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D001600:Berberine Alkaloids; D001599:Berberine; C005413:palmatine; D010971:Plastoquinone