A biochemical approach to the problem of aging: “Megaproject” on membrane-penetrating ions. The first results and prospects

Abstract

REVIEW 1385Abbreviations: ∆ψ) transmembrane electric potential; BLM) planar bilayer phospholipid membrane; C 12 TPP) dodecyl triphenylphosphonium; DMQ) demethoxyMitoQ; MitoQ) compound of ubiquinone and decyl triphenylphosphonium; ROS) reactive oxygen species; SkQ) compounds of plastoquinone or methylplastoquinone and decyl (or amyl) triphenylphosphonium, methylcarninite, or tributylammonium; SkQ1) compound of plastoquinone and decyl triphenylphosphonium (other SkQ derivatives are shown in Fig. 3 Abstract-Antioxidants specifically addressed to mitochondria have been studied for their ability to decelerate aging of organisms. For this purpose, a project has been established with participation of several research groups from Belozersky Institute of Physico-Chemical Biology and some other Russian research institutes as well as two groups from the USA and Sweden, with support by the "Mitotechnology" company founded by "RAInKo" company (O. V. Deripaska and Moscow State University). This paper summarizes the first results of the project and estimates its prospects. Within the framework of the project, antioxidants of a new type (SkQ) were synthesized comprising plastoquinone (an antioxidant moiety), a penetrating cation, and decane or pentane linker. Using planar bilayer phospholipid membranes, we selected SkQ derivatives with the highest penetrating ability, namely plastoquinonyl-decyl-triphenylphosphonium (SkQ1), plastoquinonyl-decylrhodamine 19 (SkQR1), and methylplastoquinonyl-decyl-triphenylphosphonium (SkQ3). Anti-and prooxidant properties of these substances and also of ubiquinone and ubiquinonyl-decyl-triphenylphosphonium (MitoQ) were tested on isolated mitochondria. Micromolar concentrations of cationic quinones are found to be very strong prooxidants, but in lower (submicromolar) concentrations they display antioxidant activity. The antioxidant activity decreases in the series SkQ1 = SkQR1 > SkQ3 > MitoQ, so the window between the anti-and prooxidant effects is smallest for MitoQ. SkQ1 is rapidly reduced by complexes I and II of the mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Extremely low concentrations of SkQ1 and SkQR1 completely arrest the H 2 O 2 -induced apoptosis in human fibroblasts and HeLa cells (for SkQ1 C 1/2 = 1⋅10 -9 M). Higher concentrations of SkQ are required to block necrosis initiated by reactive oxygen species (ROS). In mice, SkQ1 decelerates the development of three types of accelerated aging (progeria) and also of normal aging, and this effect is especially demonstrative at early stages of aging. The same pattern is shown in invertebrates (drosophila and daphnia). In mammals, the effect of SkQs on aging is accompanied by inhibition of development of such age-related diseases as osteoporosis, involution of thymus, cataract, retinopathy, etc. SkQ1 manifests a strong therapeutic action on some already developed retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM SkQ1, vision is recovered in 50 of 66 animals who became blind be...

Behavioral Effects Induced by Mitochondria-Targeted Antioxidant SkQ1 in Wistar and Senescence-Accelerated OXYS Rats

“…One of the important advantages of SkQ1 is its rapid reduction by mitochondrial respiratory chain complexes I and II, that is, SkQ1 is a reusable antioxidant [21]. Like other mitoquinone, SkQ1 can behave as an antioxidant or prooxidant in dependency on the concentration and mitochondrial energization.…”

Nitrones for understanding and ameliorating the oxidative stress associated with aging

“…Recently, a 4-amino-TEMPO (the oxidized form of a hydroxylamine hydrogen atom transfer agent) conjugated to a pentapeptide fragment of the mitochondrial membranetargeting antibiotic Gramicidin S has been reported by Wipf and co-workers (Wipf et al 2005). Another potential method that attracted our attention is to attach the amino acid, (−)-(R)-carnitine (Skulachev 2007), which is used in the transport of fatty acids into the matrix of the mitochondrion for catabolism (Lohninger et al 2005). We here report that we have prepared a nitrone-carnitine conjugate, CarnDOD-7C (Fig.…”

Производные Трифенилфосфония Как Альтернатива Обычным Антибиотикам

“…Недавно были разработаны вещества, имеющие в своем составе антиоксидантную группу и компонент, воздействующий на митохондрии. Примером таких соединений являются конъюгированные с трифенилом фосфония убихинон (MitoQ) [29] и пласто-хинон (SkQ1) [30]. В недавних работах сообщается, что эти соединения успешно уничтожают бактерии Bacillus subtilis [31,32].…”