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Mitochondria-Targeted Plastoquinone Derivatives as Anti-Senescence Drugs

Abstract: 

Recently a concept was developed assuming that senescence is programmed by genome, being the last step of ontogenesis. It was also suggested that senescence was invented by biological evolution to accelerate this evolution. A consequence of such kind of reasoning consists in that for human senescence should be regarded as an atavism since humans do not rely on their evolution which is too slow. If senescence is programmed, it might be prevented by inhibition of this program just as inhibition of the programmed cell death (apoptosis) is shown to prevent apoptosis. There are numerous indications that senescence program declines physiological functions by means of toxic reactive oxygen species (ROS) produced in mitochondria. Hence, one may hope that mitochondrial-targeted antioxidants might be inhibitors of the senescence program. To study such a possibility, a project has been established with participation of several research groups from Russia, Sweden and USA. A new type of compounds (SkQs) composed of plastoquinone (an antioxidant moiety), a penetrating cation, and a decane or pentane linker has been synthesized. Using planar bilayer phospholipid membrane (BLM), we selected SkQ derivatives with the highest permeability, namely plastoquinonyldecyltriphenylphosphonium (SkQ1), plastoquinonyldecylrhodamine 19 (SkQR1), and methylplastoquinonyldecyltriphenylphosphonium (SkQ3). Anti- and prooxidant properties of these substances and also of ubiquinonyldecyltriphenylphosphonium (MitoQ) were tested in aqueous solutions, detergent micelles, liposomes, BLM, isolated mitochondria, cell cultures, and organisms. In mitochondria, micromolar cationic quinone derivatives were found to be prooxidants, but at lower (sub-micromolar) concentrations they displayed antioxidant activity that decreases in the series SkQ1 = SkQR1 > SkQ3 >MitoQ. SkQ1 was reduced by mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Nanomolar SkQ1 specifically prevented oxidation of mitochondrial cardiolipin. In cell cultures, SkQR1, a fluorescent SkQ derivative, stained only one type of organelles, namely mitochondria. Extremely low concentrations of SkQ1 or SkQR1 arrested H2O2-induced apoptosis in human fibroblasts and HeLa cells. Higher concentrations of SkQ were required to block necrosis initiated by reactive oxygen species (ROS). In the fungus Podosporaanserina, the crustacean Ceriodaphniaaffinis, drosophila, and mice, SkQ1 prolonged lifespan, being especially effective at early and middle stages of aging. In mammals, the effect of SkQs on aging was accompanied by inhibition of development of such age-related diseases and traits as cataract, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, anemia, disappearance of estrous cycles in females and libido in males, peroxidation of lipids and proteins, etc. SkQ1 manifested a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM SkQ1, vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy. Instillation of SkQ1-containing drops prevented the loss of sight in rabbits with experimental uveitis and restored vision to animals that had already become blind. A favorable effect of the same drops was also achieved in experimental glaucoma in rabbits. Moreover, the SkQ1 pretreatment of rats significantly decreased the H2O2- or ischemia-induced arrhythmia of the isolated heart. SkQs strongly reduced the damaged area in experimental myocardial infarction or stroke and prevented the death of animals from kidney ischemia. In p53-/- mice, 5 nmol SkQ1/kg x day decreased the ROS level in the spleen and inhibited appearance of lymphomas to the same degree as million-fold higher concentration of conventional antioxidant N-acetylcysteine. Thus, SkQs look promising as potential tools for treatment of senescence and age-related diseases.

Source: Sens Research Foundation
“Mitochondria-targeted plastoquinone derivatives as anti-senescence drugs” by V.P. Skulachev

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