During recent years, several lines of evidence have been obtained suggesting that reactive oxygen species (ROS) formed in mitochondria operate as poisons inducing programmed death of cells (apoptosis) and organisms (phenoptosis). In the latter case, this can be (i) fast "biochemical suicide" which is exemplified by sepsis caused by substances of bacterial or mitochondrial origin (bacterial septic shock or post-traumatic shock, respectively) and (ii) slow development of age-dependent concerted decline of many physiological functions (senescence) [1–4]. A strategy for medical treatment of such pathologies may consist in finding antioxidants that are specifically targeted to mitochondria to avoid inhibition of regulatory functions of non-mitochondrial ROS and prevent decomposition of the antioxidants by extramitochondrial xenobiotic-removing systems like cytochrome P450 of the endoplasmic reticulum. In 2005, we synthesized such compounds (SkQs) composed of plastoquinone (a very active chloroplast electron carrier and antioxidant) linked via decane residue with a penetrating cation whose charge is strongly delocalized. In this case, the cation acts as an "electric locomotive" transporting the linked "cargo" into mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. This transport should be specifically addressed to mitochondria since the mitochondrial interior attracts penetrating cations, being the only negatively-charged compartment in the living cell. The same respiratory chain also regenerates reduced SkQs, so SkQs are rechargeable antioxidants, in contrast to the great majority of conventional antioxidants that are irreversibly destroyed as a result of their antioxidant activity. SkQs were shown to be reduced at center i of complex III of the respiratory chain. This center is localized to the inner leaflet of the inner mitochondrial membrane, i.e. just in the place where SkQs are accumulated.

Like all quinones, SkQs at high concentrations has a prooxidant activity, but the "window" between anti- and prooxidant SkQs concentrations is as large as about 1000 (MitoQ containing ubiquinone instead of plastoquinone has the "window" about 2) [5,6]. Both in isolated mitochondria in vitro and in mice in vivo, it was shown that SkQs prevent oxidative stress-induced peroxidation of cardiolipin, the mitochondria-specific phospholipid that is damaged prior to other phospholipids during oxidative stress [5,6]. Higher SkQs concentrations were found to organize a fatty acid cycling and "mild" uncoupling of respiration and membrane potential generation, an effect resulting in preventing ROS formation by the respiratory chain [7, 7a]. Experiments on human cell cultures showed that (i) SkQs specifically accumulate in all the mitochondria and (ii) at nanomolar concentrations they arrest apoptosis initiated by added H2O2 [5,6,8].

Short-term In vivo treatment of animals with SkQs was shown to decrease tissue damage and to save life under conditions of experimental heart, brain, or kidney ischemia, septic shock, pielonephritis and rhabdomyolysis [5,6,9, 9a]. Life-long treatment with SkQs prolonged the lifespan of lymphoma-prone p53–/– mice [6,10]. Moreover, SkQs increased the median lifespan of normal mice. The effect reached two-fold if mice were living in a non-sterile vivarium [6,11]. Under sterile conditions, females lived without SkQs as long as with SkQs under non-sterile conditions, whereas SkQs failed to increase the lifespan in this case. The lifespan of males was increased by SkQs even under sterile conditions, but the effect was smaller than in the non-sterile vivarium. These relationships can be explained by prevention by SkQs of aging of the immune system. This assumption was confirmed by the facts that (i) the SkQs effect were especially strong when probability of death caused by infections was measured [11], (ii) SkQs decelerated age-dependent involution of thymus and spleen follicles [6,12,13] as well as decrease in lymphocyte/neutrophil ratio in the blood [14]. Life-long treatment with SkQs prolonged the lifespan of fungi, crustaceans, drosophila, fish, mole-vole, and dwarf hamsters, appearance of traits of aging being decelerated, stopped, or even reversed. These traits include osteoporosis, lordokyphosis, achromotrichia, balding, slow wound healing, disappearance of estrual cycles in females, decrease in sexual motivation in males, retinopathies, cataract, glaucoma, ect. In the case of the eye diseases, drops of 250 nM SkQ1 were efficient in rats, rabbits, dogs, cats, and horses [5, 6, 12, 15]. In 2010, we initiated clinical trials of the SkQ1 drops in two Moscow ophthalmological hospitals. Forty patients suffering from such an age-linked disease as "dry eye" were treated for three weeks. An obvious positive therapeutic effect and no adverse side effects were observed. We are now carrying out clinical trials on patients with glaucoma, cataract, and macular dystrophy. In parallel, trials of a per os SkQ1 treatment are in preparation.

In conclusion, a new class of mitochondria-targeted drugs, i.e. cationic plastoquinone-containing antioxidants SkQs, have been synthesized and studied. They are efficient in preventing apoptosis at the cellular level and in curing diseases caused by severe metabolic crisis or to aging. Clinical trials of SkQs are already started.