Skulachev 2014 Abstract MiP2014
|Mitochondria are sources, rather than sinks, of reactive oxygen species. Effects of mitochondria-targeted antioxidants.|
Skulachev VP (2014)
Assuming that mitochondria are sources of reactive oxygen species (ROS), causing a number of pathologies, predicts that mitochondria-targeted antioxidants should decrease intracellular ROS and cure humans suffering from various ROS-linked diseases much stronger than non-targeted antioxidants or antioxidants targeted to compartments other than mitochondria. The first observation of this kind was done by Murphy’s group, where mitochondria-targeted CoQ derivative MitoQ was found to inhibit ROS-induced apoptosis of cell cultures at 5∙102 times lower concentration than non-targeted CoQ . Later, Chernyak’s group in our laboratory showed an even larger difference between mitochondria-targeted plastoquinones (SkQ1 or SkQR1) and non-targeted N-acetyl cysteine (NAC) and trolox [2-4]. The stronger effect of SkQs, compared to MitoQ, was mainly due to a much larger window between anti- and prooxidant activities of these quinones. A 106 difference between doses of SkQ1 and NAC was shown in our group by Kopnin and coworkers, who studied an increase in lifespan of p53-/- mice who died due to lymphoma . Such a great advantage of SkQ1 over NAC could be predicted if one takes into account that (1) the antioxidant effect of SkQ1 results in a prevention of the chain reaction of cardiolipin peroxidation, localized in the inner mitochondrial membrane; and (2) extracellular SkQ1, in contrast to NAC, electrophoretically accumulates by a factor of 10 in cytosol, 103 in the mitochondrial matrix and 104 in the membrane, because of a high octanol/water distribution coefficient. As a result, SkQ1 concentration in the inner mitochondrial membrane can be 108 (10∙103∙104) times higher than extramitochondrial [SkQ1] [6,7]. Large differences between acting concentrations of SkQ1 and those of vitamin E or NAC were revealed by Kolosova and coworkers when studying progeric OXYS rats (age-dependent development of cataract, retinopathy and an IGF-1 decrease were investigated) [5-8]. Rabinovich and his colleagues succeeded in an in vivo targeting of catalase to mitochondria [9-12]. In particular, an antiprogeric effect was observed in “mutator” mice defective in the proof-reading domain of mitochondrial DNA polymerase . Such mice were shown to have an elevated content of mitochondrial H2O2 . Targeting of catalase to nucleus or peroxisomes proved to be much less effective than to mitochondria .
The final aim of ROS studies is certainly the treatment of ROS-induced pathologies in humans. There is already a precedent when a mitochondria-targeted antioxidant - eye drops Visomitin containing 250 nM SkQ1, which is an efficient treatment of the previously incurable disease “dry eye syndrome” [14,15] - were officially recommended as a medicine and became available in pharmacies. Clinical trials of this drug showed that it is also beneficial in two other age-related diseases, i.e. cataract and glaucoma. Again, SkQ1 proved to be much more efficient than thymolol, a non-targeted antioxidant.
• O2k-Network Lab: RU Moscow Skulachev VP
Labels: MiParea: mt-Membrane, mt-Medicine, Patients Pathology: Aging;senescence, Inherited Stress:Oxidative stress;RONS Organism: Mouse, Rat
Event: B2, Oral MiP2014
Lomonosov Moscow State Univ, Belozersky Inst Physico-Chem Biol, Moscow, Russia. - [email protected]
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