(1) MitoQ cannot be regarded as a mitochondria-targeted form CoQ or CoQ precursor since it cannot replace CoQ in its master function, i.e. as a respiratory chain electron carrier. MitoQ can be reduced to MitoQH2 by the initial respiratory chain complexes I and II but MitoQH2 is very slowly oxidized by the next respiratory chain complex III. Moreover, MitoQ cannot be decomposed in a way resulting in CoQ release. This is why MitoQ can hardly help when CoQ level is lowered by aging or statin. As to another function of CoQ as an antioxidant, MitoQ is not the best one since the window between anti- and prooxidant concentrations of MitoQ is as small as several times. For SkQ (a MitoQ analog with plastoquinone instead of CoQ), this window is much larger (30 or even 1 000 times, depending on the method of measurement of this parameter). This is why plants use plastoquinone in chloroplasts (the O2-producing organelles) and CoQ in mitochondria (the O2-consuming organelles where the O2 level and hence, the oxidative stress, is always much lower than in chloroplasts).
(2) P3, para 2: ”The same molecule that is known as MitoQ in the English-speaking word is called SkQ in Russia”. It is not the case. As I already mentioned in (1), MitoQ and SkQ are different molecules. As antioxidant, SkQ is much better.
[Note – this has been corrected in the text above – JJM]
(3) P.4, the last para: “Scientists at MitoQ disagree that plastoquinone is better [antioxidants]”. In fact, there is an agreement among organic chemists that plastoquinone is several folds stronger antioxidant than CoQ [1-3].In biological experiments, our group is still the only lab in the world where MitoQ and SkQ were compared in one and the same experiment and it was found that the difference between two compounds is even much larger than in chemical test systems. This may be due to that SkQH2 is oxidized both chemically (by O2) and biochemically (by complex III) slower than MitoQH2, resulting in higher steady state level of reduced form of the antioxidant in the case of SkQ than that of MitoQ.
(4) P.2, the last para. Our contribution to the field was not limited by the first attempt to use substituted triphenylphosphonium cation (TPP) to target something useful to mitochondria but also by elucidation of the driving force for such a targeting. Using our penetration ions (called by David Green a Skulachev ions or Sk+ [4]) we described “the mitochondrial electricity”, i.e. electric potential difference between mitochondrion and cytosol (mitochondrial interior negative), which is generated by respiration and can be used for electrophoretic accumulation of any penetrating cations or of compounds conjugated with these ions [5-7]. The role of a penetrating cation in such a targeting was defined as that of “electric locomotive” [7] which seems, I am sorry, better that your “tugboat” since it indicates electrical nature of the driving force. The great contribution of M. Murphy and his colleagues [8] consisted in an attempt to use an antioxidant as a cargo.
(5) P.4, para 1. “The original papers behind this work are available is Russian”. In fact, in Russian and English. Biochemistry (Mosc.) is published in two languages. [Corrected in the text above – JJM]
(6) P.4, para 2. Dr. Skulachev reports that he personally has improved his vision using SkQ eye props”. These drops are available in Russian drugstore since July 2012. More than 100,000 vials are already sold. Not a single complaint was received by drugstores. In Moscow clinical trials of the drops as a medicine against the Dry eye syndrome, an age-related incurable disease carried out. They proved to be were very positive. Now we obtained FDA permission for clinical trials of SkQ in the U.S.A. The trials will start in February. Our pre-clinical trials on mice were sufficiently repeated by Ora laboratories (Endower, U.S.A.).
Best regards,
Vladi
References:
1. Kruk, J., Jemiola-Rzeminska, M. & Strzalka, K. (1997) Plastoquinol and alpha-tocopherol quinol are more active than ubiquinol and alpha-tocopherol in inhibition of lipid peroxidation, Chemistry and physics of lipids. 87, 73-80.
2. Roginsky, V., Barsukova, T., Loshadkin, D. & Pliss, E. (2003) Substituted p-hydroquinones as inhibitors of lipid peroxidation, Chemistry and physics of lipids. 125, 49-58.
3. Antonenko, Y. N., Avetisyan, A. V., Bakeeva, L. E., Chernyak, B. V., Chertkov, V. A., Domnina, L. V., Ivanova, O. Y., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Korshunova, G. A., Lyamzaev, K. G., Muntyan, M. S., Nepryakhina, O. K., Pashkovskaya, A. A., Pletjushkina, O. Y., Pustovidko, A. V., Roginsky, V. A., Rokitskaya, T. I., Ruuge, E. K., Saprunova, V. B., Severina, I. I., Simonyan, R. A., Skulachev, I. V., Skulachev, M. V., Sumbatyan, N. V., Sviryaeva, I. V., Tashlitsky, V. N., Vassiliev, J. M., Vyssokikh, M. Y., Yaguzhinsky, L. S., Zamyatnin, A. A., Jr. & Skulachev, V. P. (2008) Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies, Biochemistry (Moscow). 73, 1273-87.
4. Green, D. E. (1974) The electromechanochemical model for energy coupling in mitochondria, Biochimica et biophysica acta. 346, 27-78.
5. Liberman, E. A., Topaly, V. P., Tsofina, L. M., Jasaitis, A. A. & Skulachev, V. P. (1969) Mechanism of coupling of oxidative phosphorylation and the membrane potential of mitochondria, Nature. 222, 1076-8.
6. Liberman, E. A. & Skulachev, V. P. (1970) Conversion of biomembrane-produced energy into electric form. IV. General discussion, Biochimica et biophysica acta. 216, 30-42.
7. Skulachev, V. P. (1988) Membrane bioenergetics, Springer-Verlag, Berlin ; New York.
8. Burns, R. J., Smith, R. A. & Murphy, M. P. (1995) Synthesis and characterization of thiobutyltriphenylphosphonium bromide, a novel thiol reagent targeted to the mitochondrial matrix, Archives of biochemistry and biophysics. 322, 60-8.
9. Skulachev, V. P., Bogachev, A. V. & Kasparinsky, F. O. (2013) Principles of Bioenergetics, Springer, Berlin, Heidelberg.
