Skulachev 2014 Abstract MiP2014

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Mitochondria are sources, rather than sinks, of reactive oxygen species. Effects of mitochondria-targeted antioxidants.
Link:
Skulachev VP
Mitochondr Physiol Network 19.13 - MiP2014

Skulachev VP (2014)

Event: MiP2014

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 [1]. 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 [5]. 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 [12]. Such mice were shown to have an elevated content of mitochondrial H2O2 [13]. Targeting of catalase to nucleus or peroxisomes proved to be much less effective than to mitochondria [9].

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 

Affiliation

Lomonosov Moscow State Univ, Belozersky Inst Physico-Chem Biol, Moscow, Russia. - skulach@belozersky.msu.ru

References

  1. Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RA, Murphy MP (2001) J Biol Chem 276: 4588-96.
  2. Agapova LS, Chernyak BV, Domnina LV, Dugina VB, Efimenko AY, Fetisova EK, Ivanova OY, Kalinina NI, Khromova NV, Kopnin BP, Kopnin PB, Korotetskaya MV, Lichinitser MR, Lukashev AL, Pletjushkina OY, Popova EN, Skulachev MV, Shagieva GS, Stepanova EV, Titova EV, Tkachuk VA, Vasiliev JM, Skulachev VP (2008) Biochemistry (Mosc) 73: 1300-16.
  3. Chernyak BV, Antonenko YN, Galimov ER, Domnina LV, Dugina VB, Zvyagilskaya RA, Ivanova OY, Izyumov DS, Lyamzaev KG, Pustovidko AV, Rokitskaya TI, Rogov AG, Severina II, Simonyan RA, Skulachev MV, Tashlitsky VN, Titova EV, Trendeleva TA, Shagieva GS (2012) Novel mitochondria-targeted compounds composed of natural constituents: Conjugates of plant alkaloids berberine and palmatine with plastoquinone. Biochemistry (Mosc) 77: 983-95.
  4. Galkin II, Antonenko YN, Galimov ER, Domnina LV, Dugina VB, Zvyagilskaya RA, Ivanova OY, Izyumov DS, Lyamzaev KG, Pustovidko AV, Rokitskaya TI, Rogov AG, Severina II, Simonyan RA, Skulachev MV, Tashlitsky VN, Titova EV, Trendeleva TA, Shagieva GS (2014) Biochemistry (Mosc.) 79: 124-30.
  5. Skulachev VP (2009) Biochim Biophys Acta 1787: 437-61.
  6. Skulachev VP (2010) Biochim Biophys Acta 1797: 878-89.
  7. Skulachev MV, Antonenko YN, Anisimov VN, Chernyak BV, Cherepanov DA, Chistyakov VA, Egorov MV, Kolosova NG, Korshunova GA, Lyamzaev KG, Plotnikov EY, Roginsky VA, Savchenko AY, Severina II, Severin FF, Shkurat TP, Tashlitsky VN, Shidlovsky KM, Vyssokikh MY, Zamyatnin AA Jr, Zorov DB, Skulachev VP (2011) Curr Drug Targets 12: 800-26.
  8. Kolosova NG, Stefanova NA, Muraleva NA, Skulachev VP (2012) Aging (Albany NY) 4: 686-94.
  9. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, van Remmen H, Wallace DC, Rabinovitch PS (2005) Science 308: 1909-11.
  10. Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo DK, Shadel GS, Ladiges W, Rabinovitch PS, Santos JH, Petersen KF, Samuel VT, Shulman GI (2010) Cell Metab 12: 668-74.
  11. Dai DF, Rabinovitch PS (2009) Trends Cardiovasc Med 19: 213-20.
  12. Dai DF, Chen T, Wanagat J, Laflamme M, Marcinek DJ, Emond MJ, Ngo CP, Prolla TA, Rabinovitch PS (2010) Aging Cell 9: 536-44.
  13. Logan A, Shabalina IG, Prime TA, Rogatti S, Kalinovich AV, Hartley RC, Budd RC, Cannon B, Murphy MP (2014) Aging Cell. 1-4. doi: 10.1111/acel12212.
  14. Yani EV, Katargina LA, Chesnokova NB, Beznos OV, Savchenko AY, Vygodin VA, Gudkova EY, Zamyatnin AA Jr, Skulachev MV (2012) Pract Med 4: 134-7.
  15. Skulachev VP, Bogachev AV, Kasparinsky FO (2013) Principles of Bioenergetics. Springer, Berlin, Heidelberg.