Advertisement

Studies on Mitochondria Directed Plastoquinones

  • Boris A. Feniouk
  • Vladimir P. Skulachev
Chapter

Abstract

Mitochondria-targeted cationic plastoquinone derivatives (SkQs, e.g. SkQ1, SkQR1) and their analogs lacking plastoquinol moiety (C12TPP, C12R1) can pass through bilayer phospholipid membrane. Their cationic forms are accumulated in isolated mitochondria or in mitochondria of living cells, driven by membrane potential. These compounds were extensively tested in model lipid membranes, isolated mitochondria and in living human cells in culture. It was found that SkQs are antioxidants that quench reactive oxygen species (ROS) in mitochondria, and mild uncouplers that facilitate transmembrane proton transport by fatty acids. Both properties result in efficient prevention of oxidative stress and protection of mitochondria and cells from damage by ROS, making SkQs a promising drug candidate against pathologies caused by excess mitochondrial ROS generation. Recent discovery of SkQ1 antibacterial activity at concentrations not toxic to human cells opens a perspective for development of new antibiotics. In this chapter, we summarize recent in vitro experiments with mitochondria-targeted plastoquinones.

Keywords

Mitochondria-targeted cationic plastoquinone derivatives SkQ1 Mitochondria Oxidative stress Model lipid membranes 

Abbreviations

MitoQ

10-(6′-Ubiquinonyl) decyltriphenylphosphonium

MPC

membranophilic penetrating cation

MPI

membranophilic penetrating ion

PQ

Plastoquinone

ROS

Reactive oxygen species

SkQ

Cationic derivative of plastoquinone or methyl plastoquinone

SkQ1

10-(6′-Plastoquinonyl) decyltriphenylphosphonium

SkQ2M

10-(6′-Plastoquinonyl) decylmethylcarnitine

SkQ3

10-(6′-Methylplastoquinonyl) decyltriphenylphosphonium

SkQ4

10-(6′-Plastoquinonyl) decyltributylammonium

SkQ5

5-(6′-Plastoquinonyl) amyltriphenylphosphonium

SkQR1

10(Plastoquinonyl) decylrhodamine 19

TPB

Tetraphenylborate

TPP

Tetraphenylphosphonium

Δψ

Transmembrane electric potential difference

Notes

Acknowledgements

This work was supported by the Russian Science Foundation (Project No. 14-50-00029 (B.A.F.) and Project No. 14–24-00107 (V.P.S.)).

Conflict of Interest V.P.S. is a board member of Mitotech LLC, a biotech company which owns rights for compounds of SkQ type.

References

  1. Antonenko YN, Avetisyan AV, Bakeeva LE, Chernyak BV, Chertkov VA, Domnina LV, Ivanova OY, Izyumov DS, Khailova LS, Klishin SS, Korshunova GA, Lyamzaev KG, Muntyan MS, Nepryakhina OK, Pashkovskaya AA, Pletjushkina OY, Pustovidko AV, Roginsky VA, Rokitskaya TI, Ruuge EK, Saprunova VB, Severina II, Simonyan RA, Skulachev IV, Skulachev MV, Sumbatyan NV, Sviryaeva IV, Tashlitsky VN, Vassiliev JM, Vyssokikh MY, Yaguzhinsky LS, Zamyatnin AA Jr, Skulachev VP (2008) Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies. Biochemistry (Mosc) 73:1273–1287CrossRefGoogle Scholar
  2. Antonenko YN, Avetisyan AV, Cherepanov DA, Knorre DA, Korshunova GA, Markova OV, Ojovan SM, Perevoshchikova IV, Pustovidko AV, Rokitskaya TI, Severina II, Simonyan RA, Smirnova EA, Sobko AA, Sumbatyan NV, Severin FF, Skulachev VP (2011) Derivatives of rhodamine 19 as mild mitochondria-targeted cationic uncouplers. J Biol Chem 286:17831–17840CrossRefPubMedPubMedCentralGoogle Scholar
  3. Burns RJ, Smith RA, Murphy MP (1995) Synthesis and characterization of thiobutyltriphenylphosphonium bromide, a novel thiol reagent targeted to the mitochondrial matrix. Arch Biochem Biophys 322:60–68CrossRefPubMedGoogle Scholar
  4. Doughan AK, Dikalov SI (2007) Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis. Antioxid Redox Signal 9:1825–1836CrossRefPubMedGoogle Scholar
  5. Feniouk BA, Skulachev VP (2017) Cellular and molecular mechanisms of action of mitochondria-targeted antioxidants. Curr Aging Sci 10:41–48CrossRefPubMedGoogle Scholar
  6. Feniouk BA, Skulachev VP (2018) Studies on mitochondria directed plastoquinones. In: Oliveira PJ (ed) Mitochondrial biology and experimental therapeutics. Springer, New YorkGoogle Scholar
  7. Fetisova EK, Avetisian AV, Iziumov DS, Korotetskaia MV, Tashlitskii VN, Skulachev VP, Cherniak BV (2010) Multidrug resistance p-glycoprotein inhibits the antiapoptotic action of mitochondria-targeted antioxidant SkQR1. Tsitologiia 52:1031–1040PubMedGoogle Scholar
  8. Fetisova EK, Antoschina MM, Cherepanynets VD, Izumov DS, Kireev II, Kireev RI, Lyamzaev KG, Riabchenko NI, Chernyak BV, Skulachev VP (2015) Radioprotective effects of mitochondria-targeted antioxidant SkQR1. Radiat Res 183:64–71CrossRefPubMedGoogle Scholar
  9. Foyer CH, Noctor G (2003) Redox sensing and signalling associated with reactive oxygen in chloroplasts, peroxisomes and mitochondria. Physiol Plant 119:355–364CrossRefGoogle Scholar
  10. Galimov ER, Chernyak BV, Sidorenko AS, Tereshkova AV, Chumakov PM (2014) Prooxidant properties of p66shc are mediated by mitochondria in human cells. PLoS One 9:e86521CrossRefPubMedPubMedCentralGoogle Scholar
  11. Galkin II, Pletjushkina OY, Zinovkin RA, Zakharova VV, Birjukov IS, Chernyak BV, Popova EN (2014) Mitochondria-targeted antioxidants prevent TNFalpha-induced endothelial cell damage. Biochemistry (Mosc) 79:124–130CrossRefGoogle Scholar
  12. Galkin II, Pletjushkina OY, Zinovkin RA, Zakharova VV, Chernyak BV, Popova EN (2016) Mitochondria-targeted antioxidant SkQR1 reduces TNF-induced endothelial permeability in vitro. Biochemistry (Mosc) 81:1188–1197CrossRefGoogle Scholar
  13. Gill SS, Tuteja N (2010) Reactive oxygen species and antioxidant machinery in abiotic stress tolerance in crop plants. Plant Physiol Biochem 48:909–930CrossRefPubMedGoogle Scholar
  14. Green DE (1974) The electromechanochemical model for energy coupling in mitochondria. Biochim Biophys Acta 346:27–78CrossRefPubMedGoogle Scholar
  15. Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333:1109–1112CrossRefPubMedPubMedCentralGoogle Scholar
  16. Hundal T, Forsmark-Andree P, Ernster L, Andersson B (1995) Antioxidant activity of reduced plastoquinone in chloroplast thylakoid membranes. Arch Biochem Biophys 324:117–122CrossRefPubMedGoogle Scholar
  17. Izyumov DS, Domnina LV, Nepryakhina OK, Avetisyan AV, Golyshev SA, Ivanova OY, Korotetskaya MV, Lyamzaev KG, Pletjushkina OY, Popova EN, Chernyak BV (2010) Mitochondria as source of reactive oxygen species under oxidative stress. Study with novel mitochondria-targeted antioxidants—the “Skulachev-ion” derivatives. Biochemistry (Mosc) 75:123–129CrossRefGoogle Scholar
  18. James AM, Cocheme HM, Smith RA, Murphy MP (2005) Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools. J Biol Chem 280:21295–21312CrossRefPubMedGoogle Scholar
  19. Jauslin ML, Meier T, Smith RAJ, Murphy MP (2003) Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J 17:1972–1974CrossRefPubMedGoogle Scholar
  20. Jezek J, Engstova H, Jezek P (2017) Antioxidant mechanism of mitochondria-targeted plastoquinone SkQ1 is suppressed in aglycemic HepG2 cells dependent on oxidative phosphorylation. Biochim Biophys Acta 1858:750–762CrossRefPubMedGoogle Scholar
  21. Kasahara A, Scorrano L (2014) Mitochondria: from cell death executioners to regulators of cell differentiation. Trends Cell Biol 24:761–770CrossRefPubMedGoogle Scholar
  22. Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RA, Murphy MP (2001) Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 276:4588–4596CrossRefPubMedGoogle Scholar
  23. Kelso GF, Porteous CM, Hughes G, Ledgerwood EC, Gane AM, Smith RAJ, Murphy MP (2002) Prevention of mitochondrial oxidative damage using targeted antioxidants. Ann N Y Acad Sci 959:263–274CrossRefPubMedGoogle Scholar
  24. Korshunov SS, Skulachev VP, Starkov AA (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 416:15–18CrossRefPubMedGoogle Scholar
  25. Korshunova GA, Shishkina AV, Skulachev MV (2017) Design, synthesis and some aspects of biological activity of mitochondria-targeted antioxidants. Biochemistry (Mosc) 82(7):760–777CrossRefGoogle Scholar
  26. Kruk J, Trebst A (2008) Plastoquinol as a singlet oxygen scavenger in photosystem II. BBA-Bioenergetics 1777:154–162CrossRefPubMedGoogle Scholar
  27. Kruk J, Jemiolarzeminska M, Strzalka K (1997) Plastoquinol and alpha-tocopherol quinol are more active than ubiquinol and alpha-tocopherol in inhibition of lipid peroxidation. Chem Phys Lipids 87:73–80CrossRefGoogle Scholar
  28. Li L, Chen YQ, Gibson SB (2013) Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation. Cell Signal 25:50–65CrossRefPubMedGoogle Scholar
  29. Lokhmatikov AV, Voskoboynikova NE, Cherepanov DA, Sumbatyan NV, Korshunova GA, Skulachev MV, Steinhoff HJ, Skulachev VP, Mulkidjanian AY (2014) Prevention of peroxidation of cardiolipin liposomes by quinol-based antioxidants. Biochemistry (Mosc) 79:1081–1100CrossRefGoogle Scholar
  30. Lopez-Armada MJ, Riveiro-Naveira RR, Vaamonde-Garcia C, Valcarcel-Ares MN (2013) Mitochondrial dysfunction and the inflammatory response. Mitochondrion 13:106–118CrossRefPubMedGoogle Scholar
  31. Lukashev AN, Skulachev MV, Ostapenko V, Savchenko AY, Pavshintsev VV, Skulachev VP (2014) Advances in development of rechargeable mitochondrial antioxidants. Prog Mol Biol Transl Sci 127:251–265CrossRefPubMedGoogle Scholar
  32. Miwa S, Brand MD (2003) Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. Biochem Soc Trans 31:1300–1301CrossRefPubMedGoogle Scholar
  33. Mubarakshina MM, Ivanov BN (2010) The production and scavenging of reactive oxygen species in the plastoquinone pool of chloroplast thylakoid membranes. Physiol Plant 140:103–110CrossRefPubMedGoogle Scholar
  34. Murphy MP, Smith RAJ (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol 47:629–656CrossRefPubMedGoogle Scholar
  35. Nazarov PA, Osterman IA, Tokarchuk AV, Karakozova MV, Korshunova GA, Lyamzaev KG, Skulachev MV, Kotova EA, Skulachev VP, Antonenko YN (2017) Mitochondria-targeted antioxidants as highly effective antibiotics. Sci Rep 7:1394CrossRefPubMedPubMedCentralGoogle Scholar
  36. Nowicka B, Kruk J (2012) Plastoquinol is more active than alpha-tocopherol in singlet oxygen scavenging during high light stress of Chlamydomonas reinhardtii. BBA-Bioenergetics 1817:389–394CrossRefPubMedGoogle Scholar
  37. O’malley Y, Fink BD, Ross NC, Prisinzano TE, Sivitz WI (2006) Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria. J Biol Chem 281:39766–39775CrossRefPubMedGoogle Scholar
  38. Omarova EO, Antonenko YN (2014) Inhibition of oxidative hemolysis in erythrocytes by mitochondria-targeted antioxidants of SkQ series. Biochemistry (Mosc) 79:139–145CrossRefGoogle Scholar
  39. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922CrossRefPubMedGoogle Scholar
  40. Paglialunga S, van Bree B, Bosma M, Valdecantos MP, Amengual-Cladera E, Jorgensen JA, van Beurden D, den Hartog GJM, Ouwens DM, Briede JJ, Schrauwen P, Hoeks J (2012) Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice. Diabetologia 55:2759–2768CrossRefPubMedGoogle Scholar
  41. Pustovidko AV, Rokitskaya TI, Severina II, Simonyan RA, Trendeleva TA, Lyamzaev KG, Antonenko YN, Rogov AG, Zvyagilskaya RA, Skulachev VP, Chernyak BV (2013) Derivatives of the cationic plant alkaloids berberine and palmatine amplify protonophorous activity of fatty acids in model membranes and mitochondria. Mitochondrion 13:520–525CrossRefPubMedGoogle Scholar
  42. Roginsky V, Barsukova T, Loshadkin D, Pliss E (2003) Substituted p-hydroquinones as inhibitors of lipid peroxidation. Chem Phys Lipids 125:49–58CrossRefPubMedGoogle Scholar
  43. Rogov AG, Ovchenkova AP, Goleva TN, Kireev II, Zvyagilskaya RA (2017) New yeast models for studying mitochondrial morphology as affected by oxidative stress and other factors. Anal Biochem.  https://doi.org/10.1016/j.ab.2017.04.003
  44. Rokitskaya TI, Murphy MP, Skulachev VP, Antonenko YN (2016) Ubiquinol and plastoquinol triphenylphosphonium conjugates can carry electrons through phospholipid membranes. Bioelectrochemistry 111:23–30CrossRefPubMedGoogle Scholar
  45. Saretzki G, Murphy MP, von Zglinicki T (2003) MitoQ counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress. Aging Cell 2:141–143CrossRefPubMedGoogle Scholar
  46. Severin SE, Skulachev VP, Yaguzhinsky LS (1970) Possible role of carnitine in transport of fatty acids through mitochondrial membrane. Biokhimiya 35:1250–1252Google Scholar
  47. Severin FF, Severina II, Antonenko YN, Rokitskaya TI, Cherepanov DA, Mokhova EN, Vyssokikh MY, Pustovidko AV, Markova OV, Yaguzhinsky LS, Korshunova GA, Sumbatyan NV, Skulachev MV, Skulachev VP (2010) Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc Natl Acad Sci U S A 107:663–668CrossRefPubMedGoogle Scholar
  48. Severina II, Severin FF, Korshunova GA, Sumbatyan NV, Ilyasova TM, Simonyan RA, Rogov AG, Trendeleva TA, Zvyagilskaya RA, Dugina VB, Domnina LV, Fetisova EK, Lyamzaev KG, Vyssokikh MY, Chernyak BV, Skulachev MV, Skulachev VP, Sadovnichii VA (2013) In search of novel highly active mitochondria-targeted antioxidants: thymoquinone and its cationic derivatives. FEBS Lett 587:2018–2024CrossRefPubMedGoogle Scholar
  49. Shagieva G, Domnina L, Makarevich O, Chernyak B, Skulachev V, Dugina V (2017) Depletion of mitochondrial reactive oxygen species downregulates epithelial-to-mesenchymal transition in cervical cancer cells. Oncotarget 8:4901–4913CrossRefPubMedGoogle Scholar
  50. Skulachev VP, Antonenko YN, Cherepanov DA, Chernyak BV, Izyumov DS, Khailova LS, Klishin SS, Korshunova GA, Lyamzaev KG, Pletjushkina OY, Roginsky VA, Rokitskaya TI, Severin FF, Severina II, Simonyan RA, Skulachev MV, Sumbatyan NV, Sukhanova EI, Tashlitsky VN, Trendeleva TA, Vyssokikh MY, Zvyagilskaya RA (2010) Prevention of cardiolipin oxidation and fatty acid cycling as two antioxidant mechanisms of cationic derivatives of plastoquinone (SkQs). Biochim Biophys Acta 1797:878–889CrossRefPubMedGoogle Scholar
  51. 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) Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. Curr Drug Targets 12:800–826CrossRefPubMedGoogle Scholar
  52. Smith RA, Porteous CM, Coulter CV, Murphy MP (1999) Selective targeting of an antioxidant to mitochondria. Eur J Biochem 263:709–716CrossRefPubMedGoogle Scholar
  53. Vorobjeva N, Prikhodko A, Galkin I, Pletjushkina O, Zinovkin R, Sud’ina G, Chernyak B, Pinegin B (2017) Mitochondrial reactive oxygen species are involved in chemoattractant-induced oxidative burst and degranulation of human neutrophils in vitro. Eur J Cell Biol 96:254–265CrossRefPubMedGoogle Scholar
  54. Votyakova TV, Reynolds IJ (2001) DeltaPsi(m)-dependent and -independent production of reactive oxygen species by rat brain mitochondria. J Neurochem 79:266–277CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia
  2. 2.A.N. Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia

Personalised recommendations