Molecular Biology

, Volume 52, Issue 3, pp 295–305 | Cite as

Perhydroxyl Radical (HO2) as Inducer of the Isoprostane Lipid Peroxidation in Mitochondria

  • A. Panov


The nonenzymatic isoprostane pathway of lipid peroxidation of polyunsaturated fatty acids results in formation of products, termed isoprostanes, which have very large positional and stereo isomerism, possess various biological activities, produce adducts with proteins, and thus contribute to pathogeneses of the agedependent diseases. However, it was unclear what mechanism drives this type of lipid autoxidation, and why the products have very large isomerism. We propose a mechanism when perhydroxyl radicals (HO2) react with polyunsaturated fatty acids in the hydrophobic milieu of membranes. In the membrane HO2 initiates a chain of reactions with formation first H2O2, which undergoes homolytic fission producing two OH radicals, thus very rapidly abstracting three H atoms from a polyunsaturated fatty acid. As a result, the HO2 molecule is converted to two molecules of water, and the molecule of a polyunsaturated fatty acid loses two double bonds, becomes highly unstable and undergoes peroxidation and random intramolecular re-arrangements causing a very large isomerism of the final products. The extremely high reactivity of 2 with polyunsaturated fatty acids is the cause of very subtle and slow accumulation of damages in the membrane and membrane associated proteins, even though the concentration of 2 relative to superoxide radical may be very low.


lipid peroxidation superoxide radical perhydroxyl radical mitochondria isoprostanes oxidative stress 



arachidonic acid


docosahexaenoic acid


Ca2+-independent phospholipase A2

Е2-IsoК and D2-IsoК

isoketals with rings Е2 and D2 correspondingly



IsoTxA2 and IsoTxB2

isothromboxanes with ring А2 and В2


inner mitochondrial membrane


isoprostane type lipid peroxidation




lipid peroxidation


outer mitochondrial membrane




polyunsaturated fatty acid


reactive oxygen species


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  1. 1.
    Murphy M.P., Partridge L. 2008. Toward a control theory analysis of aging. Ann. Rev. Biochem. 77, 777–798.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Sovari A.A. 2016. Cellular and molecular mechanisms of arrhythmia by oxidative stress. Cardiol. Res. Pract. 2016, 9656078. doi 10.1155/2016/9656078CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Radi E., Formichi P., Battisti C., Federico A. 2014. Apoptosis and oxidative stress in neurodegenerative diseases. J. Alzheimers Dis. 42, (Suppl. 3), S125–S152.CrossRefPubMedGoogle Scholar
  4. 4.
    Andreyev A.Y., Kushnareva Y.E., Murphy A.N., Starkov A.A. 2015. Mitochondrial ROS metabolism: 10 years later. Biochemistry (Moscow). 80 (5), 517–531.CrossRefGoogle Scholar
  5. 5.
    McCord J.M., Fridovich I. 1978. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J. Biol. Chem. 244, 6049–6055.Google Scholar
  6. 6.
    Bielski B.H.J. 1978. Reevaluation of the spectral and kinetic properties of HO2 and free radicals. Photochem. Photobiol. 28, 645–649.CrossRefGoogle Scholar
  7. 7.
    Bielski B.H., Arudi R.L., Sutherland M.W. 1983. A study of the reactivity of HO2/with unsaturated fatty acids. J. Biol. Chem. 258, 4759–4761.PubMedGoogle Scholar
  8. 8.
    Murphy M.P. 2009. How mitochondria produce reactive oxygen species. Biochem. J. 417, 1–13.CrossRefPubMedGoogle Scholar
  9. 9.
    Indo H.P., Yen H.C., Nakanishi I., et al. 2015. A mitochondrial superoxide theory for oxidative stress diseases and aging. J. Clin. Biochem. Nutr. 56, 1–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Fridovich S.E., Porter N.A. 1981. Oxidation of arachidonic acid in micelles by superoxide and hydrogen peroxide. J. Biol. Chem., 256, 260–265.PubMedGoogle Scholar
  11. 11.
    Halliwell B., Gutteridge J.M. 1984. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem. J. 218, 1–14.CrossRefGoogle Scholar
  12. 12.
    Halliwell B. 2006. Oxidative stress and neurodegeneration: Where are we now? J. Neurochem. 97, 1634–1658.CrossRefPubMedGoogle Scholar
  13. 13.
    Sala A., Zarini S., Folco G., et al. 1999. Differential metabolism of exogenous and endogenous arachidonic acid in human neutrophils. J. Biol. Chem. 274, 8264–28269.CrossRefGoogle Scholar
  14. 14.
    Aoki T., Narumiya S. 2012. Prostaglandins and chronic inflammation. Trends Pharmacol. Sci. 33, 304–311.CrossRefPubMedGoogle Scholar
  15. 15.
    Chwieśko-Minarowska S., Kowal K., Bielecki M., Kowal-Bielecka O. 2012. The role of leukotrienes in the pathogenesis of systemic sclerosis. Folia Histochem. Cytobiol. 50, 180–185.CrossRefPubMedGoogle Scholar
  16. 16.
    Tootle T.M. 2013. Genetic insights into the in vivo functions of prostaglandin signaling. Int. J. Biochem. Cell Biol. 45, 1629–1632.CrossRefPubMedGoogle Scholar
  17. 17.
    Vinik A.I., Nevoret M., Casellini C., Parson H. 2013. Neurovascular function and sudorimetry in health and disease. Curr. Diabetes Rep. 13, 517–532.CrossRefGoogle Scholar
  18. 18.
    Pryor W.A., Stanley J.P., Blair E. 1976. Autoxidation of polyunsaturated fatty acids: 2. A suggested mechanism for the formation of TBA-reactive materials from prostaglandin-like endoperoxides. Lipids. 11, 370–379. − O2 − O2PubMedGoogle Scholar
  19. 19.
    Wendelborn D.F., Seibert K., Roberts L.J. 2nd. 1988. Isomeric prostaglandin F2 compounds arising from prostaglandin D2: A family of icosanoids produced in vivo in humans. Proc. Natl. Acad. Sci. U. S. A. 85, 304–308.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Morrow J.D., Hill K.E., Burk R.F., et al. 1990. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc. Natl. Acad. Sci. U. S. A. 87, 9383–9387.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Morrow J.D., Awad J.A., Boss H.A., et al. 1992. Noncyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids. Proc. Natl. Acad. Sci. U. S. A. 89, 10721–10725.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Roberts L.J. 2nd., Fessel J.P. 2004. The biochemistry of the isoprostane, neuroprostane, and isofuran pathways of lipid peroxidation. Chem. Phys. Lipids. 128, 173–186.CrossRefPubMedGoogle Scholar
  23. 23.
    Brame C.J., Boutaud O., Davies S.S., et al. 2004. Modification of proteins by isoketal-containing oxidized phospholipids. J. Biol. Chem. 279, 13447–13451.CrossRefPubMedGoogle Scholar
  24. 24.
    Montuschi P., Barnes P.J., Roberts L.J. 2nd. 2004. Isoprostanes: Markers and mediators of oxidative stress. FASEB J. 18, 1791–1800.CrossRefPubMedGoogle Scholar
  25. 25.
    Davies S.S., Roberts L.J. 2nd. 2011. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Radical Biol. Med. 50, 559–566.CrossRefGoogle Scholar
  26. 26.
    Milne G.L., Yin H., Morrow J.D. 2008. Human biochemistry of the isoprostane pathway. J. Biol. Chem. 283, 15533–15537.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Musiek E.S., Yin H., Milne G.L., Morrow J.D. 2005. Recent advances in the biochemistry and clinical relevance of the isoprostane pathway. Lipids. 40, 987–994.CrossRefPubMedGoogle Scholar
  28. 28.
    Yin H., Gao L., Tai H.H., et al. 2007. Urinary prostaglandin F2alpha is generated from the isoprostane pathway and not the cyclooxygenase in humans. J. Biol. Chem. 282, 329–336.CrossRefPubMedGoogle Scholar
  29. 29.
    Roberts L.J. 2nd., Milne G.L. 2009. Isoprostanes. J. Lipid Res. 50, Suppl. S219–S223.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Roberts L.J. 2nd., Montine T.J., Markesbery W.R., et al. 1998. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J. Biol. Chem. 273, 13605–13612.CrossRefPubMedGoogle Scholar
  31. 31.
    Morrow J.D., Awad J.A., Boss H.J., et al. 1992. Noncyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids. Proc. Natl. Acad. Sci. U. S. A. 89, 10721–10725.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Morrow J.D., Roberts L.J., Daniel V.C. et al. 1998. Comparison of formation of D2/E2-isoprostanes and F2-isoprostanes in vitro and in vivo-effects of oxygen tension and glutathione. Arch. Biochem. Biophys. 353, 160–171.CrossRefPubMedGoogle Scholar
  33. 33.
    Morrow J.D., Hill K.E., Burk R.F., et al. 1990. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc. Natl. Acad. Sci. U. S. A. 87, 9383–9387.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Brame C.J., Salomon R.G., Morrow J.D. et al. 1999. Identification of extremely reactive gamma-ketoaldehydes (isolevuglandins) as products of the isoprostane pathway and characterization of their lysyl protein adducts. J. Biol. Chem. 274, 13139–13146.CrossRefPubMedGoogle Scholar
  35. 35.
    Gao L., Yin H., Milne G.L., et al. 2006. Formation of F-ring isoprostane-like compounds (F3-isoprostanes) in vivo from eicosapentaenoic acid. J. Biol. Chem. 281, 14092–14099.CrossRefPubMedGoogle Scholar
  36. 36.
    Repetto M., Semprine J., Boveris A. 2012. Lipid peroxidation: Chemical mechanism, biological implications and analytical determination. In: Lipid Peroxidation, Ed. Catala A. Rijeka, Croatia: InTech, pp. 3–30. doi doi 10.5772/45943Google Scholar
  37. 37.
    Davies S.S. 2008. Modulation of protein function by isoketals and levuglandins. Subcell. Biochem. 49, 49–70.CrossRefPubMedGoogle Scholar
  38. 38.
    Beckman J.S., Koppenol W.H. 1996. Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and ugly. Am. J. Physiol. 271, C1424–C1437.CrossRefPubMedGoogle Scholar
  39. 39.
    Brand M.D. 2016. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radical Biol. Med. 100, 14–31.CrossRefGoogle Scholar
  40. 40.
    Gebicki J.M., Bielski B.H.J. 1981. Comparison of the capacities of the perhydroxyl and the superoxide radicals to initiate chain oxidation of linoleic acid. J. Am. Chem. Soc. 103, 7020–7022.CrossRefGoogle Scholar
  41. 41.
    Pryor W.A., Squadrito G.L. 1995. The chemistry of peroxynitrite: A product from the reaction of nitric oxide with superoxide. Am. J. Physiol. 268, L699–L722.PubMedGoogle Scholar
  42. 42.
    Pryor W.A., Houk K.N., Foote C.S., et al. 2006. Free radical biology and medicine: It’s a gas, man! Am. J. Physiol. 291, R491–R511.Google Scholar
  43. 43.
    Pryor W.A. 1986. Oxy-radicals and related species: Their formation, lifetimes and reactions. Ann. Rev. Physiol. 48, 657–667.CrossRefGoogle Scholar
  44. 44.
    Gutteridge J.M. 1995. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin. Chem. 41, 1819–1828.PubMedGoogle Scholar
  45. 45.
    Barber J. 1980. Membrane surface charges and potentials in relation to photosynthesis. Biochim. Biophys. Acta. 594, 253–308.CrossRefPubMedGoogle Scholar
  46. 46.
    Gus’kova R.R., Ivanov I., Akhobadze A.A., et al. 1984. Permeability of bilayer lipid membranes for superoxide ( ) radicals. Biochim. Biophys. Acta. 778, 579–583.CrossRefPubMedGoogle Scholar
  47. 47.
    Serowy S., Saparov S.M., Antonenko Y.N., et al. 2003. Structural proton diffusion along lipid bilayers. Biophys. J. 84 (1), 1031–1037.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Wraight C.A. 2006. Chance and design: Proton transfer in water, channels and bioenergetic proteins. Biochim. Biophys. Acta. 1757, 886–912.CrossRefPubMedGoogle Scholar
  49. 49.
    Ilan Y.A., Czapski G., Meisel D. 2006. The one-electron transfer redox potentials of free radicals: 1. The oxygen/superoxide system. Biochim. Biophys. Acta. 430, 209–224.CrossRefGoogle Scholar
  50. 50.
    Owen M.C., Viskolcz B., Csizmadia L.G. 2011. Quantum chemical analysis of the unfolding of a pentaalanyl 3 (10)-helix initiated by •OH, and. J. Phys. Chem. B. 115, 8014–8023.CrossRefPubMedGoogle Scholar
  51. 51.
    Antonenko Y.N., Kovbasnjuk O.N., Yaguzhinsky L.S. 1993. Evidence in favor of the existence of a kinetic barrier for proton transfer from a surface of bilayer phosi− O2 i HO2 i O2 pholipid membrane to bulk water. Biochim. Biophys. Acta. 1150, 45–50.CrossRefPubMedGoogle Scholar
  52. 52.
    Heberle J., Riesle J., Thiedemann G., et al. 1994. Proton migration along the membrane surface and retarded surface to bulk transfer. Nature. 370 (6488), 379–382.CrossRefPubMedGoogle Scholar
  53. 53.
    Guckenberger R., Heim M., Cevc G., et al. 1994. Scanning tunneling microscopy of insulators and biological specimens based on lateral conductivity of ultrathin water films. Science. 266 (5190), 1538–1540.CrossRefPubMedGoogle Scholar
  54. 54.
    Krasinskaya I.P., Lapin M.V., Yaguzhinsky L.S. 1998. Detection of the local H+ gradients on the internal mitochondrial membrane. FEBS Lett. 440, 223–225.CrossRefPubMedGoogle Scholar
  55. 55.
    Cherepanov D.A., Feniouk B.A., Junge W., et al. 2003. Low dielectric permittivity of water at the membrane interface: Effect on the energy coupling mechanism in biological membranes. Biophys. J. 85, 1307–1316.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Springer A., Hagen V., Cherepanov D.A. et al. 2011. Protons migrate along interfacial water without significant contributions from jumps between ionizable groups on the membrane surface. Proc. Natl. Acad. Sci. U. S. A. 108, 14461–14466.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    De Grey A.D. 2002. •HO2: The forgotten radical. DNA Cell Biol. 21, 251–257.CrossRefPubMedGoogle Scholar
  58. 58.
    McLaughlin S. 1977. Electrostatic potentials at membrane-solution interfaces. Curr. Topics Membr. Transp. 9, 71–144CrossRefGoogle Scholar
  59. 59.
    Hovius R., Lambrechts H., Nicolay K., et al. 1990. Improved methods to isolate and subfructionate rat liver mitochondria. Lipid composition of the inner and outer membrane. Biochim. Biophys. Acta. 1021, 217–226.CrossRefPubMedGoogle Scholar
  60. 60.
    Horvath S.E., Daum G. 2013. Lipids of mitochondria. Progr. Lipid Res. 52, 590–614.CrossRefGoogle Scholar
  61. 61.
    Mileykovskaya E., Dowhan W. 2009. Cardiolipin membrane domains in prokaryotes and eukaryotes. Biochim. Biophys. Acta. 1788, 2084–2091.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Haines T.H., Dencher N.A. 2002. Cardiolipin: A proton trap for oxidative phosphorylation. FEBS Lett. 528, 35–39.CrossRefPubMedGoogle Scholar
  63. 63.
    Adelroth P., Brzezinski P. 2004. Surface-mediated proton-transfer reactions in membrane-bound proteins. Biochim. Biophys. Acta. 1655, 102–115.CrossRefPubMedGoogle Scholar
  64. 64.
    Gutman M., Nachliel E. 1995. The dynamics of proton-exchange between bulk and surface groups. Biochim. Biophys. Acta. 1231, 123–138.CrossRefGoogle Scholar
  65. 65.
    Emanuel N.M., Knorre D.G. 1984. Kurs khimicheskoi kinetiki (A Course in Chemical Kinetics), 4th ed. Moscow: Vysshaya Shkola.Google Scholar
  66. 66.
    Mikheev Yu.A., Zajkov G.E. 2006. Nano-phases and kinetic model of chain reactions of polypropilens with dibenzoyl peroxide. In: Diversity in Chemical Reactions: Pure and Applied Chemistry. Eds. Zajkov G.E., Rakovsky S.K., Schiraldi S.A. New York: Nova Science.Google Scholar
  67. 67.
    Seal P., Papajak E., Truhlar D.G. 2012. Kinetics of the hydrogen abstraction from carbon-3 of 1-butanol by hydroperoxyl radical: Multi-structural variational transition-state calculations of a reaction with 262 conformations of the transition state. J. Phys. Chem. Let. 2012, 264–271.CrossRefGoogle Scholar
  68. 68.
    Mendes J., Zhou C.W., Curran H.J. 2013. Theoretical and kinetic study of the hydrogen atom abstraction reactions of esters with radicals. J. Phys. Chem. A. 117, 14006–14018.CrossRefPubMedGoogle Scholar
  69. 69.
    Aikens J., Dix T.A. 1991. Perhydroxyl radical (HOO•) initiated lipid peroxidation. The role of fatty acid hydroperoxides. J. Biol. Chem. 266, 15091–15098.PubMedGoogle Scholar
  70. 70.
    Aikens J., Dix T.A. 1993. Hydrodioxyl (perhydroxyl), peroxyl, and hydroxyl radical-initiated lipid peroxidation of large unilamellar vesicles (liposomes): Comparative and mechanistic studies. Arch. Biochem. Biophys. 305, 516–525.CrossRefPubMedGoogle Scholar
  71. 71.
    Antunes F., Salvador A., Marinho H.S., et al. 1996. Lipid peroxidation in mitochondrial inner membranes: 1. An integrative kinetic model. Free Radical Biol. Med. 21, 917–943.CrossRefGoogle Scholar
  72. 72.
    Dix T.A., Hess K.M., Medina M.A., et al. 1996. Mechanism of site-selective DNA nicking by the hydrodioxyl (perhydroxyl) radical. Biochemistry. 35, 4578–4583.CrossRefPubMedGoogle Scholar
  73. 73.
    Montine T.J., Morrow J.D. 2005. Fatty acid oxidation in the pathogenesis of Alzheimer’s disease. Am. J. Pathol. 166, 1283–12895.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Haines T.H. 2009. A new look at Cardiolipin. Biochim. Biophys. Acta. 1788, 1997–2002.CrossRefPubMedGoogle Scholar
  75. 75.
    Paradies G., Petrosillo G., Paradies V., et al. 2009. Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium. 45, 643–650.CrossRefPubMedGoogle Scholar
  76. 76.
    Paradies G., Petrosillo G., Paradies V., et al. 2011. Mitochondrial dysfunction in brain aging: Role of oxidative stress and cardiolipin. Neurochem. Int. 58, 447–457.CrossRefPubMedGoogle Scholar
  77. 77.
    Han X., Yang J., Yang K., et al. 2007. Alterations in myocardial cardiolipin content and composition occur at the very earliest stages of diabetes: A shotgun lipidomics study. Biochemistry. 46, 6417–6428.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Lee H.J., Mayette J., Rapoport S.I., et al. 2006. Selective remodeling of cardiolipin fatty acids in the aged rat heart. Lipids Health Dis. 5, 2.CrossRefPubMedPubMedCentralGoogle Scholar

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© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  1. 1.Institute of Molecular Biology and BiophysicsSiberian Division of the Russian Academy of SciencesNovosibirskRussia

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