Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers

Alexander M. Firsov, Maksim A. Fomich, Andrei V. Bekish, Olga L. Sharko, Elena A. Kotova, Harry J. Saal, Dragoslav Vidovic, Vadim V. Shmanai, Derek A. Pratt, Yuri N. Antonenko, Mikhail S. Shchepinov

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Autoxidation of polyunsaturated fatty acids (PUFAs) damages lipid membranes and generates numerous toxic by-products implicated in neurodegeneration, aging, and other pathologies. Abstraction of bis-allylic hydrogen atoms is the rate-limiting step of PUFA autoxidation, which is inhibited by replacing bis-allylic hydrogens with deuterium atoms (D-PUFAs). In cells, the presence of a relatively small fraction of D-PUFAs among natural PUFAs is sufficient to effectively inhibit lipid peroxidation (LPO). Here, we investigate the effect of various D-PUFAs on the stability of liposomes under oxidative stress conditions. The permeability of vesicle membranes to fluorescent dyes was measured as a proxy for bilayer integrity, and the formation of conjugated dienes was monitored as a proxy for LPO. Remarkably, both approaches reveal a similar threshold for the protective effect of D-PUFAs in liposomes. We show that protection rendered by D-PUFAs depends on the structure of the deuterated fatty acid. Our findings suggest that protection of PUFAs against autoxidation depends on the total level of deuterated bi-sallylic (CD 2 ) groups present in the lipid bilayer. However, the phospholipid containing 6,6,9,9,12,12,15,15,18,18-d 10 -docosahexaenoic acid exerts a stronger protective effect than should be expected from its deuteration level. These findings further support the application of D-PUFAs as preventive/therapeutic agents in numerous pathologies that involve LPO.

Original languageEnglish
Pages (from-to)2099-2117
Number of pages19
JournalFEBS Journal
Volume286
Issue number11
DOIs
Publication statusPublished - 2019

Keywords

  • conjugated dienes
  • deuterated polyunsaturated fatty acids
  • lipid peroxidation
  • liposome leakage
  • reactive oxygen species

Cite this

Firsov, A. M., Fomich, M. A., Bekish, A. V., Sharko, O. L., Kotova, E. A., Saal, H. J., ... Shchepinov, M. S. (2019). Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers. FEBS Journal, 286(11), 2099-2117. https://doi.org/10.1111/febs.14807
Firsov, Alexander M. ; Fomich, Maksim A. ; Bekish, Andrei V. ; Sharko, Olga L. ; Kotova, Elena A. ; Saal, Harry J. ; Vidovic, Dragoslav ; Shmanai, Vadim V. ; Pratt, Derek A. ; Antonenko, Yuri N. ; Shchepinov, Mikhail S. / Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers. In: FEBS Journal. 2019 ; Vol. 286, No. 11. pp. 2099-2117.
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abstract = "Autoxidation of polyunsaturated fatty acids (PUFAs) damages lipid membranes and generates numerous toxic by-products implicated in neurodegeneration, aging, and other pathologies. Abstraction of bis-allylic hydrogen atoms is the rate-limiting step of PUFA autoxidation, which is inhibited by replacing bis-allylic hydrogens with deuterium atoms (D-PUFAs). In cells, the presence of a relatively small fraction of D-PUFAs among natural PUFAs is sufficient to effectively inhibit lipid peroxidation (LPO). Here, we investigate the effect of various D-PUFAs on the stability of liposomes under oxidative stress conditions. The permeability of vesicle membranes to fluorescent dyes was measured as a proxy for bilayer integrity, and the formation of conjugated dienes was monitored as a proxy for LPO. Remarkably, both approaches reveal a similar threshold for the protective effect of D-PUFAs in liposomes. We show that protection rendered by D-PUFAs depends on the structure of the deuterated fatty acid. Our findings suggest that protection of PUFAs against autoxidation depends on the total level of deuterated bi-sallylic (CD 2 ) groups present in the lipid bilayer. However, the phospholipid containing 6,6,9,9,12,12,15,15,18,18-d 10 -docosahexaenoic acid exerts a stronger protective effect than should be expected from its deuteration level. These findings further support the application of D-PUFAs as preventive/therapeutic agents in numerous pathologies that involve LPO.",
keywords = "conjugated dienes, deuterated polyunsaturated fatty acids, lipid peroxidation, liposome leakage, reactive oxygen species",
author = "Firsov, {Alexander M.} and Fomich, {Maksim A.} and Bekish, {Andrei V.} and Sharko, {Olga L.} and Kotova, {Elena A.} and Saal, {Harry J.} and Dragoslav Vidovic and Shmanai, {Vadim V.} and Pratt, {Derek A.} and Antonenko, {Yuri N.} and Shchepinov, {Mikhail S.}",
year = "2019",
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Firsov, AM, Fomich, MA, Bekish, AV, Sharko, OL, Kotova, EA, Saal, HJ, Vidovic, D, Shmanai, VV, Pratt, DA, Antonenko, YN & Shchepinov, MS 2019, 'Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers', FEBS Journal, vol. 286, no. 11, pp. 2099-2117. https://doi.org/10.1111/febs.14807

Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers. / Firsov, Alexander M.; Fomich, Maksim A.; Bekish, Andrei V.; Sharko, Olga L.; Kotova, Elena A.; Saal, Harry J.; Vidovic, Dragoslav; Shmanai, Vadim V.; Pratt, Derek A.; Antonenko, Yuri N.; Shchepinov, Mikhail S.

In: FEBS Journal, Vol. 286, No. 11, 2019, p. 2099-2117.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers

AU - Firsov, Alexander M.

AU - Fomich, Maksim A.

AU - Bekish, Andrei V.

AU - Sharko, Olga L.

AU - Kotova, Elena A.

AU - Saal, Harry J.

AU - Vidovic, Dragoslav

AU - Shmanai, Vadim V.

AU - Pratt, Derek A.

AU - Antonenko, Yuri N.

AU - Shchepinov, Mikhail S.

PY - 2019

Y1 - 2019

N2 - Autoxidation of polyunsaturated fatty acids (PUFAs) damages lipid membranes and generates numerous toxic by-products implicated in neurodegeneration, aging, and other pathologies. Abstraction of bis-allylic hydrogen atoms is the rate-limiting step of PUFA autoxidation, which is inhibited by replacing bis-allylic hydrogens with deuterium atoms (D-PUFAs). In cells, the presence of a relatively small fraction of D-PUFAs among natural PUFAs is sufficient to effectively inhibit lipid peroxidation (LPO). Here, we investigate the effect of various D-PUFAs on the stability of liposomes under oxidative stress conditions. The permeability of vesicle membranes to fluorescent dyes was measured as a proxy for bilayer integrity, and the formation of conjugated dienes was monitored as a proxy for LPO. Remarkably, both approaches reveal a similar threshold for the protective effect of D-PUFAs in liposomes. We show that protection rendered by D-PUFAs depends on the structure of the deuterated fatty acid. Our findings suggest that protection of PUFAs against autoxidation depends on the total level of deuterated bi-sallylic (CD 2 ) groups present in the lipid bilayer. However, the phospholipid containing 6,6,9,9,12,12,15,15,18,18-d 10 -docosahexaenoic acid exerts a stronger protective effect than should be expected from its deuteration level. These findings further support the application of D-PUFAs as preventive/therapeutic agents in numerous pathologies that involve LPO.

AB - Autoxidation of polyunsaturated fatty acids (PUFAs) damages lipid membranes and generates numerous toxic by-products implicated in neurodegeneration, aging, and other pathologies. Abstraction of bis-allylic hydrogen atoms is the rate-limiting step of PUFA autoxidation, which is inhibited by replacing bis-allylic hydrogens with deuterium atoms (D-PUFAs). In cells, the presence of a relatively small fraction of D-PUFAs among natural PUFAs is sufficient to effectively inhibit lipid peroxidation (LPO). Here, we investigate the effect of various D-PUFAs on the stability of liposomes under oxidative stress conditions. The permeability of vesicle membranes to fluorescent dyes was measured as a proxy for bilayer integrity, and the formation of conjugated dienes was monitored as a proxy for LPO. Remarkably, both approaches reveal a similar threshold for the protective effect of D-PUFAs in liposomes. We show that protection rendered by D-PUFAs depends on the structure of the deuterated fatty acid. Our findings suggest that protection of PUFAs against autoxidation depends on the total level of deuterated bi-sallylic (CD 2 ) groups present in the lipid bilayer. However, the phospholipid containing 6,6,9,9,12,12,15,15,18,18-d 10 -docosahexaenoic acid exerts a stronger protective effect than should be expected from its deuteration level. These findings further support the application of D-PUFAs as preventive/therapeutic agents in numerous pathologies that involve LPO.

KW - conjugated dienes

KW - deuterated polyunsaturated fatty acids

KW - lipid peroxidation

KW - liposome leakage

KW - reactive oxygen species

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