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Energy Barrier of a Monolayer Stalk Formation during Lipid Droplet Fusion

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Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract

Lipid droplets are organelles responsible for the accumulation and breakdown of neutral fats in the human body. Lipid droplets have a monolayer shell of phospholipids, which prevents their spontaneous fusion. The fusion of lipid droplets is carried out by specialized fusion proteins and is regulated by the lipid composition of the monolayer membrane. The efficiency of fusion is determined by the energy needed for the local approach of lipid droplets and the topological rearrangement of their monolayers. In this work, the fusion of monolayers is modeled within the framework of the theory of membrane elasticity. The energy barrier for fusion is calculated under various conditions simulating possible compositions of monolayers, as well as the possible effects of proteins. The calculation results show that the height of the barrier is most dependent on the distance between lipid droplets, which is determined by the fusion proteins. Lipid composition also affects the fusion efficiency and can change it several tens of times, which is consistent with previously obtained data on bilayer fusion.

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REFERENCES

  1. Martens S., McMahon H.T. 2008. Mechanisms of membrane fusion: Disparate players and common principles. Nat. Rev. Mol. Cell Biol. 9, 543–556.

    Article  CAS  PubMed  Google Scholar 

  2. Akimov S.A., Molotkovsky R.J., Kuzmin P.I., Galimzyanov T.R. Batishchev O.V. 2020. Continuum models of membrane fusion: Evolution of the theory. Int. J. Mol. Sci. 21, 3875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chernomordik L.V., Kozlov M.M. 2008. Mechanics of membrane fusion. Nat. Struct. Mol. Biol. 15, 675–683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Markin V., Kozlov M., Borovjagin V. 1984. On the theory of membrane fusion. The stalk mechanism. Gen. Physiol. Biophys. 5, 361–377.

    Google Scholar 

  5. Yang L., Huang H.W. 2002. Observation of a membrane fusion intermediate structure. Science. 297, 1877–1879.

    Article  CAS  PubMed  Google Scholar 

  6. Akimov S.A., Molotkovsky R.J., Galimzyanov T.R., Radaev A.V., Shilova L.A., Kuzmin P.I., Batishchev O.V., Voronina G.F., Chizmadzhev Yu.A. 2014. Model of membrane fusion: Continuous transition to fusion pore with regard of hydrophobic and hydration interactions. Biochem. (Mosc.) Suppl. A: Membr. Cell Biol. 8, 153–161.

    Google Scholar 

  7. Fuhrmans M., Marelli G., Smirnova Y.G., Müller M. 2015. Mechanics of membrane fusion/pore formation. Chem. Phys. Lipids. 185, 109–128.

    Article  CAS  PubMed  Google Scholar 

  8. Ryham R.J., Klotz T.S., Yao L., Cohen F. S. 2016. Calculating transition energy barriers and characterizing activation states for steps of fusion. Biophys. J. 110, 1110–1124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cohen F.S., Melikyan G.B. 2004. The energetics of membrane fusion from binding, through hemifusion, pore formation, and pore enlargement. J. Membr. Biol. 199, 1–14.

    Article  CAS  PubMed  Google Scholar 

  10. Kuzmin P.I., Zimmerberg J., Chizmadzhev Yu.A., Cohen F.S. 2001. A quantitative model for membrane fusion based on low-energy intermediates. Proc. Natl. Acad. Sci. USA. 98, 7235–7240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kawamoto S., Klein M.L., Shinoda W. 2015. Coarse-grained molecular dynamics study of membrane fusion: Curvature effects on free energy barriers along the stalk mechanism. J. Chem. Phys. 143, 243112.

    Article  PubMed  Google Scholar 

  12. Poojari C.S., Scherer K.C., Hub J.S. 2021. Free energies of membrane stalk formation from a lipidomics perspective. Nat. Commun. 12, 6594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tauchi-Sato K., Ozeki S., Houjou T., Taguchi R., Fujimoto T. 2002. The surface of lipid droplets is a phospholipid monolayer with a unique fatty acid composition. J. Biol. Chem. 277, 44 507–44 512.

    Article  Google Scholar 

  14. Gao G., Chen F.J., Zhou L., Su L., Xu D., Xu L., Li P. 2017. Control of lipid droplet fusion and growth by CIDE family proteins. BBA – Mol. Cell Biol. L. 1862, 1197–1204.

    CAS  Google Scholar 

  15. Boström P., Andersson L., Rutberg M., Perman J., Lidberg U., Johansson B.R., Fernandez-Rodriguez J., Ericson J., Nilsson T., Borén J., Olofsson S.O. 2007. SNARE proteins mediate fusion between cytosolic lipid droplets and are implicated in insulin sensitivity. Nat. Cell Biol. 9, 1286–1293.

    Article  PubMed  Google Scholar 

  16. Fei W., Shui G., Zhang Y., Krahmer N., Ferguson C., Kapterian T.S., Lin R.C., Dawes I.W., Brown A.J., Li P., Huang X., Parton R.G., Wenk M.R., Yang H. 2011. A role for phosphatidic acid in the formation of “supersized” lipid droplets. PLoS Genet. 7, e1002201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chernomordik L.V., Kozlov M.M., Melikyan G.B., Abidor I.G., Markin V.S., Chizmadzhev Y.A. 1985. The shape of lipid molecules and monolayer membrane fusion. Biochim. Biophys. ActaBiomembr. 812, 643–655

    Article  CAS  Google Scholar 

  18. Kooijman E.E., Chupin V., Fuller N.L., Kozlov M.M., de Kruijff B., Burger K.N., Rand P.R. 2005. Spontaneous curvature of phosphatidic acid and lysophosphatidic acid. Biochem. 44, 2097–2102.

    Article  CAS  Google Scholar 

  19. Penno A., Hackenbroich G., Thiele C. 2013. Phospholipids and lipid droplets. BBA – Mol. Cell Biol. L. 1831, 589–594.

    CAS  Google Scholar 

  20. Mather I.H., Masedunskas A., Chen Y., Weigert R. 2019. Symposium review: Intravital imaging of the lactating mammary gland in live mice reveals novel aspects of milk-lipid secretion. JDS. 102, 2760–2782.

  21. Molotkovsky R.J., Kuzmin P.I., Akimov S.A. 2015. Membrane fusion. Two possible mechanisms underlying a decrease in the fusion energy barrier in the presence of fusion proteins. Biochem. (Mosc.) Suppl. A: Membr. Cell Biol. 9, 65–76.

    Google Scholar 

  22. Molotkovsky R.J., Galimzyanov T.R., Jiménez-Munguía I., Pavlov K.V., Batishchev O.V., Akimov S.A. 2017. Switching between successful and dead-end intermediates in membrane fusion. Int. J. Mol. Sci. 18, 2598.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kalutsky M.A., Galimzyanov T.R., Molotkovsky R.J. 2022. A model of lipid monolayer–bilayer fusion of lipid droplets and peroxisomes. Membranes. 12, 992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hamm M., Kozlov M.M. 2000. Elastic energy of tilt and bending of fluid membranes. Eur. Phys. J. E 3, 323–335.

    Article  CAS  Google Scholar 

  25. Molotkovsky R.J., Kuzmin P.I. 2022. Fusion of peroxisome and lipid droplet membranes: Expansion of a π-shaped structure. Biochem. (Mosc.) Suppl. A: Membr. Cell Biol. 16 (4), 356–367.

    CAS  Google Scholar 

  26. Aeffner S., Reusch T., Weinhausen B., Salditt T. 2012. Energetics of stalk intermediates in membrane fusion are controlled by lipid composition. Proc. Natl. Acad. Sci. USA. 109, E1609–E1618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bashkirov P.V., Kuzmin P.I., Vera Lillo J., Frolov V.A. 2022. Molecular shape solution for mesoscopic remodeling of cellular membranes. Annu. Rev. Biophys. 51, 473–497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rawicz W., Olbrich K.C., McIntosh T., Needham D., Evans E. 2000. Effect of chain length and unsaturation on elasticity of lipid bilayers. Biophys. J. 79, 328–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kollmitzer B., Heftberger P., Rappolt M., Pabst G. 2013. Monolayer spontaneous curvature of raft-forming membrane lipids. Soft Matter. 9, 10 877–10 884.

    Article  Google Scholar 

  30. Hamm M., Kozlov M.M. 1998. Tilt model of inverted amphiphilic mesophases. Eur. Phys. J. B 6, 519–528.

    Article  CAS  Google Scholar 

  31. Shnyrova A.V., Bashkirov P.V., Akimov S.A., Pucadyil T.J., Zimmerberg J., Schmid S.L., Frolov V.A. 2013. Geometric catalysis of membrane fission driven by flexible dynamin rings. Science. 339, 1433–1436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Siegel D.P., Kozlov M.M. 2004. The Gaussian curvature elastic modulus of N-monomethylated dioleoylphosphatidylethanolamine: Relevance to membrane fusion and lipid phase behavior. Biophys. J. 87, 366–374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hu M., Briguglio J.J., Deserno M. 2012. Determining the Gaussian curvature modulus of lipid membranes in simulations. Biophys. J. 102, 1403–1410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chernomordik L.V., Kozlov M.M. 2003. Protein-lipid interplay in fusion and fission of biological membranes. Annu. Rev. Biochem. 72, 175–207.

    Article  CAS  PubMed  Google Scholar 

  35. Akimov S.A., Polynkin M.A., Jiménez-Munguía I., Pavlov K.V., Batishchev O.V. 2018. Phosphatidylcholine membrane fusion is pH-dependent. Int. J. Mol. Sci. 19, 1358.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Siegel D.P. 2008. The Gaussian curvature elastic energy of intermediates in membrane fusion. Biophys. J. 95, 5200–5215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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ACKNOWLEDGMENTS

The author thanks P.I. Kuzmin for his help and constructive comments during the calculations and preparation of the manuscript.

Funding

This work was supported by the Russian Science Foundation (project no. 22-23-00551).

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Correspondence to R. J. Molotkovsky.

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Translated by R. Molotkovsky

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Molotkovsky, R.J. Energy Barrier of a Monolayer Stalk Formation during Lipid Droplet Fusion. Biochem. Moscow Suppl. Ser. A 18, 22–30 (2024). https://doi.org/10.1134/S199074782470003X

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  • DOI: https://doi.org/10.1134/S199074782470003X

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