Membran lipit profilinin membran kapasitansı, hücresel uyarılabilirlik ve patofizyolojik mekanizmalar üzerindeki rolü

Öz

Plazma membranı, hücrelerin çevresiyle olan etkileşimlerini düzenleyen ve lipit çift tabaka organizasyonu aracılığıyla hücresel sinyal iletimi, uyarılabilirlik ve homeostazın sürdürülmesinde merkezi rol oynayan dinamik bir yapıdır. Kolesterol, fosfolipitler, sfingolipitler ve glikolipitlerden oluşan membran lipit bileşimi; akışkanlık, geçirgenlik ve elektriksel özellikler gibi temel biyofiziksel parametreleri belirleyerek hücresel yanıtların mekânsal ve zamansal organizasyonunu şekillendirir. Bu lipitlerin asimetrik dağılımı ve kolesterol-sfingolipit açısından zengin lipit raft mikrodomainleri, reseptör aktivasyonu, iyon kanalı fonksiyonu ve sinyal proteinlerinin lokalizasyonu açısından lipit adacıklar sunar. Membran lipit bileşiminde ve lipit raft organizasyonunda meydana gelen bozulmalar, kanser, kardiyovasküler hastalıklar ve enfeksiyon hastalıklarının patogenezinde ortak ve belirleyici mekanizmalar olarak öne çıkmaktadır. Kanserde lipit metabolizmasının yeniden programlanması, onkojenik sinyal yolaklarının (ör. PI3K/Akt, Ras, EGFR) membran bağlı aktivasyonunu kolaylaştırarak proliferasyon, invazyon ve tedavi direncini destekler. Kardiyovasküler hastalıklarda lipit raftlar inflamatuar sinyalizasyon, oksidatif stres yanıtları ve iyon kanalı regülasyonu üzerinden vasküler disfonksiyon ve kardiyak yeniden yapılanmaya neden olur. Enfeksiyon hastalıklarında ise lipit raftlar, patojen bağlanması, hücreye giriş ve replikasyon süreçlerinin düzenlenmesinde işlevsel platformlar oluşturarak konak-patojen etkileşiminin seyrini belirler. Bu çerçevede, plazma membranının lipit profilinin ve elektriksel özelliklerinin hedeflenmesi, lipit temelli biyobelirteçlerin geliştirilmesi ve meliterapi gibi yenilikçi yaklaşımlar için güçlü bir moleküler zemin sunmaktadır. Membran fizyolojisinin bütüncül olarak değerlendirilmesi, hastalık patogenezinin daha iyi anlaşılmasına ve hedefe yönelik tanı ve tedavi stratejilerinin geliştirilmesine katkı sağlayacaktır.

Anahtar Kelimeler

• Plazma membranı
• lipit raft tabaka
• membran kapasitansı
• kablo teorisi
• patofizyolojik süreçlerde membran lipit profili

The role of membrane lipid profile in membrane capacitance, cellular excitability, and pathophysiological mechanisms

Öz

The plasma membrane is a dynamic structure that regulates cellular interactions with the extracellular environment and plays a central role in signal transduction, excitability, and the maintenance of cellular homeostasis through its lipid bilayer organization. The membrane lipid composition—comprising cholesterol, phospholipids, sphingolipids, and glycolipids—determines key biophysical parameters such as fluidity, permeability, and electrical properties, thereby shaping the spatial and temporal organization of cellular responses. The asymmetric distribution of these lipids and the presence of cholesterol- and sphingolipid- enriched lipid raft microdomains provide critical platforms for receptor activation, ion channel function, and the localization of signaling proteins. Disruptions in membrane lipid composition and lipid raft organization have emerged as common and decisive mechanisms in the pathogenesis of cancer, cardiovascular diseases, and infectious disorders. In cancer, metabolic reprogramming of lipid pathways facilitates membrane-associated activation of oncogenic signaling cascades (e.g., PI3K/Akt, Ras, and EGFR), thereby promoting proliferation, invasion, and therapeutic resistance. In cardiovascular diseases, lipid rafts contribute to vascular dysfunction and cardiac remodeling by modulating inflammatory signaling, oxidative stress responses, and ion channel regulation. In infectious diseases, lipid rafts act as functional platforms for pathogen attachment, cellular entry, and replication, critically shaping the outcome of host-pathogen interactions. In this context, targeting the lipid architecture and electrical properties of the plasma membrane provides a strong molecular basis for the development of lipid-based biomarkers and innovative therapeutic strategies, including membrane lipid therapy. A comprehensive understanding of membrane physiology is therefore essential for elucidating disease mechanisms and advancing targeted diagnostic and therapeutic approaches.

Anahtar Kelimeler

• Plasma membrane
• lipid rafts
• membrane capacitance
• cable theory
• lipid profile in pathophysiological processes

Kaynakça

1. Coskun Ü, Simons K. Cell membranes: the lipid perspective. Structure. 2011;19(11):1543-1548. https://doi.org/10.1016/j.str.2011.10.010
2. Harayama T, Riezman H. Understanding the diversity of membrane lipid composition. Nat Rev Mol Cell Biol. 2018;19(5):281-296. https://doi.org/10.1038/nrm.2017.138
3. Ernst R, Ballweg S, Levental I. Homeoviscous adaptation and the regulation of membrane lipids. J Mol Biol. 2016;428(24):4776-4791. https://doi.org/10.1016/j.jmb.2016.08.013
4. Simons K, Sampaio JL. Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol. 2011;3(10):a004697. https://doi.org/10.1101/cshperspect.a004697
5. Anselmo S, Bonaccorso E, Gangemi C, Sancataldo G, Conti Nibali V, D’Angelo G. Lipid rafts in signalling, diseases, and infections: what can be learned from fluorescence techniques? Membranes. 2025;15(1):6. https://doi.org/10.3390/membranes15010006
6. Viljetić B, Blažetić S, Labak I, Ivić V, Zjalić M, Heffer M, Balog M. Lipid rafts: The maestros of normal brain development. Biomolecules. 2024;14(3):362. https://doi.org/10.3390/biom14030362
7. Kusumi A, Fujiwara TK, Chadda R, Xie M, Tsunoyama TA, Kalay Z, et al. Dynamic organizing principles of the plasma membrane. Nat Rev Mol Cell Biol. 2020;21(9):527-545. https://doi.org/10.1038/s41580-020-0236-1
8. Casares D, Escribá PV, Rosselló CA. Membrane lipid composition: effect on membrane and organelle structure, function and compartmentalization and therapeutic avenues. Int J Mol Sci. 2019;20(9):2167. https://doi.org/10.3390/ijms20092167

9. Cerone M, Smith TK. Desaturases: structural and mechanistic insights into the biosynthesis of unsaturated fatty acids. IUBMB Life. 2022;74(9):770-785. https://doi.org/10.1002/iub.2671
10. Nelson DL, Cox MM. Lehninger principles of biochemistry. 8th ed. New York (NY): W.H. Freeman; 2021.
11. Saito RF, Andrade LNS, Bustos SO, Chammas R. Phosphatidylcholine-derived lipid mediators: the crosstalk between cancer cells and immune cells. Front Immunol. 2022;13:768606. https://doi.org/10.3389/fimmu.2022.768606
12. Segawa K, Nagata S. An apoptotic “eat me” signal: phosphatidylserine exposure. Trends Cell Biol. 2015;25(11):639-650. https://doi.org/10.1016/j.tcb.2015.08.003
13. Vance JE. Phospholipid synthesis and transport in mammalian cells. Traffic. 2015;16(1):1-18. https://doi.org/10.1111/tra.12230
14. Balla T. Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol Rev. 2013;93(3):1019-1137. https://doi.org/10.1152/physrev.00028.2012
15. Kuo A, Hla T. Regulation of cellular and systemic sphingolipid homeostasis. Nat Rev Mol Cell Biol. 2024;25(10):802-821. https://doi.org/10.1038/s41580-024-00742-y
16. Luo J, Yang H, Song BL. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2020;21(4):225-245. https://doi.org/10.1038/s41580-019-0190-7
17. Imamura A, Ando H, Ishida H. Chemical synthesis of gangliosides. Methods Mol Biol. 2023;2613:89-100. https://doi.org/10.1007/978-1-0716-2910-9_8
18. Kandel ER, Koester JD, Mack SH, Siegelbaum SA. Principles of neural science. 6th ed. New York: McGraw-Hill; 2021.
19. Santos CR, Schulze A. Lipid metabolism in cancer. FEBS J. 2012;279(15):2610-2623. https://doi.org/10.1111/j.1742-4658.2012.08644.x
20. Zhang F, Du G. Dysregulated lipid metabolism in cancer. World J Biol Chem. 2012;3(8):167-174. https://doi.org/10.4331/wjbc.v3.i8.167
21. Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16(11):732-749. https://doi.org/10.1038/nrc.2016.89
22. Muro E, Atilla-Gokcumen GE, Eggert US. Lipids in cell biology: how can we understand them better? Mol Biol Cell. 2014;25(12):1819-1823. https://doi.org/10.1091/mbc.E13-09-0516
23. Lingwood D, Simons K. Lipid rafts as organizing principles in cell membranes. Science. 2010;327(5961):46-50. https://doi.org/10.1126/science.1174621
24. Vogel FCE, Chaves-Filho AB, Schulze A. Lipids as mediators of cancer progression and metastasis. Nat Cancer. 2024;5(1):16-29. https://doi.org/10.1038/s43018-023-00702-z
25. Huang B, Song BL, Xu C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab. 2020;2(2):132-141. https://doi.org/10.1038/s42255-020-0174-0
26. Morad SAF, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer. 2013;13(1):51-65. https://doi.org/10.1038/nrc3398
27. Carracedo A, Cantley LC, Pandolfi PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer. 2013;13(4):227-232. https://doi.org/10.1038/nrc3483
28. Prior IA, Hancock JF. Ras trafficking, localization and compartmentalized signalling. Semin Cell Dev Biol. 2012;23(2):145-153. https://doi.org/10.1016/j.semcdb.2011.09.002
29. Ahearn IM, Haigis K, Bar-Sagi D, Philips MR. Regulating the regulator: post-translational modification of RAS. Nat Rev Mol Cell Biol. 2012;13(1):39-51. https://doi.org/10.1038/nrm3255
30. Zhou Y, Hancock JF. Ras nanoclusters: versatile lipid-based signaling platforms. Biochim Biophys Acta. 2015;1853(4):841-849. https://doi.org/10.1016/j.bbamcr.2014.09.008
31. Coskun Ü, Grzybek M, Drechsel D, Simons K. Regulation of human EGF receptor by lipids. Proc Natl Acad Sci U S A. 2011;108(22):9044-9048. https://doi.org/10.1073/pnas.1105666108
32. Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169(6):985-999. https://doi.org/10.1016/j.cell.2017.05.016
33. Ingham PW. Hedgehog signaling. Curr Top Dev Biol. 2022;149:1-58. https://doi.org/10.1016/bs.ctdb.2022.04.003
34. Zhang Y, Beachy PA. Cellular and molecular mechanisms of Hedgehog signalling. Nat Rev Mol Cell Biol. 2023;24(9):668-687. https://doi.org/10.1038/s41580-023-00591-1
35. Escribá PV, Busquets X, Inokuchi JI, Balogh G, Török Z, Horváth I, et al. Membrane-lipid therapy: modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment. Prog Lipid Res. 2015;59:38-53. https://doi.org/10.1016/j.plipres.2015.04.003
36. Terés S, Lladó V, Higuera M, Barceló-Coblijn G, Martin ML, Noguera-Salvà MA, et al. 2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy. Proc Natl Acad Sci U S A.2012;109(22):8489-8494. https://doi.org/10.1073/pnas.1118349109
37. Mancini A, Colapietro A, Cristiano L, Rossetti A, Mattei V, Gravina GL, et al. Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models. Front Oncol. 2022;12:943064. https://doi.org/10.3389/fonc.2022.943064
38. Muñoz-Guardiola P, Casas J, Megías-Roda E, Solé S, Perez-Montoyo H, Yeste-Velasco M, et al. The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells. Autophagy. 2021;17(6):1349-1366. https://doi.org/10.1080/15548627.2020.1761651
39. Ravnskov U, McCully KS, Rosch PJ. The statin-low cholesterol-cancer conundrum. QJM. 2012;105(4):383-388. https://doi.org/10.1093/qjmed/hcr243
40. Stasi I, Cappuzzo F. Profile of bavituximab and its potential in the treatment of non-small-cell lung cancer. Lung Cancer (Auckl). 2014; 5:43-50. https://doi.org/10.2147/LCTT.S37981
41. Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell. 2015;6(4):254-264. https://doi.org/10.1007/s13238-014-0131-3
42. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis. 2012;223(2):262-268. https://doi.org/10.1016/j.atherosclerosis.2012.02.019
43. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472. https://doi.org/10.1093/eurheartj/ehx144
44. Li PL, Zhang Y, Yi F. Lipid raft redox signaling platforms in endothelial dysfunction. Antioxid Redox Signal. 2007;9(9):1457-1470. https://doi.org/10.1089/ars.2007.1667
45. Manea A. NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology. Cell Tissue Res. 2010;342(3):325-339. https://doi.org/10.1007/s00441-010-1060-y
46. Liu S, Tao J, Duan F, Li H, Tan H. HHcy induces pyroptosis and atherosclerosis via the lipid Raft-Mediated NOX-ROS-NLRP3 inflammasome pathway in apoE(-/-) mice. Cells. 2022;11(15):2438. https://doi.org/10.3390/cells11152438
47. Gong W, Jiao Q, Yuan J, Luo H, Liu Y, Zhang Y, et al. Cardioprotective and anti-inflammatory effects of Caveolin 1 in experimental diabetic cardiomyopathy. Clin Sci (Lond). 2023;137(6):511-525. https://doi.org/10.1042/CS20220874
48. Lopez JP, Nouri MZ, Ebrahim A, Chacko KM, Schramm WC, Gholam MF, et al. Lipid profiles of urinary extracellular vesicles released during the inactive and active phases of aged male mice with spontaneous hypertension. Int J Mol Sci. 2022;23(23):15397. https://doi.org/10.3390/ijms232315397
49. Fecchi K, Anticoli S, Peruzzu D, Iessi E, Gagliardi MC, Matarrese P, et al. Coronavirus interplay with lipid rafts and autophagy unveils promising therapeutic targets. Front Microbiol. 2020; 11:1821. https://doi.org/10.3389/fmicb.2020.01821
50. Kulkarni R, Wiemer EAC, Chang W. Role of lipid rafts in Pathogen-Host Interac- tion - A mini review. Front Immunol. 2021;12:815020. https://doi.org/10.3389/fimmu.2021.815020
51. Bukrinsky MI, Mukhamedova N, Sviridov D. Lipid rafts and pathogens: the Art of deception and exploitation: thematic review series: biology of lipid rafts. J Lipid Res. 2020;61(5):601-610. https://doi.org/10.1194/jlr.TR119000391
52. Wang Q, Yang SQ, Yang K, Li XR, Dai Y, Zheng Y, et al. CD4 is an important host factor for Japanese encephalitis virus entry and replication in PK-15 cells. Vet Microbiol. 2023;287:109913. https://doi.org/10.1016/j.vetmic.2023.109913
53. Jin C, Che B, Guo ZY, Li C, Liu Y, Wu W, et al. Single virus tracking of ebola virus entry through lipid rafts in living host cells. Biosaf Health. 2020;2(1):25-31. https://doi.org/10.1016/j.bsheal.2019.12.009
54. Kim JY, Wang L, Lee J, Ou JJ. Hepatitis C virus induces the localization of lipid rafts to autophagosomes for its RNA replication. J Virol. 2017;91(20). https://doi.org/10.1128/JVI.00541-17
55. Gee YJ, Sea YL, Lal SK. Viral modulation of lipid rafts and their potential as putative antiviral targets. Rev Med Virol. 2023;33(2):e2413. https://doi.org/10.1002/rmv.2413
56. Li L, Yu L, Hou X. Cholesterol-rich lipid rafts play a critical role in bovine para- influenza virus type 3 (BPIV3) infection. Res Vet Sci. 2017;114:341-347. https://doi.org/10.1016/j.rvsc.2017.04.009
57. Gagliardi MC, Lai CH, Iwabuchi K, Editorial. Role of lipid rafts in anti-microbial immune response II. Front Immunol. 2022;13. https://doi.org/10.3389/fimmu.2022.1043181
58. Schlegel J, Peters S, Doose S, Schubert-Unkmeir A, Sauer M. Super-resolution microscopy reveals local accumulation of plasma membrane gangliosides at invasion sites. Front Cell Dev Biol. 2019;7:194. https://doi.org/10.3389/fcell.2019.00194
59. Butt L, Unnersjo-Jess D, Reilly D, Hahnfeldt R, Rinschen MM, Bozek K, et al. In vivo characterization of a podocyte- expressed short Podocin isoform. BMC Nephrol. 2023;24(1):378. https://doi.org/10.1186/s12882-023-03420-x
60. Yu CP, Zhang H, Liu SX, Li RZ, Zhao XC, Chen YH, et al. Flot2 acts as a novel mediator of podocyte injury in proteinuric kidney disease. Int J Biol Sci. 2023;19(2):502-520. https://doi.org/10.7150/ijbs.78945