Pub Date : 2025-11-18DOI: 10.1016/j.bbamem.2025.184484
Emad Ghazizadeh , Mahdi Zeidi , Wylie Stroberg
The endoplasmic reticulum (ER) is a highly dynamic organelle that undergoes continuous remodeling between tubular and sheet-like structures, driven by curvature-inducing proteins and membrane mechanics. Understanding the physical principles underlying ER shape transitions is crucial for elucidating its role in cellular homeostasis and disease. In this study, we use a mesoscopic model of membrane-protein interactions to investigate how intrinsic curvature, protein concentration, and membrane stiffening collectively regulate ER tubulation. Our results demonstrate that the critical concentration for tubulation depends nonlinearly on intrinsic curvature due to a competition between adsorption and remodeling ability. Additionally, increased membrane stiffness upon protein adsorption enhances tubulation efficiency at lower intrinsic curvatures and changes tubule geometry at higher intrinsic curvatures. Phase diagrams are constructed to map the conditions necessary for membrane remodeling, revealing critical protein concentration thresholds for ER transformation. These findings provide a quantitative framework for ER shape regulation, offering insights into how different curvature-inducing proteins coordinate ER morphogenesis.
{"title":"Tubulation of membrane sheets by curvature-inducing proteins","authors":"Emad Ghazizadeh , Mahdi Zeidi , Wylie Stroberg","doi":"10.1016/j.bbamem.2025.184484","DOIUrl":"10.1016/j.bbamem.2025.184484","url":null,"abstract":"<div><div>The endoplasmic reticulum (ER) is a highly dynamic organelle that undergoes continuous remodeling between tubular and sheet-like structures, driven by curvature-inducing proteins and membrane mechanics. Understanding the physical principles underlying ER shape transitions is crucial for elucidating its role in cellular homeostasis and disease. In this study, we use a mesoscopic model of membrane-protein interactions to investigate how intrinsic curvature, protein concentration, and membrane stiffening collectively regulate ER tubulation. Our results demonstrate that the critical concentration for tubulation depends nonlinearly on intrinsic curvature due to a competition between adsorption and remodeling ability. Additionally, increased membrane stiffness upon protein adsorption enhances tubulation efficiency at lower intrinsic curvatures and changes tubule geometry at higher intrinsic curvatures. Phase diagrams are constructed to map the conditions necessary for membrane remodeling, revealing critical protein concentration thresholds for ER transformation. These findings provide a quantitative framework for ER shape regulation, offering insights into how different curvature-inducing proteins coordinate ER morphogenesis.</div></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184484"},"PeriodicalIF":2.5,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/j.bbamem.2025.184483
Anna Seelig
This personal review in memory of Joachim Seelig covers half a century of membrane biophysics. The topics chosen give insight into the structure and function of our innate immune system, consisting in the membranes covering the external and internal body surfaces in contact with the outside world. Their core is the lipid bilayer in its liquid crystalline state. We investigated its average structure and fluidity by deuterium-nuclear magnetic resonance spectroscopy (D-NMR) using selectively deuterated lipids. Close to the lipid-water interface, lipids retain a defined average structure with the glycerol backbone oriented perpendicular to the membrane surface. The characteristic structure of lipids remains in the presence of transmembrane proteins and guarantees a tight membrane packing near the aqueous phases. The order of lipid segments remains approximately constant decreasing only towards the membrane center. Were cells surrounded by lipids only, hydrophobic molecules would nevertheless penetrate the membranes and reach the nucleus, the smaller ones more rapidly and the larger one more slowly. To protect cells from intruding mutagenic compounds, a significant number of defense proteins have evolved, including ATP binding cassette (ABC) transporters and pattern recognition receptors (PRR). Interestingly, the different defense proteins recognize compounds that carry specific hydrogen bond acceptor patterns and could interfere with DNA or RNA. ABC transporters and pattern recognition receptors remove them from the lipid bilayer before they reach the cytosol to prevent mutagenesis. While these proteins are well known to contribute to multidrug resistance (MDR), their significant role in innate immunity only starts to emerge.
{"title":"Contribution to the special BBA issue dedicated to Joachim Seelig from lipid bilayers to the innate immune system","authors":"Anna Seelig","doi":"10.1016/j.bbamem.2025.184483","DOIUrl":"10.1016/j.bbamem.2025.184483","url":null,"abstract":"<div><div>This personal review in memory of Joachim Seelig covers half a century of membrane biophysics. The topics chosen give insight into the structure and function of our innate immune system, consisting in the membranes covering the external and internal body surfaces in contact with the outside world. Their core is the lipid bilayer in its liquid crystalline state. We investigated its average structure and fluidity by deuterium-nuclear magnetic resonance spectroscopy (D-NMR) using selectively deuterated lipids. Close to the lipid-water interface, lipids retain a defined average structure with the glycerol backbone oriented perpendicular to the membrane surface. The characteristic structure of lipids remains in the presence of transmembrane proteins and guarantees a tight membrane packing near the aqueous phases. The order of lipid segments remains approximately constant decreasing only towards the membrane center. Were cells surrounded by lipids only, hydrophobic molecules would nevertheless penetrate the membranes and reach the nucleus, the smaller ones more rapidly and the larger one more slowly. To protect cells from intruding mutagenic compounds, a significant number of defense proteins have evolved, including ATP binding cassette (ABC) transporters and pattern recognition receptors (PRR). Interestingly, the different defense proteins recognize compounds that carry specific hydrogen bond acceptor patterns and could interfere with DNA or RNA. ABC transporters and pattern recognition receptors remove them from the lipid bilayer before they reach the cytosol to prevent mutagenesis. While these proteins are well known to contribute to multidrug resistance (MDR), their significant role in innate immunity only starts to emerge.</div></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184483"},"PeriodicalIF":2.5,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1016/j.bbamem.2025.184482
Khoa Nguyen , Alvaro Garcia , Marc-Antoine Sani , Vikas Dubey , Daniel Clayton , Giovanni Dal Poggetto , Flemming Cornelius , Richard J. Payne , Frances Separovic , Himanshu Khandelia , Ronald J. Clarke
{"title":"Corrigendum to “Interaction of N-terminal peptide analogues of the Na+,K+-ATPase with membranes” [BBA Biomembr. 1860 (6) (2018) 1282–1291]","authors":"Khoa Nguyen , Alvaro Garcia , Marc-Antoine Sani , Vikas Dubey , Daniel Clayton , Giovanni Dal Poggetto , Flemming Cornelius , Richard J. Payne , Frances Separovic , Himanshu Khandelia , Ronald J. Clarke","doi":"10.1016/j.bbamem.2025.184482","DOIUrl":"10.1016/j.bbamem.2025.184482","url":null,"abstract":"","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184482"},"PeriodicalIF":2.5,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145480895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.bbamem.2025.184479
Mariana Biscaia-Caleiras , Ana Sofia Lourenço , João Nuno Moreira , Sérgio Simões
{"title":"Corrigendum to “Unveiling the impact of membrane fluidity in shaping lipid-based drug delivery systems development.” [Biochim. Biophys. Acta (BBA) – Biomembr. Volume 1868, Issue 1, January 2026, 184461]","authors":"Mariana Biscaia-Caleiras , Ana Sofia Lourenço , João Nuno Moreira , Sérgio Simões","doi":"10.1016/j.bbamem.2025.184479","DOIUrl":"10.1016/j.bbamem.2025.184479","url":null,"abstract":"","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184479"},"PeriodicalIF":2.5,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.bbamem.2025.184481
Ivan Klbik , Milan Melicherčík , Dušan Račko , Igor Maťko , Ján Lakota , Ondrej Šauša
The interaction of dimethyl sulfoxide (DMSO) with lipid membranes has been extensively studied using molecular dynamics (MD) simulations, yet discrepancies with experimental findings persist. Here, we re-evaluate the effects of low DMSO concentrations (1.5–10 vol%) on dimyristoyl phosphatidylcholine (DMPC) membranes using updated AMBER force fields (LIPID17, OPC, GAFF2) to assess its cryoprotective role. Simulations were performed in both fluid (330K) and gel (260 K) phases as well as under ice-forming conditions. Across three independent replicas, no statistically significant effects of DMSO were detected on membrane thickness, area per lipid, hydration, or acyl-chain order, indicating that low levels of DMSO do not alter bilayer structure. This represents an improvement over earlier force-field descriptions, which often exaggerated DMSO–lipid interactions, and provides results more consistent with experimental evidence. DMSO showed mild enrichment at the hydrophobic–hydrophilic interface, particularly near carbonyl and glycerol groups, but most molecules remained in the solvent. The strongest effects therefore emerged in the solvent phase: DMSO slowed ice crystal growth by about a factor of five, was excluded from the ice lattice, and accumulated at the ice–membrane boundary forming an ice-free layer. Surprisingly, even without DMSO, ice formation in contact with the bilayer did not cause structural disruption, suggesting that cryoinjury involves additional membrane components beyond lipids. DMSO also strongly inhibited the temperature-driven variation of water density in the amorphous state. These findings suggest that at low concentrations, DMSO's cryoprotective action arises mainly from modulation of water and ice behavior rather than direct bilayer perturbation.
{"title":"Reassessing DMSO–lipid interactions: Improved AMBER force fields emphasize solvent rather than bilayer effects in cryoprotection","authors":"Ivan Klbik , Milan Melicherčík , Dušan Račko , Igor Maťko , Ján Lakota , Ondrej Šauša","doi":"10.1016/j.bbamem.2025.184481","DOIUrl":"10.1016/j.bbamem.2025.184481","url":null,"abstract":"<div><div>The interaction of dimethyl sulfoxide (DMSO) with lipid membranes has been extensively studied using molecular dynamics (MD) simulations, yet discrepancies with experimental findings persist. Here, we re-evaluate the effects of low DMSO concentrations (1.5–10 vol%) on dimyristoyl phosphatidylcholine (DMPC) membranes using updated AMBER force fields (LIPID17, OPC, GAFF2) to assess its cryoprotective role. Simulations were performed in both fluid (330<em>K</em>) and gel (260 K) phases as well as under ice-forming conditions. Across three independent replicas, no statistically significant effects of DMSO were detected on membrane thickness, area per lipid, hydration, or acyl-chain order, indicating that low levels of DMSO do not alter bilayer structure. This represents an improvement over earlier force-field descriptions, which often exaggerated DMSO–lipid interactions, and provides results more consistent with experimental evidence. DMSO showed mild enrichment at the hydrophobic–hydrophilic interface, particularly near carbonyl and glycerol groups, but most molecules remained in the solvent. The strongest effects therefore emerged in the solvent phase: DMSO slowed ice crystal growth by about a factor of five, was excluded from the ice lattice, and accumulated at the ice–membrane boundary forming an ice-free layer. Surprisingly, even without DMSO, ice formation in contact with the bilayer did not cause structural disruption, suggesting that cryoinjury involves additional membrane components beyond lipids. DMSO also strongly inhibited the temperature-driven variation of water density in the amorphous state. These findings suggest that at low concentrations, DMSO's cryoprotective action arises mainly from modulation of water and ice behavior rather than direct bilayer perturbation.</div></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184481"},"PeriodicalIF":2.5,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145480817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-31DOI: 10.1016/j.bbamem.2025.184480
Kevin F. dos Santos , Luciano Caseli
The entry of SARS-CoV-2 into host cells primarily involves binding of the viral spike (S) protein to the angiotensin-converting enzyme 2 (ACE2) receptor and subsequent fusion of the viral envelope with the host membrane, a process facilitated by host proteases such as transmembrane serine protease 2 (TMPRSS2). Lipid raft domains are believed to influence this internalization pathway, although the precise localization and functional roles of ACE2 and TMPRSS2 within these domains remain unclear. In this study, we employed mixed Langmuir monolayers—representing the plasma membrane (PM) and two lipid raft models (LR and Chol/SM)—to investigate the interfacial behavior of ACE2 and TMPRSS2 fragments. Using tensiometric, microscopic, and spectroscopic techniques, we found that both proteins were more readily incorporated into fluid and loosely packed monolayers (PM and LR), leading to increased molecular area and disruption of lipid organization. In contrast, the tightly packed Chol/SM monolayer exhibited minimal changes, indicating limited protein insertion. These results demonstrate that monolayer composition and packing significantly influence protein incorporation and arrangement, which may in turn affect their accessibility to viral components. Although lipid rafts are proposed sites of ACE2 and TMPRSS2 enrichment, our findings suggest that their structural organization within such domains may be modulated by the physicochemical properties of the surrounding lipid environment, with potential implications for SARS-CoV-2 infection mechanisms.
{"title":"Investigating the role of lipid monolayer properties in ACE2 and TMPRSS2 incorporation","authors":"Kevin F. dos Santos , Luciano Caseli","doi":"10.1016/j.bbamem.2025.184480","DOIUrl":"10.1016/j.bbamem.2025.184480","url":null,"abstract":"<div><div>The entry of SARS-CoV-2 into host cells primarily involves binding of the viral spike (S) protein to the angiotensin-converting enzyme 2 (ACE2) receptor and subsequent fusion of the viral envelope with the host membrane, a process facilitated by host proteases such as transmembrane serine protease 2 (TMPRSS2). Lipid raft domains are believed to influence this internalization pathway, although the precise localization and functional roles of ACE2 and TMPRSS2 within these domains remain unclear. In this study, we employed mixed Langmuir monolayers—representing the plasma membrane (PM) and two lipid raft models (LR and Chol/SM)—to investigate the interfacial behavior of ACE2 and TMPRSS2 fragments. Using tensiometric, microscopic, and spectroscopic techniques, we found that both proteins were more readily incorporated into fluid and loosely packed monolayers (PM and LR), leading to increased molecular area and disruption of lipid organization. In contrast, the tightly packed Chol/SM monolayer exhibited minimal changes, indicating limited protein insertion. These results demonstrate that monolayer composition and packing significantly influence protein incorporation and arrangement, which may in turn affect their accessibility to viral components. Although lipid rafts are proposed sites of ACE2 and TMPRSS2 enrichment, our findings suggest that their structural organization within such domains may be modulated by the physicochemical properties of the surrounding lipid environment, with potential implications for SARS-CoV-2 infection mechanisms.</div></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184480"},"PeriodicalIF":2.5,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145430323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-25DOI: 10.1016/j.bbamem.2025.184478
Paulo Henrique Lima do Nascimento , Kevin Figueiredo dos Santos , Cristiano Giordani , Joelle Mergola-Greef , Marcel Jaspars , Luciano Caseli
Patellamides are cyclic pseudo-octapeptides derived from marine cyanobacteria with promising selective cytotoxic, antimicrobial, and neuroprotective activities. While their biological potential is increasingly recognized, the mechanisms underlying their interaction with lipid membranes remain poorly understood. In this study, we investigated the interfacial behavior of patellamide D using Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoserine (DPPS), which model the outer leaflets of healthy and cancer cell membranes, respectively. Surface pressure–area isotherms, compressional modulus analysis, surface potential measurements, Brewster angle microscopy, Polarization-modulated infrared reflection-absorption spectroscopy, and interfacial rheology were employed to elucidate peptide–lipid interactions. Patellamide exhibited a lipid-specific condensing effect and induced subtle reorganization within the monolayers, particularly in anionic DPPS films. Despite these interactions, the compressional and viscoelastic properties of the monolayers were largely preserved, suggesting stable incorporation of the peptide without compromising film integrity. These findings reveal that patellamide can modulate lipid packing and interface properties in a selective and controlled manner. Such behavior underscores its potential in the design of membrane-active therapeutic agents and lipid-based drug delivery systems.
{"title":"Patellamide–lipid interactions at the air–water interface: Biophysical insights into membrane modulation","authors":"Paulo Henrique Lima do Nascimento , Kevin Figueiredo dos Santos , Cristiano Giordani , Joelle Mergola-Greef , Marcel Jaspars , Luciano Caseli","doi":"10.1016/j.bbamem.2025.184478","DOIUrl":"10.1016/j.bbamem.2025.184478","url":null,"abstract":"<div><div>Patellamides are cyclic pseudo-octapeptides derived from marine cyanobacteria with promising selective cytotoxic, antimicrobial, and neuroprotective activities. While their biological potential is increasingly recognized, the mechanisms underlying their interaction with lipid membranes remain poorly understood. In this study, we investigated the interfacial behavior of patellamide D using Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoserine (DPPS), which model the outer leaflets of healthy and cancer cell membranes, respectively. Surface pressure–area isotherms, compressional modulus analysis, surface potential measurements, Brewster angle microscopy, Polarization-modulated infrared reflection-absorption spectroscopy, and interfacial rheology were employed to elucidate peptide–lipid interactions. Patellamide exhibited a lipid-specific condensing effect and induced subtle reorganization within the monolayers, particularly in anionic DPPS films. Despite these interactions, the compressional and viscoelastic properties of the monolayers were largely preserved, suggesting stable incorporation of the peptide without compromising film integrity. These findings reveal that patellamide can modulate lipid packing and interface properties in a selective and controlled manner. Such behavior underscores its potential in the design of membrane-active therapeutic agents and lipid-based drug delivery systems.</div></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184478"},"PeriodicalIF":2.5,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-20DOI: 10.1016/j.bbamem.2025.184477
Eric Umehara , Carlos Henrique T. dos Santos , Laura F. da Silva , Fernanda Thevenard , André G. Tempone , Matheus E. Rosa , Luciano Caseli , João Henrique G. Lago
This study evaluated the antiprotozoal activity of viscidone, an acetophenone isolated from Baccharis retusa, against trypomastigote forms of Trypanosoma cruzi. Viscidone showed potent antiparasitic effects (EC₅₀ = 21.3 ± 1.4 μM), comparable to benznidazole, and exhibited no cytotoxicity toward NCTC mammalian cells (CC₅₀ > 200 μM), resulting in a selectivity index (SI) higher than 9.4. To explore its mechanism of action, biophysical analyses using DPPE Langmuir monolayers as biomimetic membranes revealed that viscidone strongly interacts with lipid interfaces - expanding monolayers, decreasing compressional and viscoelastic moduli, and inducing microdomain formation, as observed by Brewster angle microscopy. These results indicate that viscidone disrupts PE-rich lipid domains, a hallmark of protozoan membranes. Its ability to insert into lipid layers under high surface pressures and its synergistic behavior with the membrane matrix support membrane perturbation as a likely mechanism underlying its antiparasitic effect. Overall, this multidisciplinary study identifies viscidone as a promising lead for antitrypanosomal drug development and highlights the value of membrane biophysics in antiparasitic research.
{"title":"Exploring the antitrypanosomal activity of viscidone, an acetophenone derivative from Baccharis retusa (Asteraceae), using biomembrane models","authors":"Eric Umehara , Carlos Henrique T. dos Santos , Laura F. da Silva , Fernanda Thevenard , André G. Tempone , Matheus E. Rosa , Luciano Caseli , João Henrique G. Lago","doi":"10.1016/j.bbamem.2025.184477","DOIUrl":"10.1016/j.bbamem.2025.184477","url":null,"abstract":"<div><div>This study evaluated the antiprotozoal activity of viscidone, an acetophenone isolated from <em>Baccharis retusa</em>, against trypomastigote forms of <em>Trypanosoma cruzi</em>. Viscidone showed potent antiparasitic effects (EC₅₀ = 21.3 ± 1.4 μM), comparable to benznidazole, and exhibited no cytotoxicity toward NCTC mammalian cells (CC₅₀ > 200 μM), resulting in a selectivity index (SI) higher than 9.4. To explore its mechanism of action, biophysical analyses using DPPE Langmuir monolayers as biomimetic membranes revealed that viscidone strongly interacts with lipid interfaces - expanding monolayers, decreasing compressional and viscoelastic moduli, and inducing microdomain formation, as observed by Brewster angle microscopy. These results indicate that viscidone disrupts PE-rich lipid domains, a hallmark of protozoan membranes. Its ability to insert into lipid layers under high surface pressures and its synergistic behavior with the membrane matrix support membrane perturbation as a likely mechanism underlying its antiparasitic effect. Overall, this multidisciplinary study identifies viscidone as a promising lead for antitrypanosomal drug development and highlights the value of membrane biophysics in antiparasitic research.</div></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184477"},"PeriodicalIF":2.5,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-15DOI: 10.1016/j.bbamem.2025.184476
Svetlana I. Pavlova , Victor N. Samartsev , Alexander V. Chulkov , Ekaterina I. Khoroshavina , Mikhail V. Dubinin
This study investigates the interaction between α,ω-hexadecanedioic acid (HDA ()) and сomplex III () electron transport chain in liver mitochondria, focusing on complex formation during succinate and glutamate/malate oxidation. A key emphasis is placed on the “idling” state of , where electron transfer occurs without proton translocation. The decoupling effect of HDA was quantified using three parameters: 1) and : apparent dissociation constants of the complex, calculated based on the total HDA concentration and the HDA quantity within the mitochondrial effective volume, respectively; 2) : the maximal mitochondrial respiration rate under saturating HDA concentrations (as [HDA] approaches infinity); 3) : the HDA concentration at which the decoupling effect () equals half of its maximal value (), where represents the mitochondrial respiration rate in State 4. Methodologies for parameter determination were established through HDA concentration-dependent respiration profiles. Key findings reveal that remains substrate-independent but in contrast to varies with mitochondrial protein concentration. In contrast, and were significantly higher during succinate oxidation compared to glutamate/malate. Classical protonophores 3,5-di(tret-butyl)-4-hydroxybenzylidenemalononitrile (SF6847) and 2,4-dinitrophenol (DNP), as well as chenodeoxycholic acid (CDCA) at low concentrations, increased without affecting , suggesting reduced HDA efficacy. Molecular docking identified potential HDA binding sites on сomplex III. Based on these findings, we discuss a possible mechanism underlying the decoupling action (intrinsic uncoupli
{"title":"α,ω-Hexadecanedioic acid induces proton-translocating decoupling at complex III via Q-cycle disruption: evidence from kinetic and structural analyses","authors":"Svetlana I. Pavlova , Victor N. Samartsev , Alexander V. Chulkov , Ekaterina I. Khoroshavina , Mikhail V. Dubinin","doi":"10.1016/j.bbamem.2025.184476","DOIUrl":"10.1016/j.bbamem.2025.184476","url":null,"abstract":"<div><div>This study investigates the interaction between α,ω-hexadecanedioic acid (HDA (<span><math><mi>D</mi></math></span>)) and сomplex III (<span><math><msub><mi>E</mi><mi>III</mi></msub></math></span>) electron transport chain in liver mitochondria, focusing on <span><math><mi>D</mi><msub><mi>E</mi><mi>III</mi></msub></math></span> complex formation during succinate and glutamate/malate oxidation. A key emphasis is placed on the “idling” state of <span><math><mi>D</mi><msub><mi>E</mi><mi>III</mi></msub></math></span>, where electron transfer occurs without proton translocation. The decoupling effect of HDA was quantified using three parameters: 1) <span><math><msubsup><mi>K</mi><mi>d</mi><mi>ap</mi></msubsup></math></span> and <span><math><msubsup><mi>K</mi><mi>d</mi><mo>∗</mo></msubsup></math></span>: apparent dissociation constants of the <span><math><mi>D</mi><msub><mi>E</mi><mi>III</mi></msub></math></span> complex, calculated based on the total HDA concentration and the HDA quantity within the mitochondrial effective volume, respectively; 2) <span><math><msub><mi>J</mi><mi>Dmax</mi></msub></math></span>: the maximal mitochondrial respiration rate under saturating HDA concentrations (as [HDA] approaches infinity); 3) <span><math><msub><mi>K</mi><mn>0.5</mn></msub></math></span>: the HDA concentration at which the decoupling effect (<span><math><msub><mi>J</mi><mi>D</mi></msub><mo>−</mo><msub><mi>J</mi><mn>4</mn></msub></math></span>) equals half of its maximal value (<span><math><msub><mi>J</mi><mi>Dmax</mi></msub><mo>−</mo><msub><mi>J</mi><mn>4</mn></msub></math></span>), where <span><math><msub><mi>J</mi><mn>4</mn></msub></math></span> represents the mitochondrial respiration rate in State 4. Methodologies for parameter determination were established through HDA concentration-dependent respiration profiles. Key findings reveal that <span><math><msubsup><mi>K</mi><mi>d</mi><mi>ap</mi></msubsup></math></span> remains substrate-independent but in contrast to <span><math><msubsup><mi>K</mi><mi>d</mi><mo>∗</mo></msubsup></math></span> varies with mitochondrial protein concentration. In contrast, <span><math><msub><mi>K</mi><mn>0.5</mn></msub></math></span> and <span><math><msub><mi>J</mi><mi>Dmax</mi></msub><mo>/</mo><msub><mi>J</mi><mn>4</mn></msub></math></span> were significantly higher during succinate oxidation compared to glutamate/malate. Classical protonophores 3,5-di(tret-butyl)-4-hydroxybenzylidenemalononitrile (SF6847) and 2,4-dinitrophenol (DNP), as well as chenodeoxycholic acid (CDCA) at low concentrations, increased <span><math><msubsup><mi>K</mi><mi>d</mi><mi>ap</mi></msubsup></math></span> without affecting <span><math><msub><mi>J</mi><mi>Dmax</mi></msub><mo>/</mo><msub><mi>J</mi><mn>4</mn></msub></math></span>, suggesting reduced HDA efficacy. Molecular docking identified potential HDA binding sites on сomplex III. Based on these findings, we discuss a possible mechanism underlying the decoupling action (intrinsic uncoupli","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184476"},"PeriodicalIF":2.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell membranes provide vital biological functions by separating the cell components from the surrounding environment and providing a bioactive interface for several biological processes. The direct extraction of intact cell membranes and their investigation with biophysical methods is heavily limited by their compositional complexity and intrinsic fragility. Therefore, over the years, membrane models including vesicles, lipid monolayers, supported lipid bilayers and lipid multilayers, were suggested as alternatives to study the physico-chemical properties of cell membranes. These membrane models are typically produced with 1-3 synthetic lipid species and their application is therefore restricted by their composition, being too simple as compared to native cell membranes.
In this review, we discuss the latest efforts towards producing more biologically relevant membrane models by utilizing natural lipid extracts. These are produced by extracting and purifying lipids expressed by different types of microbial cells. In part I, we present a detailed discussion of the methods currently available for obtaining the extracts, and in part II, we discuss how to use them for preparing cell membrane models and characterizing their structure. The majority of the discussed studies refer to Escherichia coli and Pichia pastoris glycerophospholipid extracts. For these extracts, optimized extraction and purification protocols were recently reported, which enable the efficient production of both hydrogenous and deuterated natural lipid mixtures. Deuterated lipids are of particular relevance for membrane characterization with techniques such as NMR, vibrational spectroscopies, and neutron scattering. In part III, we provide some future perspectives on the application of the currently available natural lipid extracts as well as on the development of protocols for the production of extracts from other cell types, e.g. mammalian cells and for isolating individual lipid molecules from such extracts. We also discuss methods to design genetically engineer microbial strains for enhancing the biosynthesis of target lipid molecules.
{"title":"Designing biologically-relevant cell membrane models with natural lipid mixtures","authors":"Krishna Chaithanya Batchu , Giacomo Corucci , Valérie Laux , Frank Gabel , Giovanna Fragneto , Alessandra Luchini","doi":"10.1016/j.bbamem.2025.184474","DOIUrl":"10.1016/j.bbamem.2025.184474","url":null,"abstract":"<div><div>Cell membranes provide vital biological functions by separating the cell components from the surrounding environment and providing a bioactive interface for several biological processes. The direct extraction of intact cell membranes and their investigation with biophysical methods is heavily limited by their compositional complexity and intrinsic fragility. Therefore, over the years, membrane models including vesicles, lipid monolayers, supported lipid bilayers and lipid multilayers, were suggested as alternatives to study the physico-chemical properties of cell membranes. These membrane models are typically produced with 1-3 synthetic lipid species and their application is therefore restricted by their composition, being too simple as compared to native cell membranes.</div><div>In this review, we discuss the latest efforts towards producing more biologically relevant membrane models by utilizing natural lipid extracts. These are produced by extracting and purifying lipids expressed by different types of microbial cells. In part I, we present a detailed discussion of the methods currently available for obtaining the extracts, and in part II, we discuss how to use them for preparing cell membrane models and characterizing their structure. The majority of the discussed studies refer to <em>Escherichia coli</em> and <em>Pichia pastoris</em> glycerophospholipid extracts. For these extracts, optimized extraction and purification protocols were recently reported, which enable the efficient production of both hydrogenous and deuterated natural lipid mixtures. Deuterated lipids are of particular relevance for membrane characterization with techniques such as NMR, vibrational spectroscopies, and neutron scattering. In part III, we provide some future perspectives on the application of the currently available natural lipid extracts as well as on the development of protocols for the production of extracts from other cell types, e.g. mammalian cells and for isolating individual lipid molecules from such extracts. We also discuss methods to design genetically engineer microbial strains for enhancing the biosynthesis of target lipid molecules.</div></div>","PeriodicalId":8831,"journal":{"name":"Biochimica et biophysica acta. Biomembranes","volume":"1868 1","pages":"Article 184474"},"PeriodicalIF":2.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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