The bile salt/phospholipid ratio determines the extent of in vitro intestinal lipolysis of triglycerides: Interfacial and emulsion studies.

This study focused on the protein-stabilised triglyceride (TG)/water interfaces and oil-in-water emulsions, and explored the influence of varying molar ratios of bile salts (BSs) and phospholipids (PLs) on the intestinal lipolysis of TGs. The presence of these two major groups of biosurfactants delivered with human bile to the physiological environment of intestinal digestion was replicated in our experiments by using mixtures of individual BSs and PLs under in vitro small intestinal lipolysis conditions. Conducted initially, retrospective analysis of available scientific literature revealed that an average molar ratio of 9:4 for BSs to PLs (BS/PL) can be considered physiological in the postprandial adult human small intestine. Our experimental data showed that combining BSs and PLs synergistically enhanced interfacial activity, substantially reducing oil-water interfacial tension (IFT) during interfacial lipolysis experiments with pancreatic lipase, especially at the BS/PL-9:4 ratio. Other BS/PL molar proportions (BS/PL-6.5:6.5 and BS/PL-4:9) and an equimolar amount of BSs (BS-13) followed in IFT reduction efficiency, while using PLs alone as biosurfactants was the least efficient. In the following emulsion lipolysis experiments, BS/PL-9:4 outperformed other BS/PL mixtures in terms of enhancing the TG digestion extent. The degree of TG conversion and the desorption efficiency of interfacial material post-lipolysis correlated directly with the BS/PL ratio, decreasing as the PL proportion increased. In conclusion, this study highlights the crucial role of biliary PLs, alongside BSs, in replicating the physiological function of bile in intestinal lipolysis of emulsified TGs. Our results showed different contributions of PLs and BSs to lipolysis, strongly suggesting that any future in vitro studies aiming to simulate the human digestion conditions should take into account the impact of biliary PLs - not just BSs - to accurately mimic the physiological role of bile in intestinal lipolysis. This is particularly crucial given the fact that existing in vitro digestion protocols typically focus solely on applying specific concentrations and/or compositions of BSs to simulate the action of human bile during intestinal digestion, while overlooking the presence and concentration of biliary PLs under physiological gut conditions.

The Role of Phospholipid Alterations in Mitochondrial and Brain Dysfunction after Cardiac Arrest.

The human brain possesses three predominate phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), which account for approximately 35-40%, 35-40%, and 20% of the brain's phospholipids, respectively. Mitochondrial membranes are relatively diverse, containing the aforementioned PC, PE, and PS, as well as phosphatidylinositol (PI) and phosphatidic acid (PA); however, cardiolipin (CL) and phosphatidylglycerol (PG) are exclusively present in mitochondrial membranes. These phospholipid interactions play an essential role in mitochondrial fusion and fission dynamics, leading to the maintenance of mitochondrial structural and signaling pathways. The essential nature of these phospholipids is demonstrated through the inability of mitochondria to tolerate alteration in these specific phospholipids, with changes leading to mitochondrial damage resulting in neural degeneration. This review will emphasize how the structure of phospholipids relates to their physiologic function, how their metabolism facilitates signaling, and the role of organ- and mitochondria-specific phospholipid compositions. Finally, we will discuss the effects of global ischemia and reperfusion on organ- and mitochondria-specific phospholipids alongside the novel therapeutics that may protect against injury.

Protective effect of phospholipids in lipoproteins against diabetic kidney disease: A Mendelian randomization analysis.

BACKGROUND: The etiology of diabetic kidney disease is complex, and the role of lipoproteins and their lipid components in the development of the disease cannot be ignored. However, phospholipids are an essential component, and no Mendelian randomization studies have yet been conducted to examine potential causal associations between phospholipids and diabetic kidney disease. METHODS: Relevant exposure and outcome datasets were obtained through the GWAS public database. The exposure datasets included various phospholipids, including those in LDL, IDL, VLDL, and HDL. IVW methods were the primary analytical approach. The accuracy of the results was validated by conducting heterogeneity, MR pleiotropy, and F-statistic tests. MR-PRESSO analysis was utilized to identify and exclude outliers. RESULTS: Phospholipids in intermediate-density lipoprotein (OR: 0.8439; 95% CI: 0.7268-0.9798), phospholipids in large low- density lipoprotein (OR: 0.7913; 95% CI: 0.6703-0.9341), phospholipids in low- density lipoprotein (after removing outliers, OR: 0.788; 95% CI: 0.6698-0.9271), phospholipids in medium low- density lipoprotein (OR: 0.7682; 95% CI: 0.634-0.931), and phospholipids in small low-density lipoprotein (after removing outliers, OR: 0.8044; 95% CI: 0.6952-0.9309) were found to be protective factors. CONCLUSIONS: This study found that a higher proportion of phospholipids in intermediate-density lipoprotein and the various subfractions of low-density lipoprotein, including large LDL, medium LDL, and small LDL, is associated with a lower risk of developing diabetic kidney disease.

Elucidating Daptomycin's Antibacterial Efficacy: Insights into the Tripartite Complex with Lipid II and Phospholipids in Bacterial Septum Membrane.

This study elucidated the mechanism of formation of a tripartite complex containing daptomycin (Dap), lipid II, and phospholipid phosphatidylglycerol in the bacterial septum membrane, which was previously reported as the cause of the antibacterial action of Dap against gram-positive bacteria via molecular dynamics and enhanced sampling methods. Others have suggested that this transient complex ushers in the inhibition of cell wall synthesis by obstructing the downstream polymerization and cross-linking processes involving lipid II, which is absent in the presence of cardiolipin lipid in the membrane. In this work, we observed that the complex was stabilized by Ca2+-mediated electrostatic interactions between Dap and lipid head groups, hydrophobic interaction, hydrogen bonds, and salt bridges between the lipopeptide and lipids and was associated with Dap concentration-dependent membrane depolarization, thinning of the bilayer, and increased lipid tail disorder. Residues Orn6 and Kyn13, along with the DXDG motif, made simultaneous contact with constituent lipids, hence playing a crucial role in the formation of the complex. Incorporating cardiolipin into the membrane model led to its competitively displacing lipid II away from the Dap, reducing the lifetime of the complex and the nonexistence of lipid tail disorder and membrane depolarization. No evidence of water permeation inside the membrane hydrophobic interior was noted in all of the systems studied. Additionally, it was shown that using hydrophobic contacts between Dap and lipids as collective variables for enhanced sampling gave rise to a free energy barrier for the translocation of the lipopeptide. A better understanding of Dap's antibacterial mechanism, as studied through this work, will help develop lipopeptide-based antibiotics for rising Dap-resistant bacteria.

Molecular mechanisms of ferroptosis and its effects on bladder cancer. / é“æ­»äº¡çš„åˆ†å­æœºåˆ¶åŠå ¶å¯¹è†€èƒ±ç™Œçš„å½±å“.

Bladder cancer (BC) is one of the 3 common malignant tumors in the urinary system, with high incidence, easy metastasis, poor therapeutic efficacy, and poor prognosis, which seriously threatens the health of human. Tumor cells exhibit a strong demand for iron, and iron overload can induce ferroptosis, which is an iron dependent cell death caused by lipid peroxidation and cell membrane damage. Therefore, ferroptosis has strong anti-tumor potential. The molecular mechanisms of ferroptosis is associated with abnormalities in cellular phospholipid metabolism and iron metabolism, and dysregulation of antioxidant and non-antioxidant systems Xc-/glutathione (GSH)/glutathione peroxidase 4 (GPX4). Ferroptosis relevant molecules play important roles in the occurrence and development, metastasis, drug resistance, and immune response of BC, and are expected to become targets for the treatment of BC.

Nitrogen starvation causes lipid remodeling in Rhodotorula toruloides.

BACKGROUND: The oleaginous yeast Rhodotorula toruloides is a promising chassis organism for the biomanufacturing of value-added bioproducts. It can accumulate lipids at a high fraction of biomass. However, metabolic engineering efforts in this organism have progressed at a slower pace than those in more extensively studied yeasts. Few studies have investigated the lipid accumulation phenotype exhibited by R. toruloides under nitrogen limitation conditions. Consequently, there have been only a few studies exploiting the lipid metabolism for higher product titers. RESULTS: We performed a multi-omic investigation of the lipid accumulation phenotype under nitrogen limitation. Specifically, we performed comparative transcriptomic and lipidomic analysis of the oleaginous yeast under nitrogen-sufficient and nitrogen deficient conditions. Clustering analysis of transcriptomic data was used to identify the growth phase where nitrogen-deficient cultures diverged from the baseline conditions. Independently, lipidomic data was used to identify that lipid fractions shifted from mostly phospholipids to mostly storage lipids under the nitrogen-deficient phenotype. Through an integrative lens of transcriptomic and lipidomic analysis, we discovered that R. toruloides undergoes lipid remodeling during nitrogen limitation, wherein the pool of phospholipids gets remodeled to mostly storage lipids. We identify specific mRNAs and pathways that are strongly correlated with an increase in lipid levels, thus identifying putative targets for engineering greater lipid accumulation in R. toruloides. One surprising pathway identified was related to inositol phosphate metabolism, suggesting further inquiry into its role in lipid accumulation. CONCLUSIONS: Integrative analysis identified the specific biosynthetic pathways that are differentially regulated during lipid remodeling. This insight into the mechanisms of lipid accumulation can lead to the success of future metabolic engineering strategies for overproduction of oleochemicals.

Essentiality of dietary cholesterol and its interactions with phospholipid in juvenile slipper lobster (Thenus australiensis).

This study was conducted to verify the essentiality of dietary cholesterol for early juvenile slipper lobster, Thenus australiensis (initial weight 4.50 ± 0.72 g, mean ± SD, CV = 0.16), and to explore the potential for interactions between dietary cholesterol and phospholipid. An 8-week experiment was conducted using six experimental feeds containing three supplemental cholesterol concentrations (0, 0.2 and 0.4% dry matter) at two supplemental phospholipid concentrations (0% and 1.0% dry matter). Dietary cholesterol concentrations of ≥ 0.2% resulted in up to threefold greater weight gain compared to 0% dietary cholesterol, but without any significant main or interactive dietary phospholipid effect. An interaction was observed for lobster survival with lowest survival (46%) recorded for combined 0% cholesterol and 0% phospholipid compared to every other treatment (71-100%). However, all surviving lobsters at 0% dietary cholesterol, regardless of dietary phospholipid level, were in poor nutritional condition. Apparent feed intake (AFI) was significantly higher at dietary cholesterol ≥ 0.2% but was lower for each corresponding dietary cholesterol level at 1% dietary phospholipid. This implied that the feed conversion ratio was improved with supplemental phospholipid. In conclusion, this study confirms the essential nature of dietary cholesterol and that dietary phospholipid can provide additional benefits.

YdbH and YnbE form an intermembrane bridge to maintain lipid homeostasis in the outer membrane of Escherichia coli.

The outer membrane (OM) of didermic gram-negative bacteria is essential for growth, maintenance of cellular integrity, and innate resistance to many antimicrobials. Its asymmetric lipid distribution, with phospholipids in the inner leaflet and lipopolysaccharides (LPS) in the outer leaflet, is required for these functions. Lpt proteins form a transenvelope bridge that transports newly synthesized LPS from the inner membrane (IM) to OM, but how the bulk of phospholipids are transported between these membranes is poorly understood. Recently, three members of the AsmA-like protein family, TamB, YhdP, and YdbH, were shown to be functionally redundant and were proposed to transport phospholipids between IM and OM in Escherichia coli. These proteins belong to the repeating ß-groove superfamily, which includes eukaryotic lipid-transfer proteins that mediate phospholipid transport between organelles at contact sites. Here, we show that the IM-anchored YdbH protein interacts with the OM lipoprotein YnbE to form a functional protein bridge between the IM and OM in E. coli. Based on AlphaFold-Multimer predictions, genetic data, and in vivo site-directed cross-linking, we propose that YnbE interacts with YdbH through ß-strand augmentation to extend the continuous hydrophobic ß-groove of YdbH that is thought to shield acyl chains of phospholipids as they travel through the aqueous intermembrane periplasmic compartment. Our data also suggest that the periplasmic protein YdbL prevents extensive amyloid-like multimerization of YnbE in cells. We, therefore, propose that YdbL has a chaperone-like function that prevents uncontrolled runaway multimerization of YnbE to ensure the proper formation of the YdbH-YnbE intermembrane bridge.

The novel molecular mechanism of pulmonary fibrosis: insight into lipid metabolism from reanalysis of single-cell RNA-seq databases.

Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids' biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.

Oxidized phospholipid POVPC contributes to vascular calcification by triggering ferroptosis of vascular smooth muscle cells.

Vascular calcification is an actively regulated biological process resembling bone formation, and osteogenic differentiation of vascular smooth muscle cells (VSMCs) plays a crucial role in this process. 1-Palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), an oxidized phospholipid, is found in atherosclerotic plaques and has been shown to induce oxidative stress. However, the effects of POVPC on osteogenic differentiation and calcification of VSMCs have yet to be studied. In the present study, we investigated the role of POVPC in vascular calcification using in vitro and ex vivo models. POVPC increased mineralization of VSMCs and arterial rings, as shown by alizarin red staining. In addition, POVPC treatment increased expression of osteogenic markers Runx2 and BMP2, indicating that POVPC promotes osteogenic transition of VSMCs. Moreover, POVPC increased oxidative stress and impaired mitochondria function of VSMCs, as shown by increased ROS levels, impairment of mitochondrial membrane potential, and decreased ATP levels. Notably, ferroptosis triggered by POVPC was confirmed by increased levels of intracellular ROS, lipid ROS, and MDA, which were decreased by ferrostatin-1, a ferroptosis inhibitor. Furthermore, ferrostatin-1 attenuated POVPC-induced calcification of VSMCs. Taken together, our study for the first time demonstrates that POVPC promotes vascular calcification via activation of VSMC ferroptosis. Reducing the levels of POVPC or inhibiting ferroptosis might provide a novel strategy to treat vascular calcification.

Membrane phospholipids activate the inflammatory response in macrophages by various mechanisms.

Exosomes, which are small membrane-encapsulated particles derived from all cell types, are emerging as important mechanisms for intercellular communication. In addition, exosomes are currently envisioned as potential carriers for the delivery of drugs to target tissues. The natural population of exosomes is very variable due to the limited amount of cargo components present in these small vesicles. Consequently, common components of exosomes may play a role in their function. We have proposed that membrane phospholipids could be a common denominator in the effect of exosomes on cellular functions. In this regard, we have previously shown that liposomes made of phosphatidylcholine (PC) or phosphatidylserine (PS) induced a robust alteration of macrophage (Mϕ) gene expression. We herewith report that these two phospholipids modulate gene expression in Mϕs by different mechanisms. PS alters cellular responses by the interaction with surface receptors, particularly CD36. In contrast, PC is captured by a receptor-independent process and likely triggers an activity within endocytic vesicles. Despite this difference in the capture mechanisms, both lipids mounted similar gene expression responses. This investigation suggests that multiple mechanisms mediated by membrane phospholipids could be participating in the alteration of cellular functions by exosomes.

Nuclear Phospholipids and Signaling: An Update of the Story.

In the last three decades, the presence of phospholipids in the nucleus has been shown and thoroughly investigated. A considerable amount of interest has been raised about nuclear inositol lipids, mainly because of their role in signaling acting. Here, we review the main issues of nuclear phospholipid localization and the role of nuclear inositol lipids and their related enzymes in cellular signaling, both in physiological and pathological conditions.

Phospholipids Differentially Regulate Ca2+ Binding to Synaptotagmin-1.

Synaptotagmin-1 (Syt-1) is a calcium sensing protein that is resident in synaptic vesicles. It is well established that Syt-1 is essential for fast and synchronous neurotransmitter release. However, the role of Ca2+ and phospholipid binding in the function of Syt-1, and ultimately in neurotransmitter release, is unclear. Here, we investigate the binding of Ca2+ to Syt-1, first in the absence of lipids, using native mass spectrometry to evaluate individual binding affinities. Syt-1 binds to one Ca2+ with a KD ∼ 45 µM. Each subsequent binding affinity (n ≥ 2) is successively unfavorable. Given that Syt-1 has been reported to bind anionic phospholipids to modulate the Ca2+ binding affinity, we explored the extent that Ca2+ binding was mediated by selected anionic phospholipid binding. We found that phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and dioleoylphosphatidylserine (DOPS) positively modulated Ca2+ binding. However, the extent of Syt-1 binding to phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) was reduced with increasing [Ca2+]. Overall, we find that specific lipids differentially modulate Ca2+ binding. Given that these lipids are enriched in different subcellular compartments and therefore may interact with Syt-1 at different stages of the synaptic vesicle cycle, we propose a regulatory mechanism involving Syt-1, Ca2+, and anionic phospholipids that may also control some aspects of vesicular exocytosis.

Assessing the negative impact of chlorantraniliprole, isoxaflutole, and simazine pesticides on phospholipid membrane models and tilapia gill tissues.

The indiscriminate and, very often, incorrect use of pesticides in Brazil, as well as in other countries, results in severe levels of environmental pollution and intoxication of human life. Herein, we studied plasma membrane models (monolayer and bilayer) of the phospholipid Dioleoyl-sn-glycerol-3-phosphocholine (DOPC) using Langmuir films, and large (LUVs) and giant (GUVs) unilamellar vesicles, to determine the effect of the pesticides chlorantraniliprole (CLTP), isoxaflutole (ISF), and simazine (SMZ), used in sugarcane. CLTP affects the lipid organization of the bioinspired models of DOPC π-A isotherms, while ISF and SMZ pesticides significantly affect the LUVs and GUVs. Furthermore, the in vivo study of the gill tissue in fish in the presence of pesticides (2.0 × 10-10 mol/L for CLTP, 8.3 × 10-9 mol/L for ISF, and SMZ at 9.9 × 10-9 mol/L) was performed using optical and fluorescence images. This investigation was motivated by the gill lipid membranes, which are vital for regulating transporter activity through transmembrane proteins, crucial for maintaining ionic balance in fish gills. In this way, the presence of phospholipids in gills offers a model for understanding their effects on fish health. Histological results show that exposure to CLTP, ISF, and SMZ may interfere with vital gill functions, leading to respiratory disorders and osmoregulation dysfunction. The results indicate that exposure to pesticides caused severe morphological alterations in fish, which could be correlated with their impact on the bioinspired membrane models. Moreover, the effect does not depend on the exposure period (24h and 96h), showing that animals exposed to pesticides for a short period suffer irreparable damage to gill tissue. In summary, we can conclude that the harm caused by pesticides, both in membrane models and in fish gills, occurs due to contamination of the aquatic system with pesticides. Therefore, water quality is vital for the preservation of ecosystems.

Dehydration of Lipid Membranes Drives Redistribution of Cholesterol Between Lateral Domains.

Cholesterol-rich lipid rafts are found to facilitate membrane fusion, central to processes like viral entry, fertilization, and neurotransmitter release. While the fusion process involves local, transient membrane dehydration, the impact of reduced hydration on cholesterol's structural organization in biological membranes remains unclear. Here, we employ confocal fluorescence microscopy and atomistic molecular dynamics simulations to investigate cholesterol behavior in phase-separated lipid bilayers under controlled hydration. We unveiled that dehydration prompts cholesterol release from raft-like domains into the surrounding fluid phase. Unsaturated phospholipids undergo more significant dehydration-induced structural changes and lose more hydrogen bonds with water than sphingomyelin. The results suggest that cholesterol redistribution is driven by the equalization of biophysical properties between phases and the need to satisfy lipid hydrogen bonds. This underscores the role of cholesterol-phospholipid-water interplay in governing cholesterol affinity for a specific lipid type, providing a new perspective on the regulatory role of cell membrane heterogeneity during membrane fusion.

Polysaccharide intercellular adhesin and proper phospholipid composition are important for aggregation in Tetragenococcus halophilus SL10.

Aggregating strains of Tetragenococcus halophilus tend to be trapped during soy sauce mash-pressing process and are, therefore, critical for clear soy sauce production. However, the precise molecular mechanism involved in T. halophilus aggregation remains elusive. In previous studies, we isolated a number of aggregating strains, including T. halophilus AB4 and AL1, and showed that a cell surface proteinaceous aggregation factor is responsible for their aggregation phenotype. In the present study, we explored the role of polysaccharide intercellular adhesin (PIA) in aggregate formation in T. halophilus SL10, isolated from soy sauce. SL10 exhibited similar aggregation to AB4 and AL1 but formed a non-uniform precipitate with distinctive wrinkles at the bottom of the test tube, unlike AB4 and AL1. Insertion sequence mutations in each gene of the ica operon diminished aggregation and PIA production, highlighting the critical role of IcaADBC-mediated PIA production in T. halophilus aggregation. Furthermore, two non-aggregating cardiolipin synthase (cls) gene mutants with intact ica operon did not produce detectable PIA. Phospholipid composition analysis in cls mutants revealed a decrease in cardiolipin and an increase in phosphatidylglycerol levels, highlighting the association between phospholipid composition and PIA production. These findings provide evidence for the pivotal role of cls in PIA-mediated aggregation and lay the foundation for future studies to understand the intricate networks of the multiple aggregation factors governing microbial aggregation.IMPORTANCEAggregation, commonly observed in various microbes, triggers biofilm formation in pathogenic variants and plays a beneficial role in efficient food production in those used for food production. Here, we showed that Tetragenococcus halophilus, a microorganism used in soy sauce fermentation, forms aggregates in a polysaccharide intercellular adhesin (PIA)-mediated manner. Additionally, we unveiled the relationship between phospholipid composition and PIA production. This study provides evidence for the presence of aggregation factors in T. halophilus other than the proteinaceous aggregation factor and suggests that further understanding of the coordinated action of these factors may improve clarified soy sauce production.

Synthetic Vesicles for Sustainable Energy Recycling and Delivery of Building Blocks for Lipid Biosynthesis†.

ATP is a universal energy currency that is essential for life. l-Arginine degradation via deamination is an elegant way to generate ATP in synthetic cells, which is currently limited by a slow l-arginine/l-ornithine exchange. We are now implementing a new antiporter with better kinetics to obtain faster ATP recycling. We use l-arginine-dependent ATP formation for the continuous synthesis and export of glycerol 3-phosphate by including glycerol kinase and the glycerol 3-phosphate/Pi antiporter. Exported glycerol 3-phosphate serves as a precursor for the biosynthesis of phospholipids in a second set of vesicles, which forms the basis for the expansion of the cell membrane. We have therefore developed an out-of-equilibrium metabolic network for ATP recycling, which has been coupled to lipid synthesis. This feeder-utilizer system serves as a proof-of-principle for the systematic buildup of synthetic cells, but the vesicles can also be used to study the individual reaction networks in confinement.

CHARMM GUI Membrane Builder for oxidized phospholipid membrane modeling and simulation.

Oxidative stress leads to the production of oxidized phospholipids (oxPLs) that modulate the biophysical properties of phospholipid monolayers and bilayers. As many immune cells are responsible for surveilling cells and tissues for the presence of oxPLs, oxPL-dependent mechanisms have been suggested as targets for treating chronic kidney disease, atherosclerosis, diabetes, and cancer metastasis. This review details recent experimental and computational studies that characterize oxPLs' behaviors in various monolayers and bilayers. These studies investigate how the tail length and polar functional groups of OxPLs impact membrane properties, how oxidized membranes can be stabilized, and how membrane integrity is generally affected by oxidized lipids. In addition, for oxPL-containing membrane modeling and simulation, CHARMM-GUI Membrane Builder has been extended to support a variety of oxPLs, accelerating the simulation system building process for these biologically relevant lipid bilayers.

LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth.

The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.

The polarity protein Yurt associates with the plasma membrane via basic and hydrophobic motifs embedded in its FERM domain.

The subcellular distribution of the polarity protein Yurt (Yrt) is subjected to a spatio-temporal regulation in Drosophila melanogaster embryonic epithelia. After cellularization, Yrt binds to the lateral membrane of ectodermal cells and maintains this localization throughout embryogenesis. During terminal differentiation of the epidermis, Yrt accumulates at septate junctions and is also recruited to the apical domain. Although the mechanisms through which Yrt associates with septate junctions and the apical domain have been deciphered, how Yrt binds to the lateral membrane remains as an outstanding puzzle. Here, we show that the FERM domain of Yrt is necessary and sufficient for membrane localization. Our data also establish that the FERM domain of Yrt directly binds negatively charged phospholipids. Moreover, we demonstrate that positively charged amino acid motifs embedded within the FERM domain mediates Yrt membrane association. Finally, we provide evidence suggesting that Yrt membrane association is functionally important. Overall, our study highlights the molecular basis of how Yrt associates with the lateral membrane during the developmental time window where it is required for segregation of lateral and apical domains.