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1. Semipermeable Mixed Phospholipid-Fatty Acid Membranes Exhibit K+/Na+ Selectivity in the Absence of Proteins

   https://doi.org/10.3390/life10040039  

   Zhou, Xianfeng; Dalai, Punam; Sahai, Nita (April 2020, Life)

   Two important ions, K+ and Na+, are unequally distributed across the contemporary phospholipid-based cell membrane because modern cells evolved a series of sophisticated protein channels and pumps to maintain ion gradients. The earliest life-like entities or protocells did not possess either ion-tight membranes or ion pumps, which would result in the equilibration of the intra-protocellular K+/Na+ ratio with that in the external environment. Here, we show that the most primitive protocell membranes composed of fatty acids, that were initially leaky, would eventually become less ion permeable as their membranes evolved towards having increasing phospholipid contents. Furthermore, these mixed fatty acid-phospholipid membranes selectively retain K+ but allow the passage of Na+ out of the cell. The K+/Na+ selectivity of these mixed fatty acid-phospholipid semipermeable membranes suggests that protocells at intermediate stages of evolution could have acquired electrochemical K+/Na+ ion gradients in the absence of any macromolecular transport machinery or pumps, thus potentially facilitating rudimentary protometabolism. 

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2. Homeostatic regulation of intrinsic lipid curvature in eukaryotic cells

   https://doi.org/10.1101/2025.10.13.682232  

   Milshteyn, Daniel; Winnikoff, Jacob R; Kocharian, Elida; Armando, Aaron M; Dennis, Edward A; Girguis, Peter R; Budin, Itay (October 2025, bioRxiv)

   Abstract Cell membranes are composed of both bilayer-supporting and non-bilayer phospholipids, with the latter’s negative intrinsic curvature aiding in membrane trafficking and the dynamics of membrane proteins. Phospholipid metabolism has long been recognized to maintain membrane fluidity, but whether it also acts to maintain the function of high-curvature lipids is not resolved. Here, we find that cells grown under hydrostatic pressure – used to artificially reduce lipid curvature – maintain lipidome curvature through metabolic acclimation. We first observed that manipulation of the lipidome curvature via the phosphatidylethanolamine (PE) to phosphatidylcholine (PC) ratio affects high-pressure growth and viability of yeast independently of membrane fluidity. In wild-type cells, X-ray scattering measurements revealed an increased propensity for lipid extracts to form non-lamellar phases after extended pressure incubations. Unexpectedly, this change in phase behavior was not due to increased levels of PE, but of phosphatidylinositol (PI), the only major phospholipid class whose curvature had not been previously characterized. We found that PI is a non-bilayer lipid, with a negative curvature intermediate to that of PE and PC. Accounting for PI, mean lipidome curvature was defended in response to pressure by two distantly related yeasts. Lipidome curvature also responded to pressure in a human cancer cell line through ether phospholipid metabolism and chain remodeling, but not in bacterial cells. These findings indicate that eukaryotic phospholipid metabolism uses diverse mechanisms to maintain curvature frustration in cell membranes. 

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3. Opsins are phospholipid scramblases in all domains of life

   https://doi.org/10.1128/mbio.03278-25  

   Maschmann, Zachary A; Hardy, David E; Menon, Indu; Webb, Jenna; Menon, Anant K; Forest, Katrina T (January 2026, mBio)

   Laub, Michael T (Ed.)

   ABSTRACT Opsins are highly abundant retinal proteins in the membranes of photoheterotrophic bacteria. However, some microbial genomes encode anopsinbut lack the gene for the final enzyme in retinal synthesis. To account for this paradox, we hypothesized that bacterial opsins play a role in membrane structure and/or biogenesis independent of their potential for light-driven signaling or proton pumping. After purifying actinorhodopsin from a cell-free expression system and fromEscherichia colimembranes upon overexpression, we demonstrated bothin vitroandin silicothat actinorhodopsin fromNanopelagicus ca. is a phospholipid scramblase, serving in its pentameric state as a retinal-independent phospholipid diffusion channel. Phospholipid headgroups move along a transbilayer path between actinorhodopsin protomers to equilibrate lipid content in the inner and outer leaflets. Two profound activities, membrane biosynthesis and capture of light energy, are thus facilitated by one ancient bacterial polypeptide. Light-dependent activity and light-independent phospholipid scrambling are shared functions of eukaryotic, archaeal, and bacterial rhodopsins.IMPORTANCECells are surrounded by membranes that concentrate metabolites and protect cellular contents. Most biomembranes are phospholipid bilayers, in which the phospholipids of each leaflet orient their greasy tails inward and polar groups outward. Bilayer biogenesis depends on phospholipids synthesized on the cytofacial side of the membrane reorienting to the extracellular membrane leaflet. This reorientation requires proteins, termed scramblases, and it was shown that rhodopsins—7-helix photoactive membrane proteins bound to the cofactor retinal—from organisms as widely divergent as mammals and archaea possess scramblase activity. Now we conclusively demonstrate, using purified proteins in laboratory membranes as well as computational approaches, that bacterial rhodopsins are also phospholipid scramblases. This work is important because it highlights a surprising commonality among bacteria, archaea, and eukaryotes and because it shows that rhodopsins—ancient proteins found in the last universal common ancestor—manifest two seemingly unrelated biochemical functions in one protein. 

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4. Hybrid Protocells Based on Coacervate‐Templated Fatty Acid Vesicles Combine Improved Membrane Stability with Functional Interior Protocytoplasm

   https://doi.org/10.1002/smll.202406671  

   Lee, Jessica; Pir_Cakmak, Fatma; Booth, Richard; Keating, Christine D (October 2024, Small)

   Abstract Prebiotically‐plausible compartmentalization mechanisms include membrane vesicles formed by amphiphile self‐assembly and coacervate droplets formed by liquid–liquid phase separation. Both types of structures form spontaneously and can be related to cellular compartmentalization motifs in today's living cells. As prebiotic compartments, they have complementary capabilities, with coacervates offering excellent solute accumulation and membranes providing superior boundaries. Herein, protocell models constructed by spontaneous encapsulation of coacervate droplets by mixed fatty acid/phospholipid and by purely fatty acid membranes are described. Coacervate‐supported membranes form over a range of coacervate and lipid compositions, with membrane properties impacted by charge–charge interactions between coacervates and membranes. Vesicles formed by coacervate‐templated membrane assembly exhibit profoundly different permeability than traditional fatty acid or blended fatty acid/phospholipid membranes without a coacervate interior, particularly in the presence of magnesium ions (Mg²⁺). While fatty acid and blended membrane vesicles are disrupted by the addition of Mg²⁺, the corresponding coacervate‐supported membranes remain intact and impermeable to externally‐added solutes. With the more robust membrane, fluorescein diacetate (FDA) hydrolysis, which is commonly used for cell viability assays, can be performed inside the protocell model due to the simple diffusion of FDA and then following with the coacervate‐mediated abiotic hydrolysis to fluorescein. 

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5. Physical insights into biological memory using phospholipid membranes

   https://doi.org/10.1140/epje/s10189-023-00391-7  

   Bolmatov, Dima; Collier, C Patrick; Katsaras, John; Lavrentovich, Maxim O (January 2024, The European Physical Journal E)

   Electrical signals may propagate along neuronal membranes in the brain, thus enabling communication between nerve cells. In doing so, lipid bilayers, fundamental scaffolds of all cell membranes, deform and restructure in response to such electrical activity. These changes impact the electromechanical properties of the membrane, which then physically store biological memory. This memory can exist either over a short or long period of time. Traditionally, biological memory is defined by the strengthening or weakening of transmissions between individual neurons. Here, we show that electrical stimulation may also alter the properties of the lipid membrane, thus pointing toward a novel mechanism for memory storage. Furthermore, based on the analysis of existing electrophysiological data, we study molecular mechanisms underlying the long-term potentiation in phospholipid membranes. Finally, we examine possible relationships between the memory capacitive properties of lipid membranes, neuronal learning, and memory. 

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