Phospholipids in the fusion and division of biological membranes

I. Correlation between Phospholipid Structural Characteristics and Membrane Dynamics

As the basic skeleton of biological membranes, phospholipids (with polar heads + hydrophobic tails) endow membrane systems with unique physicochemical properties:

Bilayer fluidity: The saturation of fatty acid chains in phospholipid tails (e.g., presence of unsaturated bonds) determines membrane phase transition temperature. For example, phospholipids containing oleic acid (monounsaturated fatty acid) maintain liquid fluidity at physiological temperatures, providing a structural basis for fusion and fission.

Charge and curvature preference: Differences in phospholipid head groups (e.g., phosphatidylcholine PC is electrically neutral, phosphatidylserine PS is negatively charged) affect membrane surface charge and bending tendency. Negatively charged phospholipids (e.g., PS, phosphatidylinositol PI) tend to induce negative membrane curvature, while neutral phospholipids like PC maintain planar membrane structures.

II. Core Mechanisms of Phospholipids in Membrane Fusion

Membrane fusion is crucial for endocytosis, exocytosis, viral entry, etc., with phospholipids regulating this dynamics via:

1. Membrane Curvature Induction and Lipid Rearrangement

Specific phospholipid enrichment: Before synaptic vesicle fusion with the cell membrane, presynaptic membranes enrich PI(4,5)P₂ (phosphatidylinositol-4,5-bisphosphate). Its negatively charged head binds to membrane proteins (e.g., Synaptotagmin), inducing local positive curvature (protrusion) to bring vesicles close to target membranes.

Fusion pore formation: When membrane distance shortens to <1.5nm, hydrophobic interactions of phospholipid tails drive lipid rearrangement, forming temporary "fusion pores". For instance, influenza virus envelope protein HA inserts into the host membrane, inducing lipid exchange between host membrane PC and viral membrane phosphatidylethanolamine (PE), reducing fusion energy barriers.

2. Regulation by Phospholipases and Lipid Signaling Molecules

Role of phospholipase A₂ (PLA₂): During exocytosis, Ca²⁺ activates PLA₂ to hydrolyze phospholipids, releasing arachidonic acid (AA) and lysophospholipids. The single-chain structure of lysophospholipids enhances membrane bending, promoting secretory vesicle fusion with the cell membrane. For example, increased PLA₂ activity during insulin secretion in pancreatic β-cells boosts fusion efficiency by 50%.

Lipid regulation by second messengers: Phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P₃) as an intracellular signal recruits fusion-related proteins (e.g., Rabs, SNAREs) to the membrane, while altering local phospholipid composition (e.g., PE enrichment) reduces membrane fusion energy thresholds.

III. Driving Mechanisms of Phospholipids in Membrane Fission

Membrane fission is essential for vesicle formation, viral budding, etc., with phospholipids completing this process via physical properties and protein synergy:

1. Membrane Fission by Negative Curvature Lipids

Curvature effect of PE: The conical structure of PE (small head, large tail) induces negative membrane curvature (indentation), critical for clathrin-coated vesicle neck constriction during endocytosis. Studies show inhibiting intracellular PE synthesis reduces endocytic vesicle fission efficiency by 70%.

Auxiliary role of phosphatidylglycerol (PG): In bacterial cell division, PG and diphosphatidylglycerol (cardiolipin) enrich at fission sites, recruiting fission protein FtsZ via charge interactions. Their negatively charged heads promote local membrane constriction, driving mother cell division into daughter cells.

2. Synergy between Dynamin and Phospholipids

Mechanical-lipid coupling of Dynamin: During endocytosis, GTPase Dynamin assembles into a spiral ring at the vesicle neck. The mechanical force from GTP hydrolysis synergizes with neck-enriched PE. PE’s negative curvature reduces membrane fission energy, making Dynamin contraction more likely to cause fission. In vitro reconstitution shows membrane fission efficiency mediated by Dynamin decreases by 90% without PE.

IV. Examples of Phospholipid Regulation in Pathophysiology

Lipid strategies in viral infection: HIV budding selectively enriches host membrane cholesterol and PS. PS’s negative charge promotes viral envelope fission from the host membrane, while cholesterol enhances membrane rigidity for viral particle integrity. Blocking PS enrichment at budding sites reduces HIV release by 80%.

Lipid imbalance in neurodegenerative diseases: In Alzheimer’s disease (AD) patients, abnormal phospholipase activity increases membrane phospholipid (e.g., PC) degradation and PE ratio. Abnormal membrane curvature may promote β-amyloid (Aβ) aggregation, exacerbating neuronal damage.

V. Frontier Research Directions

Artificial membrane fusion systems: Designing biomimetic liposomes for drug delivery based on phospholipid properties. For example, pH-sensitive phospholipids (e.g., dioleoyl phosphatidylethanolamine DOPE) undergo phase transition under acidic tumor microenvironments, promoting liposome fusion with cancer cell membranes. In vivo experiments show 3-fold higher tumor targeting efficiency than ordinary liposomes.

Single-molecule level lipid dynamics monitoring: Real-time observation of phospholipid rearrangement trajectories during membrane fusion/fission using atomic force microscopy (AFM) and fluorescence resonance energy transfer (FRET). Recent studies find PE molecules rearrange within 10⁻³ seconds during fusion pore formation, providing data for transient dynamic regulation.

Conclusion

Phospholipids are not only the structural basis of biological membranes but also "molecular switches" for membrane fusion and fission—precisely regulating intracellular material transport and morphological changes through physical properties (curvature, charge, fluidity) and protein machinery synergy. Deepening the understanding of phospholipid roles in membrane dynamics not only sheds light on the essence of life processes but also opens new research directions for antiviral drug design, nanodrug delivery, and other applications.