From reversible to irreversible: When the membrane nanotube pearling is coupled with phase separation

Membrane nanotubes, which are ubiquitous in biology and act as channels maintaining transport between different cells and organelles, readily undergo pearling in response to external stimuli. Membrane nanotube pearling involves generation of heterogeneous curvature coupled with redistribution of membrane components that may interfere with the shape recovery of pearled nanotubes. However, the mechanism underlying such delicate process remains unclear and difficult to study at the molecular scale in vivo. By means of molecular dynamics simulation, here we investigate pearling of multi-component membrane nanotubes and reversibility through manipulating system temperature and osmotic pressure. With the equilibrium shape of membrane nanotubes controlled by the osmotic pressure, our results demonstrate that the process of membrane nanotube pearling can be reversible or irreversible, depending on the phase segregation state. For the pearled nanotube releasing high surface energy, different lipid components redistribute along the tube axial direction. Lipids with unsaturated tails prefer gathering at the high-curvature shrinking region, whereas the swelling region is constituted by saturated lipids forming the liquid-ordered phase of a higher bending rigidity. Such curvature sensitive phase segregation minimizes the system free energy by reducing both the membrane bending energy and line tension at the phase boundary. As such, the pearled nanotube fails to recover its shape upon retracting stimuli, suggesting irreversibility of the membrane nanotube pearling coupled with phase separation. Given importance of membrane nanotube pearling in various cellular activities, these results provide a new mechanism of controlling equilibrium shapes of membrane nanotubes in complex cellular environment.