LIFE SCIENCES

Abstract

Membrane topology transformations – such as scission, fusion, and pore formation – are driven by membrane tension, curvature stress, and lipid dynamics, playing critical roles in exocytosis and organelle division. The final stage of cellular compartment division involves the scission of a highly constricted membrane neck. Using self-consistent field theory (SCFT), we explore the mechanisms of scission in single- and double-membrane neck structures. In single-membrane tubes, scission proceeds via a leakless hemifusion intermediate. Double-membrane tubes, with greater complexity, exhibit additional pathways involving transient fusion and poration events. Building on our successful exploration of membrane tubes, we extend our study to the mechanisms and control factors cells employ to open pores and eject signaling molecules.

Report

To divide, reorganize cellular compartments, create new organelles, and transport material across membranes, cells rely on membranes undergoing crucial topological transformations. These transformations include scission, fusion, and pore formation and are driven by factors such as membrane tension, curvature stress, and lipid dynamics. The ability of membranes to constrict, divide, or merge is fundamental to processes like organelle division and exocytosis, where precise coordination is needed to maintain cellular integrity and compartmentalization. To gain deeper insights into the mechanisms governing these transformations, we use GPU-accelerated self-consistent field theory (SCFT) calculations combined with the string method [1, 2] to calculate the most likely, i.e.minimum free-energy paths, for these transformations.

In single-membrane systems, scission proceeds via a leakless pathway, involving a hemifusion (HF) intermediate. This process allows the membrane to constrict and divide without allowing the contents to escape, maintaining the integrity of the cell.
This process is not only crucial during organelle division but also plays a key role in exocytosis, where a vesicle, connected to the plasma membrane by a tubular neck, must undergo fission to release signaling molecules. This is illustrated in Figure 1 and explored in Refs. [3, 4]. Aside from the formation and scission of this neck, exocytosis also involves the hemifusion of the vesicle with the membrane and the poration of the fusion site. We explore how these steps occur and discuss the “control knobs” that the cell may use to carefully choreograph the formation, expansion, and closure of the pore in Ref. [5].

Double-membrane tubes present a more complex system, with additional degrees of freedom that allow 2 V1.8-2020DEC02 for multiple fission pathways. Our findings reveal that while the fission process may proceed sequentially – with the inner membrane first undergoing scission through the aforementioned leakless mechanism followed by the outer tube – we also discovered a novel “fission-by-fusion” pathway. In this alternative, transient fusion events between the inner and outer membranes lead to poration and eventual scission [3]. The free-energy landscape for these pathways is shown in Figure 2, where we compare the free-energy
barriers for both, the simple pathway and the more intricate fission-by-fusion route.