Mechanisms to control energy barriers during membrane fusion and fission

Membrane fusion and fission are essential biological processes that mediate material exchange between cellular compartments, organelle maintenance, and trafficking. Both involve extreme membrane deformations, including bending, stretching, and lipid shearing, that create substantial energy barriers. These barriers determine the kinetics of topological transitions and thus set the rate and selectivity of the reactions. Dedicated fusion and fission proteins, such as SNAREs, dynamin, and viral fusogens, act as mechanical engines that drive these transformations by exerting localized forces to overcome the barriers. While many of these events are vital for cell function, such as synaptic vesicle fusion, endocytosis, and mitochondrial fission, others can be detrimental, notably those exploited by enveloped viruses during infection. Beyond the catalytic protein machinery, cells have evolved mechanisms to tune the magnitude of the energy barriers themselves. Depending on physiological context, they can raise barriers to suppress topological changes or lower them to accelerate the processes.

Here, I will review several biophysical mechanisms contributing to this regulation: manipulation of lipid composition and asymmetry (Shendrik et al., Faraday Discuss. 2025), tuning of membrane geometry (Golani et al., Biophys. J. 2023), and modulation of membrane tension (Shendrik et al., ACS Nano 2023; Zucker et al., Biophys. J. 2023). Beyond direct fusion and fission proteins, other proteins can modulate the energy barriers indirectly by inducing lipid sorting near fusion sites (Klein et al., Cell Host Microbe 2023), generating local stress (Winter et al., EMBO J. 2023), or imposing spontaneous curvature that biases membranes toward or against topological change. Together, these mechanisms enable cells to dynamically control the energetic landscape of membrane remodelling, ensuring precise spatial and temporal regulation of fusion and fission.