Fusion of lipid membranes: an alternative pathway

Membrane fusion is ubiquitous in myriad biological processes, including presynaptic neurotransmitter release, myoblast fusion, virus entry, and fertilization. It is often considered in the presence of fusogenic proteins, which mediate the fusion by pulling the membranes into contact to overcome the high energy barrier imposed by hydration repulsion. Here we uncover an alternative pathway: membrane fusion arising from electroporation induced by transmembrane potentials in absence of proteins. Using biased molecular dynamics simulations to carry out extensive potential-of-mean-force calculations, we show how electroporation of opposing membranes promotes membrane fusion via formation of an intermembrane splayed lipid and peripore stalk, without any protein involvement. We validate our mechanism by demonstrating experimentally, via video microscopy and second harmonic generation imaging of interacting giant unilamellar vesicles (GUVs), that GUV fusion occurs in the presence of transmembrane potentials but not in their absence. The magnitude of these transmembrane potentials is biologically relevant, prevalent in transient states near the surfaces of cell membranes, underscoring the potential importance of this mechanism in biological events.