Amphiphilic molecules, such as alcohols or other bioproducts, are known to partition into cellular membranes, ultimately leading to membrane thinning, destabilization, loss of membrane potential, and finally, cell death. This accepted picture of solvent toxicity does not consider the disruptive impact of co-solvent partitioning upon membrane lateral organization.  Lateral features (rafts or functional microdomains) are an increasing recognized characteristic of cell membrane architecture, acting as platforms for membrane protein sorting and oligomerization. This work explores the hypothesis that co-solvent partitioning leads to alteration of lipid phase behavior at concentrations below those which would induce a loss of membrane potential. Such alteration or disruption of membrane domains is known to have deleterious effects on cells and cellular processes. We experimentally demonstrate co-solvent induced changes to membrane phase behavior in a well-studied phase-separating model membrane system using a combination of fluorescent microscopy, small angle neutron scattering (SANS) and molecular dynamics (MD) simulations. We observe differential partitioning of EtOH between the coexisting phases, with greater EtOH partitioning into the more disordered phase, in addition to a marked thinning and softening of the bilayer. Crucially, this manifests as an increasing thickness mismatch between the co-existing phases upon exposure to co-solvent. A greater mismatch between phases leads to increased line tension, favoring larger and/or more circular domains with a lower interfacial length to area ratio. This is consistent with our observations and represents a physical basis for the disruptive effects of co-solvent partitioning upon lateral organization in cellular membranes. This would be a novel mechanism of cellular stress and represents a new target for fermentation optimization and/or therapeutic intervention.

Physical basis for co-solvent disruption of membrane phase behavior

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