Coupling between membrane undulations and lipid curvature leads to transient local enrichment of cardiolipin in mitochondrial membranes

Organelles such as mitochondria have characteristic shapes that are critical to their function. Recent efforts have revealed that the curvature contributions of individual lipid species can be a factor in the generation of membrane shape in these organelles. Inspired by lipidomics data from yeast mitochondrial membranes, we used Martini coarse-grained molecular dynamics simulations to investigate how lipid composition facilitates membrane shaping. We found that increasing lipid saturation increases bending rigidity while reducing the monolayer spontaneous curvature. We also found that systems containing cardiolipin exhibited decreased bending rigidity and increased spontaneous curvature when compared to bilayers containing its precursor, phosphatidylglycerol. This finding contradicts some prior experimental results that suggest that bilayers containing tetraoleoyl cardiolipin have greater rigidity than dioleoyl phosphatidylcholine bilayers. To investigate this discrepancy, we analyzed our simulations for correlations between lipid localization and local curvature. We found that there are transient correlations between curved lipids such as cardiolipin (CDL) and phosphatidylethanolamine (PE) and curvature; these interactions enrich specific bilayer undulatory modes and cause bilayer softening. Furthermore, we show that curvature-localization of some lipids such as cardiolipin can influence lipids in the opposing leaflet. These observations add to the emerging evidence that lipid geometric features give rise to local interactions, which can cause membrane compositional heterogeneities. The cross-talk between composition-driven tuning of membrane properties and membrane shape has implications for membrane organization and its related functions. SIGNIFICANCEThe material properties of phospholipid membranes are a function of the lipid composition. Theabundance of cardiolipin in the mitochondrial inner membrane implies a functional role for this special lipid. We explore the interactions of cardiolipin with other lipids with varying lipid saturation using coarse-grained molecular dynamics simulations. We find that membranes containing cardiolipin have higher spontaneous curvature and lower bending rigidity when compared to membranes without cardiolipin - in line with prior models and experiments. We also show that the low bending rigidity of cardiolipin-containing symmetric, and flat bilayered systems is due to the transient partitioning of cardiolipin to undulations due to curvature sensing. This is a mechanism for forming lateral membrane heterogeneities in otherwise symmetric systems.