Driving Spontaneous Membrane Curvature by Tuning Cardiolipin Concentration and Spatial Distribution in Model Mitochondrial Membranes

Cell membranes are complex systems with diverse lipid compositions that contribute to overall cellular function. Necessary functions like respiration and oxidative phosphorylation are highly dependent on lipid spatial distributions and overall membrane morphology, particularly in the inner mitochondrial membrane (IMM) where the complex interplay between membrane lipids and bioenergetic proteins generates and maintains its characteristic curved cristae structures. The anionic diphosphatidylglycerol cardiolipin is found most abundantly in the IMM, with the majority asymmetrically distributed to the outer leaflet. Cardiolipin has an inverted cone geometry due to its four fatty acyl tails, and has been proposed to play a role in regulating the highly curved nature of the IMM. It is not well understood whether spontaneous curvature is elicited by cardiolipin alone, its interactions with IMM bioenergetic proteins and other lipids, or from a more complex molecular process. Using coarse-grained molecular dynamics, we simulate membrane bilayers with asymmetric inter-leaflet cardiolipin concentrations, and find that cardiolipin content and spatial arrangement largely determine the rate and magnitude of membrane curvature formation. We find that by constraining the lateral diffusion of cardiolipin to certain regions of the membrane, negative membrane curvature forms at those regions and remains stable over long timescales, showing that complex large-scale membrane morphologies can be robustly controlled by tuning the spatial distribution of cardiolipin. Further, we characterize the effects of other mitochondrial lipids and cardiolipin protonation state on curvature generation and stabilization. Therefore, we find that cardiolipin alone can drive the formation of negative membrane curvature at equilibrium