Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome

Cristae are high curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous mechanisms for lipids have yet to be elucidated. Here we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the IMM against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. The model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that CL is essential in low oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of CL is dependent on the surrounding lipid and protein components of the IMM. SynopsisO_LIcritical lipidic breakpoint for yeast mitochondria phenocopies the loss of cristae-shaping proteins in the IMM. C_LIO_LIsaturation controls membrane mechanical properties and modulates ATP synthase oligomerization. C_LIO_LImitochondrial-specific lipid cardiolipin can functionally compensate for increased phospholipid saturation and is required for cristae formation in low oxygen environments. C_LIO_LImathematical model for cristae membrane tubules predicts a snapthrough instability mediated by both protein and lipid-encoded curvatures. C_LI Synopsis Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/532310v3_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@196aefforg.highwire.dtl.DTLVardef@1bafcadorg.highwire.dtl.DTLVardef@122f502org.highwire.dtl.DTLVardef@35afd_HPS_FORMAT_FIGEXP M_FIG C_FIG