Kavli Affiliate: Mark Ellisman
| Authors: Kailash Venkatraman, Christopher T Lee, Guadalupe C. Garcia, Arijit Mahapatra, Guy Perkins, Keun-Young Kim, Hilda Amalia Pasolli, Sebastien Phan, Jennifer Lippincott-Schwartz, Mark Ellisman, Padmini Rangamani and Itay Budin
| Summary:
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. It has long been puzzling why loss of CL has only minor phenotype in yeast; we show that CL is in fact essential when cells are grown under natural fermentation conditions that mediate PL saturation.