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

Abstract

The inner mitochondrial membrane (IMM) is the site of bulk ATP generation in cells and has a broadly conserved lipid composition enriched in unsaturated phospholipids and cardiolipin (CL). While proteins that shape the IMM and its characteristic cristae membranes (CM) have been defined, specific mechanisms by which mitochondrial lipids dictate its structure and function have yet to be elucidated. Here we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions shape CM morphology and ATP generation. When modulating fatty acid unsaturation in engineered yeast strains, we observed that loss of di-unsaturated phospholipids (PLs) led to a breakpoint in IMM topology and respiratory capacity. We found that PL unsaturation modulates the organization of ATP synthases that shape cristae ridges. Based on molecular modeling of mitochondrial-specific membrane adaptations, we hypothesized that conical lipids like CL buffer against the effects of saturation on the IMM. In cells, we discovered that loss of CL collapses the IMM at intermediate levels of PL saturation, an effect that is independent of ATP synthase oligomerization. To explain this interaction, we employed a continuum modeling approach, finding that lipid and protein-mediated curvatures are predicted to act in concert to form curved membranes in the IMM. The model highlighted a snapthrough instability in cristae tubule formation, which could drive IMM collapse upon small changes in composition. The interaction between CL and di-unsaturated PLs suggests that growth conditions that alter the fatty acid pool, such as oxygen availability, could define CL function. While loss of CL only has a minimal phenotype under standard laboratory conditions, we show that its synthesis is essential under microaerobic conditions that better mimic natural yeast fermentation. Lipid and protein-mediated mechanisms of curvature generation can thus act together to support mitochondrial architecture under changing environments.

Remodelling of mitochondrial function by import of specific lipids at multiple membrane‐contact sites

“…The etiology of these conditions seems to be associated with defects in PE and CL composition which perturbs overall mitochondrial shape possibly by inhibiting the mitochondrial membrane fusogens in the outer and inner mitochondrial membranes [59]. Furthermore, aberrant mitochondrial lipid composition is known to disrupt the shape of IMM-cristae [60][61][62][63][64], negatively affecting the respiratory system and oxidative phosphorylation [65][66][67][68][69][70][71][72]. Cells which do not have sufficient control over their mitochondrial lipid composition are in general defective in metabolic homeostasis [59,73].…”