Protein-Induced Membrane Strain Drives Supercomplex Formation

Abstract Mitochondrial membranes harbor the electron transport chain (ETC) that powers oxidative phosphorylation (OXPHOS) and drives the synthesis of ATP. Yet, under physiological conditions, the OXPHOS proteins operate as higher-order supercomplex (SC) assemblies, although their functional role remains poorly understood and much debated. By combining large-scale atomistic and coarse-grained molecular simulations with analysis of cryo-electron microscopic data and statistical as well as kinetic models, we show here that the formation of the mammalian I/III2 supercomplex reduces the molecular strain of inner mitochondrial membranes by altering the local membrane thickness and leading to an accumulation of both cardiolipin and quinone around specific regions of the SC. We find that the SC assembly also affects the global motion of the individual ETC proteins with possible functional consequences. On a general level, our findings suggest that molecular crowding and strain effects provide a thermodynamic driving force for the SC formation, with a possible flux enhancement in crowded biological membranes under constrained respiratory conditions. Significance Statement The membrane-bound proteins of respiratory chains power oxidative phosphorylation (OXPHOS) and drive the synthesis of ATP. However, recent biochemical and structural data show that the OXPHOS proteins operate as higher-order supercomplex assemblies for reasons that remain elusive and much debated. Here we show that the mammalian respiratory supercomplexes reduce the molecular strain of inner mitochondrial membranes and enhance the allosteric crosstalk by altering the protein dynamics with important biochemical and physiological implications. Competing Interest Statement The authors have declared no competing interest. Footnotes The magnitude of the membrane curvature term is discussed in the revised manuscript.