Structural dissection of mitochondrial tethering through super-resolution imaging – MOMIT

While membrane fusion underlies fundamental biological processes, the molecular machineries that drive this process are diverse and the mechanistic knowledge of in vivo membrane fusion remains far from complete. The most studied and best-understood membrane fusion system to date is that mediated by SNAREs, a class of coil-coiled domain proteins that are expressed in all biological compartments undergoing membrane fusion except mitochondria.
Mitochondria constitute a real and remarkably dynamic network whose morphology is conditioned by a constant equilibrium between frequent fission and fusion events of their membranes. These processes are essential to shape the ultra-structure of the mitochondrial compartment and are thus also crucial for all mitochondrial functions including oxidative phosphorylation and apoptosis. Consequently, defects in mitochondrial fusion and fission are associated with numerous pathologies and severe neurodegenerative syndromes especially.
Mitochondria developed an evolutionary conserved strategy to modulate fusion and fission of their membranes that involve large GTPases of the Dynamin-Related Proteins (DRPs) family. While the mechanism by which DRPs promote membrane fission is well understood, how they can also promote mixing of lipid bilayers remains poorly defined and represents a tremendous matter of interest.
MOMIT will consequently aim at dissecting how DRPs promote tethering and fusion of mitochondrial outer membranes. For this purpose, a multidisciplinary combination of approaches allying single molecule fluorescence imaging, mass spectrometry, biochemistry and cell biology methods will be employed.
MOMIT will ultimately transcend the knowledge on how DRPs catalyze fusion of biological membranes. In turn this will elaborate a molecular basis for better apprehending the physiopathologies associated with mitochondrial fusion but also provide a mean to compare membrane fusion mechanisms promoted by other machineries thus generating a more global picture on how mixing of lipid bilayers is accomplished in vivo.