Mechanism and regulation of homotypic fusion between outer membranes.
Laetitia Cavellini1, Tobias Brandt2, Julie Meurisse1, Naïma Belgareh-Touzé1, Allan M. Weissman3, Werner Kühlbrandt2 and Mickael M. Cohen1* 1Laboratory of Membrane Dynamics and Post-Translational Modifications, IBPC, UMR8226-CNRS-UPMC, 13 rue Pierre et Marie Curie, 75005 Paris, France; 2Max Planck Institute of Biophysics, Max-von-Laue-Straße 3, 60438 Frankfurt am Main, Germany; 3Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, NCI-Frederick, MD 21702, USA * Corresponding Author
Fusion of mitochondrial outer membranes is crucial for proper organelle function and involves large GTPases called mitofusins. However, the regulation and the discrete steps that allow mitochondria to attach to one another and merge their outer membranes have long remained elusive. By combining an in vitro mitochondrial fusion assay with electron cryo-tomography (cryo-ET) analysis, we have recently unraveled key features of mitofusin-dependent membrane fusion from Saccharomyces cerevisiae. This led to the discovery of a Mitochondrial Docking Complex, which provides the first example of a macro-molecular structure assembled by mitofusins. In parallel, we have revealed that the Ubiquitin-Proteasome System regulates mitochondrial fusion by coordinating an intricate balance between the degradation of mitofusins and the status of fatty acids saturation. This pathway may link outer membrane fusion to lipids homeostasis. Together, these findings constitute important advances in our understanding of how mitochondria connect and merge. Most importantly, they open new questions that will be discussed.
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