title: Correcting mitochondrial fusion by manipulating mitofusin conformations.
abstract: Mitochondria are dynamic organelles that exchange contents and undergo remodelling during cyclic fusion and fission. Genetic mutations in MFN2 (the gene encoding mitofusin 2) interrupt mitochondrial fusion and cause the untreatable neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A). It has not yet been possible to directly modulate mitochondrial fusion, in part because the structural basis of mitofusin function is not completely understood. Here we show that mitofusins adopt either a fusion-constrained or a fusion-permissive molecular conformation, directed by specific intramolecular binding interactions, and demonstrate that mitofusin-dependent mitochondrial fusion can be regulated in mouse cells by targeting these conformational transitions. On the basis of this model, we engineered a cell-permeant minipeptide to destabilize the fusion-constrained conformation of mitofusin and promote the fusion-permissive conformation, reversing mitochondrial abnormalities in cultured fibroblasts and neurons that harbour CMT2A-associated genetic defects. The relationship between the conformational plasticity of mitofusin 2 and mitochondrial dynamism reveals a central mechanism that regulates mitochondrial fusion, the manipulation of which can correct mitochondrial pathology triggered by defective or imbalanced mitochondrial dynamics.
authors: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Antonietta
authors: A
authors: Franco
authors: Departments of Medicine (Cardiology) and Cell Biology and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Richard N
authors: RN
authors: Kitsis
authors: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Julie A
authors: JA
authors: Fleischer
authors: Departments of Biochemistry and Medicine, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Evripidis
authors: E
authors: Gavathiotis
authors: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, California, USA.
authors: Opher S
authors: OS
authors: Kornfeld
authors: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Guohua
authors: G
authors: Gong
authors: Departments of Biochemistry and Medicine, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Nikolaos
authors: N
authors: Biris
authors: Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Ann
authors: A
authors: Benz
authors: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, California, USA.
authors: Nir
authors: N
authors: Qvit
authors: Department of Anatomy and Structural Biology, Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Sara K
authors: SK
authors: Donnelly
authors: Departments of Medicine (Cardiology) and Cell Biology and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Yun
authors: Y
authors: Chen
authors: Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Steven
authors: S
authors: Mennerick
authors: Department of Anatomy and Structural Biology, Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Louis
authors: L
authors: Hodgson
authors: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, California, USA.
authors: Daria
authors: D
authors: Mochly-Rosen
authors: Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Gerald W
authors: GW II
authors: Dorn
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects* / Q000235:genetics; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010539:Permeability; D011487:Protein Conformation / Q000187:drug effects
chemical_list: D010455:Peptides; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse