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Nature. 2016 Dec 1;540(7631):74-79. doi: 10.1038/nature20156. Epub 2016 Oct 24.

Correcting mitochondrial fusion by manipulating mitofusin conformations.

Author information

1
Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Departments of Medicine (Cardiology) and Cell Biology and Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, USA.
3
Departments of Biochemistry and Medicine, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA.
4
Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, California, USA.
5
Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri, USA.
6
Department of Anatomy and Structural Biology, Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York, USA.

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.

PMID:
27775718
PMCID:
PMC5315023
DOI:
10.1038/nature20156
[Indexed for MEDLINE]
Free PMC Article

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