Correcting mitochondrial fusion by manipulating mitofusin conformations

Antonietta Franco, Richard N. Kitsis, Julie A. Fleischer, Evripidis Gavathiotis, Opher S. Kornfeld, Guohua Gong, Nikolaos Biris, Ann Benz, Nir Qvit, Sara K. Donnelly, Yun Chen, Steven Mennerick, Louis Hodgson, Daria Mochly-Rosen, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

180 Scopus citations


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.

Original languageEnglish
Pages (from-to)74-79
Number of pages6
Issue number7631
StatePublished - 1 Dec 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.


FundersFunder number
National Institutes of HealthR21CA205262
National Heart, Lung, and Blood InstituteR01HL128071


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