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 and Gerald W. Dorn ()
Additional contact information
Antonietta Franco: Center for Pharmacogenomics, Washington University School of Medicine
Richard N. Kitsis: Albert Einstein College of Medicine
Julie A. Fleischer: Center for Pharmacogenomics, Washington University School of Medicine
Evripidis Gavathiotis: Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine
Opher S. Kornfeld: Stanford University, School of Medicine
Guohua Gong: Center for Pharmacogenomics, Washington University School of Medicine
Nikolaos Biris: Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine
Ann Benz: Washington University School of Medicine
Nir Qvit: Stanford University, School of Medicine
Sara K. Donnelly: Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine
Yun Chen: Albert Einstein College of Medicine
Steven Mennerick: Washington University School of Medicine
Louis Hodgson: Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine
Daria Mochly-Rosen: Stanford University, School of Medicine
Gerald W. Dorn: Center for Pharmacogenomics, Washington University School of Medicine

Nature, 2016, vol. 540, issue 7631, 74-79

Abstract: 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.

Date: 2016
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/nature20156 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:540:y:2016:i:7631:d:10.1038_nature20156

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature20156

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().