MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A
- 20 April 2018
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 360 (6386), 336-341
- https://doi.org/10.1126/science.aao1785
Abstract
Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in Mfn2 cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met376 and His380 interactions with Asp725 and Leu727 and controlled by PINK1 kinase–mediated phosphorylation of adjacent MFN2 Ser378. Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. These first-in-class mitofusin agonists overcame dominant mitochondrial defects provoked in cultured neurons by CMT2A mutants MFN2 Arg94→Gln94 and MFN2 Thr105→Met105, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr105→Met105 mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking.Keywords
Funding Information
- National Institutes of Health (HL135736)
- National Institutes of Health (HL128071)
This publication has 30 references indexed in Scilit:
- Correcting mitochondrial fusion by manipulating mitofusin conformationsNature, 2016
- Charcot-Marie-Tooth Disease Type 2AJAMA Neurology, 2014
- PINK1-Phosphorylated Mitofusin 2 Is a Parkin Receptor for Culling Damaged MitochondriaScience, 2013
- The crystal structure of dynaminNature, 2011
- Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal OmegaMolecular Systems Biology, 2011
- Structural basis for mechanochemical role of Arabidopsis thaliana dynamin-related protein in membrane fissionJournal of Molecular Cell Biology, 2011
- I-TASSER server for protein 3D structure predictionBMC Bioinformatics, 2008
- Altered Axonal Mitochondrial Transport in the Pathogenesis of Charcot-Marie-Tooth Disease from Mitofusin 2 MutationsJournal of Neuroscience, 2007
- MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2Brain, 2006
- Patterning of Muscle Acetylcholine Receptor Gene Expression in the Absence of Motor InnervationNeuron, 2001