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MFN2 Agonists Reverse Mitochondrial Defects in Preclinical Models of Charcot-Marie-Tooth Disease Type 2A

Abstract

Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met and His interactions with Asp and Leu and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser 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 Arg→Gln and MFN2 Thr→Met, as demonstrated by amelioration of mitochondrial dysmotility, fragmentation, depolarization, and clumping. A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr→Met mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking.

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References
1.
Yang X, Arber S, William C, Li L, Tanabe Y, Jessell T . Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation. Neuron. 2001; 30(2):399-410. DOI: 10.1016/s0896-6273(01)00287-2. View

2.
Yan L, Ma Y, Sun Y, Gao J, Chen X, Liu J . Structural basis for mechanochemical role of Arabidopsis thaliana dynamin-related protein in membrane fission. J Mol Cell Biol. 2011; 3(6):378-81. DOI: 10.1093/jmcb/mjr032. View

3.
Sievers F, Wilm A, Dineen D, Gibson T, Karplus K, Li W . Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011; 7:539. PMC: 3261699. DOI: 10.1038/msb.2011.75. View

4.
Bombelli F, Stojkovic T, Dubourg O, Echaniz-Laguna A, Tardieu S, Larcher K . Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features. JAMA Neurol. 2014; 71(8):1036-42. DOI: 10.1001/jamaneurol.2014.629. View

5.
Ford M, Jenni S, Nunnari J . The crystal structure of dynamin. Nature. 2011; 477(7366):561-6. PMC: 4075756. DOI: 10.1038/nature10441. View