An innovative approach for a rare disease
Charcot-Marie-Tooth disease type 2A (CMT2A) is a rare, inherited neurodegenerative condition. Affected individuals develop severe progressive muscle weakness, motor deficits, and peripheral neuropathy. Although defects in the gene encoding mitofusin 2 (MFN2) are known to cause CMT2A, the disease remains incurable. Rocha et al. identified specific MFN2 residues contributing to the disease and developed a class of MFN2-agonist drugs. The small molecules restored mitochondrial fusion and activity in the sciatic nerves of mice; they may also help in other diseases linked to mitochondrial trafficking.
Science, this issue p. 336
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.
Materials and Methods
Figs. S1 to S31
Movies S1 to S4
Data S1 to S4
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Volume 360 | Issue 6386
20 April 2018
20 April 2018
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Received: 22 June 2017
Accepted: 27 February 2018
Published in print: 20 April 2018
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We gratefully acknowledge discussions with P. Needleman and the assistance of L. Zhang, P. Erdmann-Gilmore, Y. Mi, and R. Connors. Funding: This work was supported by NIH grants R35HL135736 (G.W.D.), R01HL128071 (R.N.K. and G.W.D.), and R01CA178394 and P30CA013330 (E.G.); a McDonnell Center for Cellular and Molecular Neurobiology postdoctoral fellowship (A.F.); and the Washington University Proteomics Shared Resource, supported by National Center for Advancing Translational Sciences grants UL1TR000448, NIGMSP41, GM103422, and NCIP30 CA091842. G.W.D. is the Philip and Sima K. Needleman–endowed professor. Author contributions: G.W.D., A.M.K., D.M.-R, and R.R.T. conceived of or designed the research, except the initial in silico screen. E.G., R.N.K., N.B., and E.Z. conceived of the small-molecule screen, designed the original pharmacophore model, and performed the initial in silico screen. G.W.D. wrote the manuscript. J.M.R. and R.R.T. performed phosphoprotein mass spectroscopy analyses. A.M.K. performed peptide nuclear magnetic resonance studies. A.G.R. screened compounds for activity and characterized agonists. A.G.R., A.F., J.M.A., and W.C.K. performed mitochondrial studies. A.F. performed cultured neuron and ex vivo sciatic nerve studies. J.W.J. analyzed and purified compounds. R.N.K., E.G., and R.H.B. provided essential reagents. Competing interests: D.M.-R. and G.W.D. are inventors on patent application 15/710,696, submitted by Stanford University, which covers the use of peptide regulators of mitochondrial fusion and small-molecule peptidomimetics derived from them. G.W.D. is an inventor on provisional patent applications 62/488,787 and 62/584,515, submitted by Washington University, which cover the use of novel small-molecule mitofusin agonists to treat chronic neurodegenerative diseases. E.G., R.N.K., N.B., and E.Z. are inventors on patent application 62/573,217, submitted by Albert Einstein College of Medicine, which covers compositions of mitofusin agonists and their uses for the treatment of diseases and disorders. D.M.-R. is the founder of Mitoconix Bio, a company focused on improving mitochondrial health as a therapeutic approach for neurodegenerative diseases. None of the research conducted in D.M.-R.’s laboratory is supported by or performed in collaboration with Mitoconix. The other authors declare no competing interests. Data and materials availability: All data are available in the manuscript or the supplementary materials. There are no material transfer agreements associated with this study.
National Institutes of Health: HL135736
National Institutes of Health: HL128071
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