MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A

Agostinho G. Rocha, Antonietta Franco, Andrzej M. Krezel, Jeanne M. Rumsey, Justin M. Alberti, William C. Knight, Nikolaos Biris, Emmanouil Zacharioudakis, James W. Janetka, Robert H. Baloh, Richard N. Kitsis, Daria Mochly-Rosen, R. Reid Townsend, Evripidis Gavathiotis, Gerald W. Dorn

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43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)336-341
Number of pages6
JournalScience
Volume360
Issue number6386
DOIs
StatePublished - Apr 20 2018

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    Rocha, A. G., Franco, A., Krezel, A. M., Rumsey, J. M., Alberti, J. M., Knight, W. C., Biris, N., Zacharioudakis, E., Janetka, J. W., Baloh, R. H., Kitsis, R. N., Mochly-Rosen, D., Townsend, R. R., Gavathiotis, E., & Dorn, G. W. (2018). MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science, 360(6386), 336-341. https://doi.org/10.1126/science.aao1785