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

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

  • Science. 2018 Apr 20;360(6386):336-341. doi: 10.1126/science.aao1785.
Agostinho G Rocha 1,  Antonietta Franco 1,  Andrzej M Krezel 2,  Jeanne M Rumsey 1,  Justin M Alberti 1,  William C Knight 1,  Nikolaos Biris 3,  Emmanouil Zacharioudakis 3,  James W Janetka 2,  Robert H Baloh 4,  Richard N Kitsis 5,  Daria Mochly-Rosen 6,  R Reid Townsend 1,  Evripidis Gavathiotis 3,  Gerald W Dorn 2nd 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 2 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
  • 3 Departments of Biochemistry and Medicine, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 4 Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 5 Departments of Medicine and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein Cancer Center, and Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 6 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 7 Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA. gdorn@wustl.edu.
PMID: 29674596 DOI: 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.

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