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Science. 2018 Apr 20;360(6386):336-341. doi: 10.1126/science.aao1785.

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

Author information

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.

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.

PMID:
29674596
PMCID:
PMC6109362
DOI:
10.1126/science.aao1785
[Indexed for MEDLINE]
Free PMC Article

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