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.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Arginine / genetics
  • Axons / drug effects
  • Axons / physiology
  • Charcot-Marie-Tooth Disease / drug therapy*
  • Charcot-Marie-Tooth Disease / genetics
  • Disease Models, Animal
  • Drug Design*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Glutamine / genetics
  • Humans
  • Methionine / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects*
  • Mitochondrial Diseases / drug therapy*
  • Mitochondrial Proteins / agonists*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Oligopeptides / therapeutic use
  • Phosphorylation
  • Protein Kinases / metabolism
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / physiopathology
  • Small Molecule Libraries / pharmacology*
  • Small Molecule Libraries / therapeutic use
  • Threonine / genetics

Substances

  • Mitochondrial Proteins
  • Oligopeptides
  • Small Molecule Libraries
  • Glutamine
  • Threonine
  • Arginine
  • Methionine
  • Protein Kinases
  • PTEN-induced putative kinase
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • Mfn2 protein, mouse

Supplementary concepts

  • Charcot-Marie-Tooth disease, Type 2A