Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy

EMBO Rep. 2018 Aug;19(8):e45241. doi: 10.15252/embr.201745241. Epub 2018 Jun 13.


Charcot-Marie-Tooth disease type 2A (CMT2A) is caused by dominant alleles of the mitochondrial pro-fusion factor Mitofusin 2 (MFN2). To address the consequences of these mutations on mitofusin activity and neuronal function, we generate Drosophila models expressing in neurons the two most frequent substitutions (R94Q and R364W, the latter never studied before) and two others localizing to similar domains (T105M and L76P). All alleles trigger locomotor deficits associated with mitochondrial depletion at neuromuscular junctions, decreased oxidative metabolism and increased mtDNA mutations, but they differently alter mitochondrial morphology and organization. Substitutions near or within the GTPase domain (R94Q, T105M) result in loss of function and provoke aggregation of unfused mitochondria. In contrast, mutations within helix bundle 1 (R364W, L76P) enhance mitochondrial fusion, as demonstrated by the rescue of mitochondrial alterations and locomotor deficits by over-expression of the fission factor DRP1. In conclusion, we show that both dominant negative and dominant active forms of mitofusin can cause CMT2A-associated defects and propose for the first time that excessive mitochondrial fusion drives CMT2A pathogenesis in a large number of patients.

Keywords: CMT2A; MFN2; mitochondrial fusion; mitofusin; peripheral neuropathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Animals
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology*
  • Charcot-Marie-Tooth Disease / physiopathology
  • Disease Models, Animal
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / metabolism*
  • Drosophila melanogaster / ultrastructure
  • Gain of Function Mutation / genetics*
  • Humans
  • Loss of Function Mutation / genetics*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics
  • Motor Activity
  • Neuromuscular Junction / metabolism
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / ultrastructure


  • Drosophila Proteins
  • Marf protein, Drosophila
  • Membrane Proteins

Supplementary concepts

  • Charcot-Marie-Tooth disease, Type 2A