Enhancing folic acid metabolism suppresses defects associated with loss of Drosophila mitofusin

Cell Death Dis. 2019 Mar 25;10(4):288. doi: 10.1038/s41419-019-1496-2.


Mutations in the mitochondrial GTPase mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2A), a form of peripheral neuropathy that compromises axonal function. Mitofusins promote mitochondrial fusion and regulate mitochondrial dynamics. They are also reported to be involved in forming contacts between mitochondria and the endoplasmic reticulum. The fruit fly, Drosophila melanogaster, is a powerful tool to model human neurodegenerative diseases, including CMT2A. Here, we have downregulated the expression of the Drosophila mitofusin (dMfn RNAi) in adult flies and showed that this activates mitochondrial retrograde signalling and is associated with an upregulation of genes involved in folic acid (FA) metabolism. Additionally, we demonstrated that pharmacological and genetic interventions designed to increase the FA metabolism pathway suppresses the phenotype of the dMfn RNAi flies. We conclude that strategies to increase FA metabolism may ameliorate diseases, such as peripheral neuropathies, that are associated with loss of mitochondrial function. A video abstract for this article is available at https://youtu.be/fs1G-QRo6xI .

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Axonal Transport / genetics
  • Charcot-Marie-Tooth Disease / metabolism
  • Disease Models, Animal
  • Down-Regulation / genetics*
  • Drosophila / metabolism*
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism*
  • Folic Acid / genetics
  • Folic Acid / metabolism*
  • Locomotion / genetics
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mitochondria / metabolism
  • Phenotype
  • RNA Interference
  • Reactive Oxygen Species / metabolism


  • Drosophila Proteins
  • Marf protein, Drosophila
  • Membrane Proteins
  • Reactive Oxygen Species
  • Activating Transcription Factor 4
  • Folic Acid

Supplementary concepts

  • Charcot-Marie-Tooth disease, Type 2A