Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich's ataxia model mice

Hum Mol Genet. 2021 Feb 25;29(24):3954-3965. doi: 10.1093/hmg/ddaa282.


Previously we showed that dimethyl fumarate (DMF) dose-dependently increased mitochondrial gene expression and function in cells and might be considered as a therapeutic for inherited mitochondrial disease, including Friedreich's ataxia (FA). Here we tested DMF's ability to dose-dependently increase mitochondrial function, mitochondrial gene expression (frataxin and cytochrome oxidase protein) and mitochondrial copy number in C57BL6 wild-type mice and the FXNKD mouse model of FA. We first dosed DMF at 0-320 mg/kg in C57BL6 mice and observed significant toxicity above 160 mg/kg orally, defining the maximum tolerated dose. Oral dosing of C57BL6 mice in the range 0-160 mg/kg identified a maximum increase in aconitase activity and mitochondrial gene expression in brain and quadriceps at 110 mg/kg DMF, thus defining the maximum effective dose (MED). The MED of DMF in mice overlaps the currently approved human-equivalent doses of DMF prescribed for multiple sclerosis (480 mg/day) and psoriasis (720 mg/day). In the FXNKD mouse model of FA, which has a doxycycline-induced deficit of frataxin protein, we observed significant decreases of multiple mitochondrial parameters, including deficits in brain mitochondrial Complex 2, Complex 4 and aconitase activity, supporting the idea that frataxin deficiency reduces mitochondrial gene expression, mitochondrial functions and biogenesis. About 110 mg/kg of oral DMF rescued these enzyme activities in brain and rescued frataxin and cytochrome oxidase expression in brain, cerebellum and quadriceps muscle of the FXNKD mouse model. Taken together, these results support the idea of using fumarate-based molecules to treat FA or other mitochondrial diseases.

Publication types

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

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / physiology*
  • Dimethyl Fumarate / pharmacology*
  • Dose-Response Relationship, Drug
  • Friedreich Ataxia / drug therapy*
  • Friedreich Ataxia / metabolism
  • Friedreich Ataxia / pathology
  • Gene Expression Regulation / drug effects*
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Muscles / drug effects
  • Muscles / physiology*


  • Immunosuppressive Agents
  • Mitochondrial Proteins
  • Dimethyl Fumarate