Src inhibitors modulate frataxin protein levels

Hum Mol Genet. 2015 Aug 1;24(15):4296-305. doi: 10.1093/hmg/ddv162. Epub 2015 May 6.


Defective expression of frataxin is responsible for the inherited, progressive degenerative disease Friedreich's Ataxia (FRDA). There is currently no effective approved treatment for FRDA and patients die prematurely. Defective frataxin expression causes critical metabolic changes, including redox imbalance and ATP deficiency. As these alterations are known to regulate the tyrosine kinase Src, we investigated whether Src might in turn affect frataxin expression. We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation. Accordingly, Src inhibitors induce accumulation of frataxin but are ineffective on a non-phosphorylatable frataxin-Y118F mutant. Importantly, all the Src inhibitors tested, some of them already in the clinic, increase frataxin expression and rescue the aconitase defect in frataxin-deficient cells derived from FRDA patients. Thus, Src inhibitors emerge as a new class of drugs able to promote frataxin accumulation, suggesting their possible use as therapeutics in FRDA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / deficiency
  • Adenosine Triphosphate / genetics
  • Enzyme Inhibitors / pharmacology
  • Friedreich Ataxia / drug therapy
  • Friedreich Ataxia / genetics*
  • Friedreich Ataxia / pathology
  • Gene Expression Regulation / drug effects
  • Humans
  • Iron-Binding Proteins / biosynthesis*
  • Iron-Binding Proteins / genetics
  • Oxidation-Reduction
  • Ubiquitination / genetics
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / genetics*
  • src-Family Kinases / metabolism


  • Enzyme Inhibitors
  • Iron-Binding Proteins
  • frataxin
  • Adenosine Triphosphate
  • src-Family Kinases