Friedreich's ataxia: iron chelators that target the mitochondrion as a therapeutic strategy?

Expert Opin Investig Drugs. 2003 Feb;12(2):235-45. doi: 10.1517/13543784.12.2.235.


Friedreich's ataxia (FA) is a severe inherited spinocerebellar ataxia that primarily affects the nervous system and heart leading to early confinement in a wheelchair and death. The gene defective in FA, FRDA, encodes a mitochondrial protein known as frataxin. A triplet repeat expansion within intron 1 of the FRDA gene results in a marked decrease in frataxin expression. Over the last 5 years it has become clear that this results in mitochondrial iron accumulation that generates oxidative stress and results in damage to critical biological molecules. Drugs that reduce oxidative stress have a limited effect on the progression and pathology of the disease, probably because these agents cannot remove the iron accumulation. In this review, the potential of iron chelators, namely the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) analogues, as agents to remove mitochondrial iron deposits is discussed. These ligands have been specifically designed to enter and target mitochondrial iron pools, which is a property lacking in desferrioxamine, the only chelator in widespread clinical use. This latter drug may not have any beneficial effect in FA patients, probably because of its hydrophilicity that prevents mitochondrial access. Indeed, standard chelation regimens will probably not work in FA, as these patients do not exhibit gross iron-loading. Considering that there is no effective treatment for FA, it is essential that the therapeutic potential of iron chelators that target mitochondrial iron pools is assessed experimentally.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drug Delivery Systems / methods*
  • Friedreich Ataxia / drug therapy*
  • Friedreich Ataxia / metabolism
  • Humans
  • Iron Chelating Agents / chemistry
  • Iron Chelating Agents / pharmacology
  • Iron Chelating Agents / therapeutic use*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism


  • Iron Chelating Agents