Functional studies of frataxin

G. Isaya, H. A. O'Neill, O. Gakh, S. Park, R. Mantcheva, S. M. Mooney

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Mitochondria generate adenosine triphosphate (ATP) but also dangerous reactive oxygen species (ROS). One-electron reduction of dioxygen in the early stages of the electron transport chain yields a superoxide radical that is detoxified by mitochondrial superoxide dismutase to give hydrogen peroxide. The hydroxyl radical is derived from decomposition of hydrogen peroxide via the Fenton reaction, catalyzed by Fe 2+ ions. Mitochondria require a constant supply of Fe 2+ for heme and iron-sulfur cluster biosyntheses and therefore are particularly susceptible to ROS attack. Two main antioxidant defenses are known in mitochondria: enzymes that catalytically remove ROS, e.g. superoxide dismutase and glutathione peroxidase, and low molecular weight agents that scavenge ROS, including coenzyme Q, glutathione, and vitamins E and C. An effective defensive system, however, should also involve means to control the availability of pro-oxidants such as Fe 2+ ions. There is increasing evidence that this function may be carried out by the mitochondrial protein frataxin. Frataxin deficiency is the primary cause of Friedreich's ataxia (FRDA), an autosomal recessive degenerative disease. Frataxin is a highly conserved mitochondrial protein that plays a critical role in iron homeostasis. Respiratory deficits, abnormal cellular iron distribution and increased oxidative damage are associated with frataxin defects in yeast and mouse models of FRDA. The mechanism by which frataxin regulates iron metabolism is unknown. The yeast frataxin homologue (mYfh1p) is activated by Fe(II) in the presence of oxygen and assembles stepwise into a 48-subunit multimer (α48) that sequesters >2000 atoms of iron in a ferrihydrite mineral core. Assembly of mYfh1p is driven by two sequential iron oxidation reactions: a fast ferroxidase reaction catalyzed by mYfh1p induces the first assembly step (α→α3), followed by a slower autoxidation reaction that promotes the assembly of higher order oligomers yielding α48. Depending on the ionic environment, stepwise assembly is associated with the sequestration of ≤50-75 Fe(II)/subunit. This Fe(II) is initially loosely bound to mYfh1p and can be readily mobilized by chelators or made available to the mitochondrial enzyme ferrochelatase to synthesize heme. However, as iron oxidation and mineralization proceed, Fe(III) becomes progressively inaccessible and a stable iron-protein complex is produced. In conclusion, by coupling iron oxidation with stepwise assembly, frataxin can successively function as an iron chaperon or an iron store. Reduced iron availability and solubility and increased oxidative damage may therefore explain the pathogenesis of FRDA.

Original languageEnglish (US)
Pages (from-to)68-73
Number of pages6
JournalActa Paediatrica, International Journal of Paediatrics, Supplement
Volume93
Issue number445
StatePublished - May 2004

Fingerprint

Iron
Reactive Oxygen Species
Friedreich Ataxia
Mitochondria
Mitochondrial Proteins
Heme
Hydrogen Peroxide
Superoxide Dismutase
frataxin
Yeasts
Ferrochelatase
Ions
Oxygen
Ceruloplasmin
Ubiquinone
Enzymes
Chelating Agents
Glutathione Peroxidase
Electron Transport
Vitamin E

Keywords

  • Frataxin
  • Friedreich's ataxia
  • Mitochondrial iron metabolism
  • Oxidative damage

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Isaya, G., O'Neill, H. A., Gakh, O., Park, S., Mantcheva, R., & Mooney, S. M. (2004). Functional studies of frataxin. Acta Paediatrica, International Journal of Paediatrics, Supplement, 93(445), 68-73.

Functional studies of frataxin. / Isaya, G.; O'Neill, H. A.; Gakh, O.; Park, S.; Mantcheva, R.; Mooney, S. M.

In: Acta Paediatrica, International Journal of Paediatrics, Supplement, Vol. 93, No. 445, 05.2004, p. 68-73.

Research output: Contribution to journalArticle

Isaya, G, O'Neill, HA, Gakh, O, Park, S, Mantcheva, R & Mooney, SM 2004, 'Functional studies of frataxin', Acta Paediatrica, International Journal of Paediatrics, Supplement, vol. 93, no. 445, pp. 68-73.
Isaya G, O'Neill HA, Gakh O, Park S, Mantcheva R, Mooney SM. Functional studies of frataxin. Acta Paediatrica, International Journal of Paediatrics, Supplement. 2004 May;93(445):68-73.
Isaya, G. ; O'Neill, H. A. ; Gakh, O. ; Park, S. ; Mantcheva, R. ; Mooney, S. M. / Functional studies of frataxin. In: Acta Paediatrica, International Journal of Paediatrics, Supplement. 2004 ; Vol. 93, No. 445. pp. 68-73.
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