Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1772, Issue 7, Pages 773-780Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2007.04.001
Keywords
RNAi; frataxin; iron-sulfur cluster; heme; adrenodoxin; hemin; theraphy
Funding
- NEI NIH HHS [EY12245] Funding Source: Medline
- NIA NIH HHS [AG23311, AG16719, AG11967] Funding Source: Medline
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Mutations in the frataxin gene cause neurodegeneration and demyelination in Friedreich's ataxia. We showed earlier that frataxin deficiency causes primary iron-sulfur cluster defects, and later causes defects in heme and cytochrome e hemoprotein levels. Iron-sulfur (Fe/S) clusters are required in two enzymes of heme biosyntliesis in humans i.e. in ferrochelatase and adrenodoxin. However, decreases in ferrochelatase activity have not been observed in frataxin-deficient HeLa cells or patient lymphoblasts. We knocked down frataxin in oligodendrogliorna cells using siRNA, which produced significant defects in the activity of the Fe/S cluster enzymes adrenodoxin and aconitase, the adrenodoxin product heme a, and cytochrome oxidase, for which heme a serves as a prosthetic group. Exogenous hemin produced a significant rescue of adrenodoxin, aconitase, heme a levels and cytochrome oxidase activity. Thus hemin rescues iron-sulfur cluster defects that are the result of frataxin-deficiency, perhaps as a consequence of increasing the pool of bioavailable iron, and thus should be more fully tested for beneficial effects in Friedreich's ataxia models. (c) 2007 Elsevier B.V. All rights reserved.
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