Hemin rescues adrenodoxin, heme a and cytochrome oxidase activity in frataxin-deficient oligodendroglioma cells

Biochim Biophys Acta. 2007 Jul;1772(7):773-80. doi: 10.1016/j.bbadis.2007.04.001. Epub 2007 Apr 10.

Abstract

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 c hemoprotein levels. Iron-sulfur (Fe/S) clusters are required in two enzymes of heme biosynthesis 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 oligodendroglioma 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.

Publication types

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

MeSH terms

  • Adrenodoxin / metabolism*
  • Base Sequence
  • Chromatography, High Pressure Liquid
  • DNA Primers
  • Electron Transport Complex IV / metabolism*
  • HeLa Cells
  • Heme / analogs & derivatives*
  • Heme / metabolism
  • Hemin / pharmacology*
  • Humans
  • Iron-Binding Proteins / genetics
  • Iron-Binding Proteins / metabolism*
  • Iron-Sulfur Proteins / metabolism
  • Oligodendroglioma / enzymology
  • Oligodendroglioma / metabolism*
  • Oligodendroglioma / pathology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • DNA Primers
  • Iron-Binding Proteins
  • Iron-Sulfur Proteins
  • frataxin
  • Adrenodoxin
  • heme a
  • Heme
  • Hemin
  • Electron Transport Complex IV