HSC20 interacts with frataxin and is involved in iron-sulfur cluster biogenesis and iron homeostasis

Hum Mol Genet. 2012 Apr 1;21(7):1457-69. doi: 10.1093/hmg/ddr582. Epub 2011 Dec 13.


Friedreich's ataxia is a neurodegenerative disorder caused by mutations in the frataxin gene that produces a predominantly mitochondrial protein whose primary function appears to be mitochondrial iron-sulfur cluster (ISC) biosynthesis. Previously we demonstrated that frataxin interacts with multiple components of the mammalian ISC assembly machinery. Here we demonstrate that frataxin interacts with the mammalian mitochondrial chaperone HSC20. We show that this interaction is iron-dependent. We also show that like frataxin, HSC20 interacts with multiple proteins involved in ISC biogenesis including the ISCU/Nfs1 ISC biogenesis complex and the GRP75 ISC chaperone. Furthermore, knockdown of HSC20 caused functional defects in activity of mitochondrial ISC-containing enzymes and also defects in ISC protein expression. Alterations up or down of frataxin expression caused compensatory changes in HSC20 expression inversely, as expected of two cooperating proteins operating in the same pathway and suggesting a potential therapeutic strategy for the disease. Knockdown of HSC20 altered cytosolic and mitochondrial iron pools and increased the expression of transferrin receptor 1 and iron regulatory protein 2 consistent with decreased iron bioavailability. These results indicate that HSC20 interacts with frataxin structurally and functionally and is important for ISC biogenesis and iron homeostasis in mammals. Furthermore, they suggest that HSC20 may act late in the ISC pathway as a chaperone in ISC delivery to apoproteins and that HSC20 should be included in multi-protein complex studies of mammalian ISC biogenesis.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carbon-Sulfur Lyases / metabolism
  • Cell Growth Processes
  • Cell Line
  • HEK293 Cells
  • HSP70 Heat-Shock Proteins / metabolism
  • Homeostasis
  • Humans
  • Iron / metabolism*
  • Iron-Binding Proteins / metabolism*
  • Iron-Sulfur Proteins / metabolism*
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondrial Proteins / metabolism
  • Molecular Chaperones / antagonists & inhibitors
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / metabolism*
  • Molecular Sequence Data
  • RNA Interference
  • Reactive Oxygen Species / metabolism


  • HSCB protein, human
  • HSP70 Heat-Shock Proteins
  • Iron-Binding Proteins
  • Iron-Sulfur Proteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • Reactive Oxygen Species
  • frataxin
  • glucose-regulated proteins
  • Iron
  • Carbon-Sulfur Lyases