Intracellular iron trafficking: role of cytosolic ligands

Biometals. 2012 Aug;25(4):711-23. doi: 10.1007/s10534-012-9529-7. Epub 2012 Feb 17.


Iron acquired by cells is delivered to mitochondria for metabolic processing via pathways comprising undefined chemical forms. In order to assess cytosolic factors that affect those iron delivery pathways, we relied on microscopy and flow-cytometry for monitoring iron traffic in: (a) K562 erythroleukemia cells labeled with fluorescent metal-sensors targeted to either cytosol or mitochondria and responsive to changes in labile iron and (b) permeabilized cells that retained metabolically active mitochondria accessible to test substrates. Iron supplied to intact cells as transferrin-Fe(III) or Fe(II)-salts evoked concurrent metal ingress to cytosol and mitochondria. With either supplementation modality, iron ingress into cytosol was mostly absorbed by preloaded chelators, but ingress into mitochondria was fully inhibited only by some chelators, indicating different cytosol-to-mitochondria delivery mechanisms. Iron ingress into cytosol or mitochondria were essentially unaffected by depletion of cytosolic iron ligands like glutathione or the hypothesized 2,5 dihydroxybenzoate (2,5-DHBA) siderophore/chaperone. These ligands also failed to affect mitochondrial iron ingress in permeabilized K562 cells suspended in cytosol-simulating medium. In such medium, mitochondrial iron uptake was >6-eightfold higher for Fe(II) versus Fe(III), showed saturable properties and submicromolar K(1/2) corresponding to cytosolic labile iron levels. When measured in iron(II)-containing media, ligands like AMP, ADP or ATP, did not affect mitochondrial iron uptake whereas in iron(III)-containing media ADP and ATP reduced it and AMP stimulated it. Thus, cytosolic iron forms demonstrably contribute to mitochondrial iron delivery, are apparently not associated with DHBA analogs or glutathione but rather with resident components of the cytosolic labile iron pool.

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Monophosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Biological Transport / genetics
  • Biological Transport / physiology
  • Cell Line, Tumor
  • Cytosol / metabolism*
  • Flow Cytometry
  • Glutathione / metabolism
  • Humans
  • Iron / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Siderophores / metabolism
  • Transferrin / genetics
  • Transferrin / metabolism


  • Siderophores
  • Transferrin
  • Adenosine Monophosphate
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Iron
  • Glutathione