FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity

J Biol Chem. 2018 Dec 21;293(51):19797-19811. doi: 10.1074/jbc.RA118.002742. Epub 2018 Oct 26.

Abstract

Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation. These defects were corrected with a lipid-soluble, small-molecule iron transporter, hinokitiol, in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter but is required for adequate mitochondrial iron import to sustain heme synthesis and iron-sulfur cluster formation during erythroid differentiation. FAM210B was also required for maximal ferrochelatase activity in differentiating erythroid cells. We propose that FAM210B functions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism.

Keywords: cell metabolism; erythrocyte; erythropoiesis; heme; iron metabolism; red blood cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Erythroid Cells / cytology
  • Erythroid Cells / metabolism*
  • Erythropoiesis
  • Erythropoietin / metabolism*
  • Ferrochelatase / metabolism*
  • HEK293 Cells
  • Heme / biosynthesis*
  • Humans
  • Iron / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Mice
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / metabolism*
  • Protein Transport

Substances

  • FAM210B protein, human
  • Membrane Proteins
  • Mitochondrial Proteins
  • Erythropoietin
  • Heme
  • Iron
  • Ferrochelatase