@article{250ccf7545db44c3a96d9cbd879350c1,
title = "FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity",
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.Wepropose thatFAM210Bfunctions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition forhemesynthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by whichEPOsignaling regulates terminal erythropoiesis and iron metabolism.",
author = "Yien, \{Yvette Y.\} and Jiahai Shi and Caiyong Chen and Cheung, \{Jesmine T.M.\} and Grillo, \{Anthony S.\} and Rishna Shrestha and Liangtao Li and Xuedi Zhang and Kafina, \{Martin D.\} and Kingsley, \{Paul D.\} and King, \{Matthew J.\} and Julien Ablain and Hojun Li and Zon, \{Leonard I.\} and James Palis and Burke, \{Martin D.\} and Bauer, \{Daniel E.\} and Orkin, \{Stuart H.\} and Koehler, \{Carla M.\} and Phillips, \{John D.\} and Jerry Kaplan and Ward, \{Diane M.\} and Lodish, \{Harvey F.\} and Paw, \{Barry H.\}",
note = "Acknowledgments{\textemdash}We thank Iman Schultz for assistance on bioin-formatics analysis, Johannes Wittig for assistance with model figure preparation, and Nicholas Huston for assistance with initial morpholino injections. We thank Mahnaz Paktinat for training on the use of the BD FACSCanto cell sorter. We also thank Bingbing Yuan for help with processing and analyzing the microarray data. The DS19 MEL clones were obtained from Arthur Skoultchi (Albert Einstein College of Medicine). We thank Eva Buys and her crew for the zebrafish animal husbandry. We also thank Harry Dailey and Amy Medlock for their critical feedback on the manuscript and Stashauna Carter for technical assistance. Fluorescence confocal microscopy was performed at the Harvard Digestive Disease Center Imaging Facility (Boston Children{\textquoteright}s Hospital, supported by National Institutes of Health Grant P30 DK34854) with assistance from Ramiro Massol. HPLC analyses of porphyrins were performed at the University of Utah Center for Iron and Heme Disorders supported by National Institutes of Health Grant U54 DK110858. This work was supported by March of Dimes Foundation Grant 6-FY09-289 (to B. H. P.); the Cooley{\textquoteright}s Anemia Foundation (to C. C. and Y. Y. Y.); the National Science Foundation (to A. S. G.); National Institutes of Health Grants F32 DK098866, R03 DK118307, and K01 DK106156 (to Y. Y. Y.), K08 DK093705 (to D. E. B.), K99CA20146 (to J. A.), R01 DK020503 and U54 DK083909 (to J. D. P.), R01 GM073981 and R01 GM61721 (to C. M. K.), R01 DK052830 and DK030534 (to D. M. W.), R01 HL116364 (to J. P.), R01 GM118185 (to M. D. B.), R01 DK070838 (to B. H. P.), P01 HL032262 (to H. F. L., S. H. O., L. I. Z., and B. H. P.); and the University of Delaware Biological Sciences Undergraduate Summer Scholar award (to X. Z.). The authors declare that they have no conflicts of interest with the contents of this article. The con-tent is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.",
year = "2018",
month = dec,
day = "21",
doi = "10.1074/jbc.RA118.002742",
language = "English (US)",
volume = "293",
pages = "19797--19811",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "51",
}