title: Iron for proliferation of cell lines and hematopoietic progenitors: Nailing down the intracellular functional iron concentration.
abstract: Iron is an essential nutrient which must be provided in sufficient amounts to support growth of eukaryotic cells. All organisms devote specialized pathways to ensure proper delivery. Yet, a quantitative assessment of the intra-cellular iron concentration needed to allow the cell cycle to proceed in mammalian cells is missing. Starting from iron-depleted cell lines or primary hematopoietic progenitors prepared with clinically implemented iron chelators, replenishment via transferrin and other iron sources has been quantitatively monitored through the main endogenous markers of the cellular iron status, namely proteins involved in the uptake (transferrin receptor), the storage (ferritin), and the sensing (Iron Regulatory Proteins) of iron. When correlated with measurements of iron concentrations and indicators of growth, this minimally intrusive approach provided an unprecedented estimate of the intracellular iron concentration acting upon iron-centered regulatory pathways. The data were analyzed with the help of a previously developed theoretical treatment of cellular iron regulation. The minimal cellular iron concentration required for cell division was named functional iron concentration (FIC) to distinguish it from previous estimates of the cellular labile iron. The FIC falls in the low nanomolar range for all studied cells, including hematopoietic progenitors. These data shed new light on basic aspects of cellular iron homeostasis by demonstrating that sensing and regulation of iron occur well below the concentrations requiring storage or becoming noxious in pathological conditions. The quantitative assessment provided here is relevant for monitoring treatments of conditions in which iron provision must be controlled to avoid unwanted cellular proliferation.
authors.affiliation: Université Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics, and Environmental and Systems Biology, Grenoble, France; Inserm, U1055, Grenoble, France; CHU Grenoble, Laboratoire d'Hématologie, Institut de Biologie et Pathologie, Grenoble, France; Université Grenoble Alpes, TIMC-Imag CNRS 5525 Grenoble, France. Electronic address: epourcelot@chu-grenoble.fr.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pourcelot
authors.affiliation: Université Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics, and Environmental and Systems Biology, Grenoble, France; Inserm, U1055, Grenoble, France. Electronic address: marine.lenon@ujf-grenoble.fr.
authors.forename: Marine
authors.initials: M
authors.lastname: Lénon
authors.affiliation: Université Grenoble Alpes, TIMC-Imag CNRS 5525 Grenoble, France. Electronic address: Nicolas.Mobilia@imag.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mobilia
authors.affiliation: CHU Grenoble, Clinique d'hématologie, Grenoble, France; Université Grenoble Alpes, TIMC-Imag CNRS 5525 Grenoble, France. Electronic address: JYCahn@chu-grenoble.fr.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Cahn
authors.affiliation: Université Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics, and Environmental and Systems Biology, Grenoble, France; Inserm, U1055, Grenoble, France; CHU Grenoble, Département de Biochimie, Toxicologie et Pharmacologie, Grenoble, France. Electronic address: JArnaud@chu-grenoble.fr.
authors.forename: Josiane
authors.initials: J
authors.lastname: Arnaud
authors.affiliation: Université Grenoble Alpes, TIMC-Imag CNRS 5525 Grenoble, France. Electronic address: Eric.Fanchon@imag.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Fanchon
authors.affiliation: Université Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics, and Environmental and Systems Biology, Grenoble, France; Inserm, U1055, Grenoble, France; Commissariat à l'Energie Atomique et aux Energies Alternatives-Institut de Recherches en Technologies et Sciences du Vivant, Grenoble, France. Electronic address: jean-marc.moulis@cea.fr.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Moulis
authors.affiliation: CHU Grenoble, Laboratoire d'Hématologie, Institut de Biologie et Pathologie, Grenoble, France; Université Grenoble Alpes, TIMC-Imag CNRS 5525 Grenoble, France. Electronic address: PMossuz@chu-grenoble.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Mossuz
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D001059:Apoproteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D007501:Iron / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D001059:Apoproteins; D007502:Iron Chelating Agents; D014168:Transferrin; D007501:Iron
keywords: Cell cycle; Cellular growth; Iron homeostasis; Leukemia; Modeling; Post-transcriptional regulation