title: Cytosolic monothiol glutaredoxins function in intracellular iron sensing and trafficking via their bound iron-sulfur cluster.
abstract: Iron is an essential nutrient for cells. It is unknown how iron, after its import into the cytosol, is specifically delivered to iron-dependent processes in various cellular compartments. Here, we identify an essential function of the conserved cytosolic monothiol glutaredoxins Grx3 and Grx4 in intracellular iron trafficking and sensing. Depletion of Grx3/4 specifically impaired all iron-requiring reactions in the cytosol, mitochondria, and nucleus, including the synthesis of Fe/S clusters, heme, and di-iron centers. These defects were caused by impairment of iron insertion into proteins and iron transfer to mitochondria, indicating that intracellular iron is not bioavailable, despite highly elevated cytosolic levels. The crucial task of Grx3/4 is mediated by a bridging, glutathione-containing Fe/S center that functions both as an iron sensor and in intracellular iron delivery. Collectively, our study uncovers an important role of monothiol glutaredoxins in cellular iron metabolism, with a surprising connection to cellular redox and sulfur metabolisms.
authors.affiliation: Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mühlenhoff
authors.affiliation: Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Molik
authors.affiliation: Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
authors.forename: José R
authors.initials: JR
authors.lastname: Godoy
authors.affiliation: Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Uzarska
authors.affiliation: Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Richter
authors.affiliation: Fachbereich Chemie, Philipps-Universität Marburg, 35032 Marburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Seubert
authors.affiliation: Chemistry Department, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Chemistry Department, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: JoAnne
authors.initials: J
authors.lastname: Stubbe
authors.affiliation: Laboratoire de Chimie et Biologie des Métaux, CEA Grenoble, 38054 Grenoble Cedex 9, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Pierrel
authors.affiliation: Departament de Ciències Mèdiques Bàsiques, IRB Lleida, Universitat de Lleida, Lleida 25198, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Herrero
authors.affiliation: Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
authors.forename: Christopher Horst
authors.initials: CH
authors.lastname: Lillig
authors.affiliation: Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany. Electronic address: lill@staff.uni-marburg.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Lill
mesh_terms: D001692:Biological Transport; D003600:Cytosol / Q000378:metabolism*; D054477:Glutaredoxins / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism; D015003:Yeasts / Q000378:metabolism
chemical_list: D054477:Glutaredoxins; C516012:Grx4 protein, S cerevisiae; D007506:Iron-Sulfur Proteins; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; D013455:Sulfur; D007501:Iron; C545181:Grx3 protein, S cerevisiae; D010088:Oxidoreductases