Cytosolic monothiol glutaredoxins function in intracellular iron sensing and trafficking via their bound iron-sulfur cluster.
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.
Mühlenhoff
Ulrich
U
Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
Molik
Sabine
S
Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
Godoy
José R
JR
Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
Uzarska
Marta A
MA
Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
Richter
Nadine
N
Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
Seubert
Andreas
A
Fachbereich Chemie, Philipps-Universität Marburg, 35032 Marburg, Germany.
Zhang
Yan
Y
Chemistry Department, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Stubbe
JoAnne
J
Chemistry Department, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Pierrel
Fabien
F
Laboratoire de Chimie et Biologie des Métaux, CEA Grenoble, 38054 Grenoble Cedex 9, France.
Herrero
Enrique
E
Departament de Ciències Mèdiques Bàsiques, IRB Lleida, Universitat de Lleida, Lleida 25198, Spain.
Lillig
Christopher Horst
CH
Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
Lill
Roland
R
Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany. Electronic address: lill@staff.uni-marburg.de.
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
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