Cytosolic Monothiol Glutaredoxins Function in Intracellular Iron Sensing and Trafficking via Their Bound Iron-Sulfur Cluster

• Main Authors: Mühlenhoff, Ulrich (Author), Molik, Sabine (Author), Godoy, José R. (Author), Uzarska, Marta A. (Author), Richter, Nadine (Author), Seubert, Andreas (Author), Zhang, Yan (Contributor), Stubbe, JoAnne (Contributor), Pierrel, Fabien (Author), Herrero, Enrique (Author), Lillig, Christopher Horst (Author), Lill, Roland (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Chemistry (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2015-03-17T20:01:20Z.
• Subjects: Article
• Online Access: Get fulltext

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.
German Research Foundation (SFB 593)
German Research Foundation (Gottfried-Wilhelm Leibniz Program)
German Research Foundation (GRK 1216)
von Behring-Röntgen Stiftung
Max Planck Society for the Advancement of Science
Hesse (Germany) (LOEWE Program)
Fonds der Chemischen Industrie (Germany)
National Institutes of Health (U.S.) (Grant GM29295)