Cytosolic monothiol glutaredoxins function in intracellular iron sensing and trafficking via their bound iron-sulfur cluster.

Ulrich Mühlenhoff (1) , Sabine Molik (1) , José R Godoy (1) , Marta A Uzarska (1) , Nadine Richter (1) , Andreas Seubert (2) , Yan Zhang (3) , Joanne Stubbe (3) , Fabien Pierrel (4) , Enrique Herrero (5) , Christopher Horst Lillig (1) , Roland Lill (1)

1 Institut für Zytobiologie und Zytopathologie
2 Fachbereich Chemie
3 Chemistry Department [Massachusetts Institute of Technology]
4 LCBM - UMR 5249 - Laboratoire de Chimie et Biologie des Métaux
5 Departament de Ciencies Mediques Basiques

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.

Domaines: Biochimie, Biologie Moléculaire

Ulrich Mühlenhoff, Sabine Molik, José R Godoy, Marta A Uzarska, Nadine Richter, et al.. Cytosolic monothiol glutaredoxins function in intracellular iron sensing and trafficking via their bound iron-sulfur cluster.. Cell Metab, 2010, 12 (4), pp.373-85. ⟨10.1016/j.cmet.2010.08.001⟩. ⟨hal-00630763⟩