The Diabetes Drug Target MitoNEET Governs a Novel Trafficking Pathway to Rebuild an Fe-S Cluster into Cytosolic Aconitase/Iron Regulatory Protein 1 [Cell Biology]
July 10th, 2014 by Ferecatu, I., Goncalves, S., Golinelli–Cohen, M.–P., Clemancey, M., Martelli, A., Riquier, S., Guittet, E., Latour, J.–M., Puccio, H., Drapier, J.–C., Lescop, E., Bouton, C.
In eukaryotes, mitochondrial Iron-Sulfur Cluster (ISC), export and Cytosolic Iron-sulfur cluster Assembly (CIA) machineries carry out biogenesis of iron-sulfur (Fe-S) clusters, which are critical for multiple essential cellular pathways. Yet little is known about their export out of mitochondria. Here, we show that Fe-S assembly of mitoNEET, the first identified Fe-S protein anchored in the mitochondrial outer membrane, strictly depends on ISC machineries and not on the CIA or CIAPIN1. We identify a dedicated ISC/export pathway, in which Augmenter of Liver Regeneration (ALR), a mitochondrial Mia40-dependent protein, is specific to mitoNEET maturation. Once inserted, the Fe-S cluster confers mitoNEET folding and stability in vitro and in vivo. The holo-form of mitoNEET is resistant to NO and H2O2, and is capable of repairing oxidatively damaged Fe-S of iron regulatory protein-1 (IRP1), a master regulator of cellular iron that has recently been involved in mitochondrial iron supply. Our findings thus point to IRP1 as the missing link to explain the function of mitoNEET in the control of mitochondrial iron homeostasis.