Abstract
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. However, 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, a mitochondrial Mia40-dependent protein, is specific to mitoNEET maturation. When 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 the mitochondrial iron supply. Therefore, our findings point to IRP1 as the missing link to explain the function of mitoNEET in the control of mitochondrial iron homeostasis.
Highlights
MitoNEET is a mammalian iron-sulfur protein with the ability to transfer iron-sulfur (Fe-S) in vitro
MitoNEET is the first mitochondrial protein found to be involved in mammalian cytosolic Fe-S repair
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
Summary
A novel mitoNEET-dependent Fe-S repair pathway affects a key regulator of iron metabolism. 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. Iron-sulfur cluster (Fe-S) proteins assist vital biological processes such as enzymatic catalysis, DNA synthesis and repair, ribosome biogenesis, iron homeostasis, and heme synthesis [1]. Biogenesis of these prosthetic centers is a com-. Iron is taken into mitochondria by the two iron transporters mitoferrin 1 and 2 (MFRN-1 and MFRN-2) [2] and assembled with inorganic sulfide produced from L-cysteine by the cysteine desulfurase NFS1-ISD11 complex to form a transient Fe-S on the ISCU scaffold protein. We provide evidence for a role of mNT in the Fe-S repair of cytosolic aconitase/IRP1, a critical regulator of genes important for iron homeostasis and oxygen sensing
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
