NEET Proteins: A New Link Between Iron Metabolism, Reactive Oxygen Species, and Cancer

Abstract

Because the function of NEET proteins depends on the lability of their clusters, drugs that target the 2Fe2S clusters of NEET proteins could be used as promising anticancer drugs. Antioxid. Redox Signal. 00, 000-000.

Crystal structure of the mitochondrial protein mitoNEET bound to a benze-sulfonide ligand

“…MitoNEET is a mitochondrial protein with redox and pH sensor activity, which has been of interest toward designing compounds to modulate bioenergetics of mitochondria 2,17,22,24 . Of late no structure has been published which contains mitoNEET protein with a small organic compound bound as a complex, which has hampered progress in designing mitoNEET ligands.…”

“…Our crystal structure was used to design compounds that could give insight into structure-activity relationships of the scaffold. The primary binding site identified correlates with the redox-active [2Fe-2S] cluster ligation site, and binding to the HIS87 and LYS55 may inhibit its redox function and/or possible cluster release/breakdown at the cytoplasmic side 2,17,24 . With the current results, discovery programs can be focused on developing probes to study the pharmacology of mitoNEET and possibly develop novel compounds as first-inclass to treat mitochondrial dysfunction such as Parkinson's disease 26 .…”

Hydrogen Sulfide Is Increased in Oral Squamous Cell Carcinoma Compared to Adjacent Benign Oral Mucosae

“…MitoNEET is an outer mitochondrial iron-sulfur protein that shows increased expression in several human malignancies (32,33). High tumor mitoNEET expression suppresses apoptosis, autophagy, and lowers intramitochondrial iron concentrations, likely allowing tumors cells to tolerate higher reactive oxygen species, while avoiding ferroptosis (33).…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…The NEET (gene symbol, 2 iron, 2 sulfur cluster binding protein. Ordered locus name: At5g51720) proteins mitoNEET {encoded by CDGSH [gene sequence, the ironsulfur (2Fe-2S) binding motif; the conserved sequence C-X-C-X2-(S/T)-X3-P-X-C-D-G-(S/A/T)-H is a defining feature of this unique family] iron sulfur domain 1 (CISD1)} is an outer mitochondrial membrane protein essential for sensing and regulation of iron and ROS homeostasis (Yuan et al, 2016;Mittler et al, 2018). MitoNEET receives its clusters from the mitochondrion and transfers them to acceptor proteins and limits mitochondrial iron uptake from LIP and therefore suppresses ferroptosis (Yuan et al, 2016).…”