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- Title
An anti-diabetic drug targets NEET (CISD) proteins through destabilization of their [2Fe-2S] clusters.
- Authors
Marjault, Henri-Baptiste; Karmi, Ola; Zuo, Ke; Michaeli, Dorit; Eisenberg-Domovich, Yael; Rossetti, Giulia; de Chassey, Benoit; Vonderscher, Jacky; Cabantchik, Ioav; Carloni, Paolo; Mittler, Ron; Livnah, Oded; Meldrum, Eric; Nechushtai, Rachel
- Abstract
Elevated levels of mitochondrial iron and reactive oxygen species (ROS) accompany the progression of diabetes, negatively impacting insulin production and secretion from pancreatic cells. In search for a tool to reduce mitochondrial iron and ROS levels, we arrived at a molecule that destabilizes the [2Fe-2S] clusters of NEET proteins (M1). Treatment of db/db diabetic mice with M1 improved hyperglycemia, without the weight gain observed with alternative treatments such as rosiglitazone. The molecular interactions of M1 with the NEET proteins mNT and NAF-1 were determined by X-crystallography. The possibility of controlling diabetes by molecules that destabilize the [2Fe–2S] clusters of NEET proteins, thereby reducing iron-mediated oxidative stress, opens a new route for managing metabolic aberration such as in diabetes. Marjault et al. report two crystal structures of a drug molecule bound to NEET proteins mNT and NAF-1 and the effects of this molecule on diabetic mice, suggesting an approach for reducing mitochondrial iron and ROS levels in diabetic patients.
- Subjects
INSULIN; DRUG target; MOLECULAR interactions; WEIGHT gain; IRON; REACTIVE oxygen species
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-03393-x