An anti-diabetic drug targets NEET (CISD) proteins through destabilization of their [2Fe-2S] clusters

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.