An anti-diabetic drug targets NEET (CISD) proteins through destabilization of their [2Fe-2S] clusters
Henri‐Baptiste Marjault, Ola Karmi, Ke Zuo, Dorit Michaeli, Y. Eisenberg-Domovich, Giulia Rossetti, Benoı̂t de Chassey, Jacky Vonderscher, Ioav Cabantchik, Paolo Carloni, Ron Mittler, Oded Livnah, Eric Meldrum, Rachel Nechushtai
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.