The Alexander Silberman Institute of Life Science and The Wolfson Centre for Applied Structural Biology, Faculty of Science and Mathematics, The Edmond J. Safra Campus at Givat Ram, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
Department of Physics, RWTH Aachen University, 52074, Aachen, Germany.
Commun Biol. 2022 May 10;5(1):437. doi: 10.1038/s42003-022-03393-x.
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.
线粒体铁水平和活性氧（ROS）升高伴随着糖尿病的发展，对胰腺细胞胰岛素的产生和分泌产生负面影响。为了寻找一种降低线粒体铁和 ROS 水平的工具，我们发现了一种能够使 NEET 蛋白的[2Fe-2S]簇不稳定的分子（M1）。用 M1 治疗 db/db 糖尿病小鼠可改善高血糖，而不会像罗格列酮等其他治疗方法那样导致体重增加。通过 X 射线晶体学确定了 M1 与 NEET 蛋白 mNT 和 NAF-1 的分子相互作用。通过使 NEET 蛋白的[2Fe-2S]簇不稳定从而降低铁介导的氧化应激的分子来控制糖尿病的可能性，为管理代谢异常（如糖尿病）开辟了新途径。
