Expanding and Improving the Toolkit of Mitochondrial Calcium Uptake Inhibitors

University Of California-Santa Barbara, Santa Barbara CA

Investigators

Abstract

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professor Justin Wilson of the University of California Santa Barbara is developing new small-molecule inhibitors of the mitochondrial calcium uniporter (MCU) and probing their mechanisms of action. The MCU is a transporter protein that is responsible for shuttling calcium ions into the mitochondria. The mitochondria, the powerhouses of the cell, are regulated by calcium levels. Excessive quantities of calcium within the mitochondria are often associated with pathological conditions of human disease, including ischemic stroke and heart failure. By developing small-molecule compounds that can inhibit the MCU, his research team will be able to understand the importance of mitochondrial calcium uptake in regulating biological processes, including those implicated in human disease. These efforts will provide training for graduate students within different interdisciplinary areas, including synthetic chemistry and cell biology. In addition, this project will also develop new science outreach activities for middle and high school students. Specifically, Professor Wilson’s team will design a game that introduces students to a range of chemists from different backgrounds and identities. This activity, which will be evaluated in middle and high school classrooms, will help students understand that scientists comprise a diverse group of individuals and that the field is not limited by one’s personal background, thereby encouraging greater participation in STEM. In this project, ruthenium- and osmium-based inhibitors of the MCU will be synthesized and characterized. This work builds upon prior studies in Professor Wilson’s lab that demonstrated dinuclear complexes of these metal ions, like the compound known as Ru265, can exhibit nanomolar inhibitory activity against the MCU and can operate in intact cell systems. The long-term goal of this proposed work is to develop new analogues with improved cell uptake and tunable properties. These efforts will be investigated via the pursuit of three objectives. In the first objective, his team will synthesize releasable analogues of Ru265 with controllable rates of activation triggered by aquation. These analogues will be made by altering their axial ligands, as well as exploring derivatives that are based on the more inert transition metal osmium. These compounds with tunable activation rates will be valuable for probing biological processes that occur on different timescales. Within the second objective, releasable MCU inhibitor that can be activated by specific external stimuli will be developed. Compounds that are triggered by both reactive oxygen species and light irradiation will be designed. In the third objective, the new MCU inhibitor tools will be investigated with in vitro cellular models. First, their abilities to inhibit mCa2+ uptake in intact cells will be investigated, in the presence and absence of different external stimuli. Then, the compound will be investigated with in vitro models of ischemia-reperfusion injury, a pathological condition for which mCa2+ overload is implicated as a key contributing factor. By using these new MCU inhibitors to understand how mCa2+ overload leads to pathological conditions, strategies to prolong quality of life could be discovered. In addition, this project will provide resources to middle and high school STEM teachers that seek to address the underrepresentation of certain groups and identities within science. Specifically, a new game that is focused on providing a personal view and perspective of scientists from diverse backgrounds will be developed. This activity will highlight the contributions of chemists from traditionally underrepresented groups, thus serving to inspire students from similar backgrounds to pursue STEM. These efforts seek to increase diversity within chemistry and related STEM fields. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.