Small Molecule Regulation of Mitochondrial Ca2+ Uniporter (MCU) Channel for Treatment of Multi-Organ Failure

The systemic inflammatory response in sepsis has devastating consequences resulting in high morbidity and mortality. Over the past decade. mortality from sepsis alone has remained greater than 25%. despite effective antimicrobial therapy. In particular. the survival rate of the Hispanic population with other complications and combat casualties are often poorer. This highlights lack of understanding of the pathways operative in sepsis and the necessity for improved therapies. One of the major changes that occur during Multi-organ-failure (MOF) in severe sepsis is mitochondrial dysfunction. Under aerobic conditions. energy conserving molecules produced in the Tri-Carboxylic Acid cycle are utilized by the Electron Transport Chain to produce ATP in a pro-cess known as oxidative phosphorylation (OXPHOS). During sepsis. OXPHOS can become impaired. and or-gans rich in mitochondria become highly susceptible to injury. While oxygen deprivation is known to compro-mise mitochondrial function. it remains poorly understood how ion channels like MCU may act as a regulator of organ function during sepsis. To identify and establish the components that participate in LPS-mediated mito-chondrial reprogramming and MOF. we will utilize multiple innovative approaches including. the newly designed small molecule MCU inhibitor. MCU knockout (Cell Reports 2016). CRISPR/Cas9-mediated MCU knock-in (Cell Reports 2019) mouse models. and multiomic tools coupled with systems biology (Science 2019). In par-allel we will develop a small molecule screening program using in silico drug design strategies based on the CryoEM structure of MCU-ligand interaction for identification and synthesis of small molecules that could be further tested for next generation MCU regulators.