Abstract P1045: Targeting The EF-hand Containing Domain 1 Protein (EFHD1) In Cardiac Disease

Abstract

Mitochondrial dysfunction due to calcium overload is common in heart disease and results in heart failure. In a mouse model of mitochondrial cardiomyopathies we noted a substantial downregulation of the gene encoding for the EF hand containing domain 1 protein (EFHD1). EFHD1 is a mitochondrial protein which binds calcium and has been shown to stimulate both apoptosis and mitoflashes. These processes involve mitochondrial calcium overload. We hypothesized that EFHD1 down regulation could represent a natural response by failing hearts to prevent mitochondrial calcium overload by increasing the calcium handling of mitochondria. We therefore studied the calcium handling properties of mice where EFHD1 had been knocked out using CRISPR Cas9. These mice are viable and we have found no adverse cardiac or metabolic phenotypes. We find that EFHD1 is expressed in the intermembrane space of the mitochondria and associates strongly with endoplasmic reticulum (ER)-associated mitochondrial membranes. Mitochondria isolated from Efhd1 knockout mice also exhibited a <250±10 % improvement in calcium retention in liver and neonatal mouse hearts were 3 times more resistant to hypoxia. Further, Efhd1-/- cardiomyocytes exhibit reduced ROS and mitoflash events at both baseline and following ischemia-reperfusion. These findings suggest that EFHD1 participates in ER-mitochondrial calcium exchange and that EFHD1 ablation is cardioprotective during ischemia-reperfusion.