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 therefore hypothesized that EFHD1 down regulation could represent a natural response by failing hearts to prevent mitochondrial calcium overload. We therefore studied the calcium handling properties of mice where Efhd1 had been knocked out (Efhd1-KO). These mice are viable and have no obvious adverse cardiac or metabolic phenotypes. We find that EFHD1 is expressed in the cytoplasm and mitochondrial outer membrane and intermembrane space. It associates strongly with endoplasmic reticulum (ER)-associated mitochondrial membranes. Moreover, mitochondria isolated from Efhd1-KO mice also exhibited 250±10 % improvement in calcium retention in liver but not heart, while neonatal mouse hearts were 3 times more resistant to hypoxia. These findings suggest that EFHD1 may modulate mitochondrial calcium uptake.
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