EMRE is essential for mitochondrial calcium uniporter activity in a mouse model
Julia C. Liu, Nicole C. Syder, Nima S. Ghorashi, Thomas B. Willingham, Randi J. Parks, Junhui Sun, Maria M. Fergusson, Jie Liu, Kira M. Holmström, Sara Menazza, Danielle A. Springer, Chengyu Liu, Brian Glancy, Toren Finkel, Elizabeth Murphy
Julia C. Liu, Nicole C. Syder, Nima S. Ghorashi, Thomas B. Willingham, Randi J. Parks, Junhui Sun, Maria M. Fergusson, Jie Liu, Kira M. Holmström, Sara Menazza, Danielle A. Springer, Chengyu Liu, Brian Glancy, Toren Finkel, Elizabeth Murphy
View: Text | PDF
Research Article Cardiology Muscle biology

EMRE is essential for mitochondrial calcium uniporter activity in a mouse model

Abstract

The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE’s impact on organismal physiology is less understood. Here we characterize a mouse model of EMRE deletion and show that EMRE is indeed required for mitochondrial calcium uniporter function in vivo. EMRE–/– mice are born less frequently; however, the mice that are born are viable, healthy, and do not manifest overt metabolic impairment, at rest or with exercise. Finally, to investigate the role of EMRE in disease processes, we examine the effects of EMRE deletion in a muscular dystrophy model associated with mitochondrial calcium overload.

Authors

Julia C. Liu, Nicole C. Syder, Nima S. Ghorashi, Thomas B. Willingham, Randi J. Parks, Junhui Sun, Maria M. Fergusson, Jie Liu, Kira M. Holmström, Sara Menazza, Danielle A. Springer, Chengyu Liu, Brian Glancy, Toren Finkel, Elizabeth Murphy

×

Figure 4

Deletion of EMRE does not alter cardiac function or cardiac injury after ischemia/reperfusion.

Options: View larger image (or click on image) Download as PowerPoint
Deletion of EMRE does not alter cardiac function or cardiac injury after...
(A and B) Echocardiography analysis of WT and EMRE–/– male (n = 4 biological replicates per group) and female (n = 5 biological replicates per group) mice assessing ejection fraction (A) and fractional shortening (B). Data are represented as mean ± SD. WT and EMRE–/– mice were compared within each sex using unpaired t test with Welch’s correction. NS, not significant. (C and D) Echocardiography analysis at baseline and 1, 2, 3, and 4 minutes following isoproterenol (2 mg/kg) injection of male WT and EMRE–/– (n = 6 biological replicates per group) mice assessing ejection fraction (C) and fractional shortening (D). Boxes were plotted extending from the 25th to 75th percentiles, with the line in between showing the median; whiskers extend from the minimum to the maximum. The “+” sign indicates the mean. Data were first compared by 2-way ANOVA followed by Bonferroni’s multiple-comparisons test to determine significance for each pair of data sets. **P < 0.01; NS, not significant. (E and F) Assessment in the hearts of WT and EMRE–/– mice with and without cyclosporine A (CsA, 0.2 μM) (n = 10 biological replicates for WT without CsA, n = 5 biological replicates for remaining groups) for 5 minutes before ischemia, following 20 minutes of global ischemia and 90 minutes of reperfusion of the rate pressure product (RPP; heart rate times systolic blood pressure) (E) and infarct size relative to the area at risk, which is the entire left ventricle (F). Data are represented as mean ± SD. Data were first compared by 1-way ANOVA followed by unpaired t test with Welch’s correction to determine significance for each pair of data sets. **P < 0.01; NS, not significant.