Abstract
Mitochondrial uptake of Ca 2+ plays critical roles in cardiac energy production as well as cell death. The mitochondrial calcium uniporter in mice and humans is a multi-protein complex that includes the channel-forming protein MCU and several other subunit proteins, including EMRE. EMRE is a single transmembrane protein that is conserved among metazoan species and is known to be essential for mitochondrial Ca 2+ uptake in cell culture. To investigate EMRE’s role in organismal physiology, we generated a mouse model of global germline EMRE deletion. We show that EMRE is indeed required for mitochondrial calcium uniporter function in isolated mitochondria from multiple tissues. Although the birth rate of Emre -/- mice is lower than expected by Mendelian genetics (~5-10% instead of ~25%), the mice that are born are viable and appear healthy. Oxygen consumption in isolated mitochondria and cells is not significantly affected by loss of EMRE, and similarly the mice do not exhibit overt metabolic impairment, even under strenuous exercise. No significant differences between Emre -/- and wild-type ( WT ) cardiac function at baseline and after isoproterenol stimulation are evident by echocardiography. Moreover, Emre -/ - hearts are not protected from ischemia/reperfusion injury in a Langendorff perfusion model (mean infarct area 61% in Emre -/- hearts; 57% in WT ). Collectively, these data and their similarities to results found via germline Mcu deletion demonstrate that EMRE is indeed essential for mitochondrial Ca 2+ uptake in vivo. Furthermore, we find evidence that EMRE protein expression is elevated in some mouse muscular dystrophy models, suggesting that modulation of EMRE levels may play a role in regulating uniporter activity in conditions of stress or disease. We therefore further explore whether and how EMRE expression changes with isoproterenol-induced cardiac hypertrophy in mice and in samples from human patients with heart failure. Understanding of how uniporter components such as EMRE can regulate MCU in a diseased state can inform better therapeutic strategies aimed at restoring mitochondrial metabolic homeostasis.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.