Sinoatrial node (SAN) cells are cardiac pacemaker cells located in the lateral right atrium that require proper Ca2+ handling to produce a rhythmic heart rate (HR). It is well accepted that SAN cells rely on slow depolarizing If channels, sarcoplasmic Ca2+ release and modulation of intracellular Ca2+ by membrane ion channels to modulate HR. The mitochondrial calcium uniporter (MCU) is a newly identified 40 kDa protein that is responsible for Ca2+ influx into mitochondria. I found that inhibiting MCU with the antagonist drug, RU360, blocks isolated SAN cells from increasing beating frequency in response to isoproterenol, a ?-adrenergic receptor agonist. This outcome was reversed when ATP was perfused in the pipette solution. Based on these data, I hypothesize that mitochondrial Ca2+ is a required signal for SAN cells to respond to isoproterenol and that inhibiting MCU prevents mitochondria from matching energy supply with demand. Sinus node dysfunction (SND) is a clinical condition marked by dysregulation of the primary cardiac pacemaker, slowing of the HR and increased risk of arrhythmias and sudden death. At present the only treatment for SND is surgical implantation of a permanent pacemaker, which costs 2 billion dollars annually and is associated with numerous morbidities. Our lab recently reported a novel mechanism in which angiotensin II (Ang II) infused mice developed SND due to SAN cell death. Mitochondrial Ca2+ is a required signal for regulation of metabolic processes, but excessive mitochondrial Ca2+ load can lead to mitochondrial induced cell death. Here I will test the novel concept that the MCU is a gatekeeper for mitochondrial Ca2+ entry but with the potential to permit mitochondrial Ca2+ overload, cell death and SND. I developed mice with genetic MCU inhibition, by myocardial-delimited transgenic expression of a dominant-negative MCU. I will use these new mice to test the potential role of MCU in SAN physiology and in Ang-II induced SND. To my knowledge, this will be the first in vivo study of the MCU in cardiac tissue. The goal of thi work is to determine how mitochondrial Ca2+ contributes to cardiac pacing and explore the effect of MCU inhibition in an Ang II infusion model of SND. My studies will test the hypothesized role of the MCU in SAN physiology and disease using two Specific Aims:
Aim 1 : Determine the physiologic effects of inhibiting Ca2+ influx through the MCU.
Aim 2 : Determine whether MCU inhibition affects physiological HR responses and/or protects against SAN cell death and SND in vivo.

Public Health Relevance

Proper Ca2+ handling in the sinoatrial node (SAN) is required to produce a rhythmic heart rate and important for responding to adrenergic stimuli. The recent identification of the mitochondrial calcium uniporter has allowed me to study how blocking Ca2+ entry into mitochondria effects SAN pacemaking. Heart disease is the leading cause of death for both men and women in the United States and worldwide. Sinus node dysfunction (SND) is a condition marked by inability for propagation of electrical stimuli to surrounding tissues, and can result from heart failure, a relatively common form of heart disease marked by an activation of the renin-angiotensin system. Patients with SND show a slowing of heart rate, increased risk for arrhythmias and heightened risk of sudden death. Currently there are no preventative or pharmacologic therapies for SND. The only treatment for SND is surgical implantation of a permanent pacemaker, a practice that costs over 2 billion dollars annually and has associated morbidities. My studies will test the novel hypothesis that mitochondrial Ca2+ is required for physiologic cardiac pacemaking, but in excess mitochondrial Ca2+ causes angiotensin II-induced sinoatrial cell death and SND. The goal for this work is to determine how mitochondrial Ca2+ contributes to cardiac pacemaking and SND. Completing this work has the potential to identify new therapeutic targets that could prevent or improve outcomes in patients vulnerable to or suffering from SND.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Wang, Wayne C
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
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