Heart failure is a major public health problem without adequate therapies. Loss of myocardial Ca2+ homeostasis and mitochondrial Ca2+ overload are fundamental events driving heart failure progression, but no currently available therapies prevent excessive mitochondrial Ca2+ entry. In 2011, after a 50 year search, two groups independently identified the molecular basis for the mitochondrial Ca2+ uniporter (MCU), the main pathway for Ca2+ entry into mitochondria. We developed new, myocardial-selective transgenic and inducible knock out mouse models of MCU inhibition to test this concept in vivo. Our new mice with myocardial MCU inhibition are viable and our preliminary data show they are resistant to myocardial death after isoproterenol infusion. Here we propose to establish how MCU inhibition contributes to myocardial physiology and disease. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) contributes to heart failure by promoting defective intracellular Ca2+ handling, including mitochondrial Ca2+ overload, but the molecular targets for cardiomyopathic actions of CaMKII are uncertain. During the original period of this competing renewal, we found that CaMKII is present in mitochondria, that mitochondrial CaMKII inhibition reduces MCU- mediated mitochondrial Ca2+ entry and protects against mitochondrial Ca2+ overload in clinically-relevant models of heart failure (Joiner Nature 2012). We identified key sites on MCU (serines 57 and 92) that are essential for CaMKII agonist actions. Thus, MCU is the first validated CaMKII target protein in mitochondria. Here we propose to test the role of mitochondrial CaMKII at MCU in myocardial physiology and disease. The overall goal of this competitive renewal application is to determine the importance of MCU and mitochondrial CaMKII-dependent MCU phosphorylation for myocardial metabolism and disease using 3 specific aims. 1. Determine the effect of MCU inhibition on myocardial physiology;2. Determine the effect of MCU inhibition on myocardial responses to pathological stress;3. Determine the effects of CaMKII-dependent MCU phosphorylation on metabolism and disease.

Public Health Relevance

Heart failure is a major public health problem without adequate therapies. Loss of myocardial calcium homeostasis and mitochondrial calcium overload are fundamental events driving heart failure progression, but no currently available therapies prevent excessive mitochondrial calcium entry. We recently found that the multifunctional calcium and calmodulin-dependent protein kinase II (CaMKII) is present in mitochondria, that mitochondrial CaMKII inhibition reduces mitochondrial calcium entry and protects against mitochondrial calcium overload in clinically-relevant models of heart failure (Joiner Nature 2012). Here we will test the idea that inhibition of mitochondrial calcium entry could become a new and effective treatment for heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL070250-11
Application #
8577808
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Krull, Holly
Project Start
2002-03-11
Project End
2018-07-31
Budget Start
2013-08-15
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$359,380
Indirect Cost
$121,380
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Luczak, Elizabeth D; Anderson, Mark E (2014) CaMKII oxidative activation and the pathogenesis of cardiac disease. J Mol Cell Cardiol 73:112-6
Wu, Yuejin; Anderson, Mark E (2014) CaMKII in sinoatrial node physiology and dysfunction. Front Pharmacol 5:48
Hund, Thomas J; Snyder, Jedidiah S; Wu, Xiangqiong et al. (2014) ?(IV)-Spectrin regulates TREK-1 membrane targeting in the heart. Cardiovasc Res 102:166-75
Zhu, Zhiyong; Sierra, Ana; Burnett, Colin M-L et al. (2014) Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads. J Gen Physiol 143:119-34
Viatchenko-Karpinski, Serge; Kornyeyev, Dmytro; El-Bizri, Nesrine et al. (2014) Intracellular Na+ overload causes oxidation of CaMKII and leads to Ca2+ mishandling in isolated ventricular myocytes. J Mol Cell Cardiol 76:247-56
Anderson, Mark E (2014) Three ways to die suddenly: do they all require calcium calmodulin-dependent protein kinase II? Trans Am Clin Climatol Assoc 125:173-85
Lai, Michael H; Wu, Yuejin; Gao, Zhan et al. (2014) BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo. Am J Physiol Heart Circ Physiol 307:H1327-38
Chakraborty, Asima; Pasek, Daniel A; Huang, Tai-Qin et al. (2014) Inhibition of CaMKII does not attenuate cardiac hypertrophy in mice with dysfunctional ryanodine receptor. PLoS One 9:e104338
Scott, Jason A; Klutho, Paula J; El Accaoui, Ramzi et al. (2013) The multifunctional Caýýýýý/calmodulin-dependent kinase IIýý (CaMKIIýý) regulates arteriogenesis in a mouse model of flow-mediated remodeling. PLoS One 8:e71550

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