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.
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.
|Wang, Heng; Do, Danh C; Liu, Jinxin et al. (2018) Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 141:586-600.e6|
|Wang, Qiongling; Quick, Ann P; Cao, Shuyi et al. (2018) Oxidized CaMKII (Ca2+/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy. Circ Arrhythm Electrophysiol 11:e005682|
|Yan, Jiajie; Zhao, Weiwei; Thomson, Justin K et al. (2018) Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis. Circ Res 122:821-835|
|Qu, Jingjing; Do, Danh C; Zhou, Yufeng et al. (2017) Oxidized CaMKII promotes asthma through the activation of mast cells. JCI Insight 2:e90139|
|Chakravarti, Bandana; Yang, Jianqi; Ahlers-Dannen, Katelin E et al. (2017) Essentiality of Regulator of G Protein Signaling 6 and Oxidized Ca2+/Calmodulin-Dependent Protein Kinase II in Notch Signaling and Cardiovascular Development. J Am Heart Assoc 6:|
|Anderson, Mark E; Ray, Stuart C (2017) It's 10 pm; Do You Know Where Your Data Are? Data Provenance, Curation, and Storage. Circ Res 120:1551-1554|
|Morris, Angie S; Sebag, Sara C; Paschke, John D et al. (2017) Cationic CaMKII Inhibiting Nanoparticles Prevent Allergic Asthma. Mol Pharm 14:2166-2175|
|Feng, Ning; Anderson, Mark E (2017) CaMKII is a nodal signal for multiple programmed cell death pathways in heart. J Mol Cell Cardiol 103:102-109|
|Sebag, Sara C; Koval, Olha M; Paschke, John D et al. (2017) Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma. JCI Insight 2:e88297|
|Unudurthi, Sathya D; Wu, Xiangqiong; Qian, Lan et al. (2016) Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability. J Am Heart Assoc 5:e002865|
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