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 #
7R01HL070250-12
Application #
8909894
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Krull, Holly
Project Start
2014-08-09
Project End
2018-07-31
Budget Start
2014-08-20
Budget End
2015-07-31
Support Year
12
Fiscal Year
2014
Total Cost
$396,900
Indirect Cost
$151,900
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Sommese, Leandro; Valverde, Carlos A; Blanco, Paula et al. (2016) Ryanodine receptor phosphorylation by CaMKII promotes spontaneous Ca(2+) release events in a rodent model of early stage diabetes: The arrhythmogenic substrate. Int J Cardiol 202:394-406
Wu, Yuejin; Valdivia, H├ęctor H; Wehrens, Xander H T et al. (2016) A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock. Circ Arrhythm Electrophysiol 9:e003180
Habecker, Beth A; Anderson, Mark E; Birren, Susan J et al. (2016) Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease. J Physiol 594:3853-75

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