Mitochondrial CaMKII causes adverse metabolic reprogramming and dilated cardiomyopathy

Elizabeth D Luczak,Wen-Wei Tseng,Nicholas R Wilson,Oscar E Reyes Gaido,Eleonora Corradini,Robert G Weiss,Yuejin Wu,Mark E Anderson,An-Chi Wei,Jonathan M Granger,Mei-Ling A Joiner,Albert J R Heck,Priya Umapathi,Amin Sabet,Yibin Wang,Kevin R Murphy,Ashish Gupta

doi:10.1038/s41467-020-18165-6

Abstract

Despite the clear association between myocardial injury, heart failure and depressed myocardial energetics, little is known about upstream signals responsible for remodeling myocardial metabolism after pathological stress. Here, we report increased mitochondrial calmodulin kinase II (CaMKII) activation and left ventricular dilation in mice one week after myocardial infarction (MI) surgery. By contrast, mice with genetic mitochondrial CaMKII inhibition are protected from left ventricular dilation and dysfunction after MI. Mice with myocardial and mitochondrial CaMKII overexpression (mtCaMKII) have severe dilated cardiomyopathy and decreased ATP that causes elevated cytoplasmic resting (diastolic) Ca2+ concentration and reduced mechanical performance. We map a metabolic pathway that rescues disease phenotypes in mtCaMKII mice, providing insights into physiological and pathological metabolic consequences of CaMKII signaling in mitochondria. Our findings suggest myocardial dilation, a disease phenotype lacking specific therapies, can be prevented by targeted replacement of mitochondrial creatine kinase or mitochondrial-targeted CaMKII inhibition.

Highlights

Despite the clear association between myocardial injury, heart failure and depressed myocardial energetics, little is known about upstream signals responsible for remodeling myocardial metabolism after pathological stress
calmodulin kinase II (CaMKII) was recently identified in mitochondria[23,25,32], and mitochondrial CaMKII inhibition protects against myocardial death, acutely, during the first hours after myocardial infarction[25]
We tested whether mitochondrial CaMKII activity is increased in failing hearts by measuring total and threonine 287 auto-phosphorylated CaMKII, a marker of CaMKII activation[33], in mitochondria isolated from mouse hearts following myocardial infarction or sham surgery

Summary

Introduction

Despite the clear association between myocardial injury, heart failure and depressed myocardial energetics, little is known about upstream signals responsible for remodeling myocardial metabolism after pathological stress. We report increased mitochondrial calmodulin kinase II (CaMKII) activation and left ventricular dilation in mice one week after myocardial infarction (MI) surgery. Loss of creatine kinase[3] and decreased mitochondrial respiration[4] are common findings in myocardium after pathological injury, including myocardial infarction (MI), a major cause of heart failure. Failing hearts have reduced energy reserves, little is known about upstream control points contributing to decreased energy metabolism, nor the specific structural and functional consequences of these defects on myocardial responses to injury. MI triggers a complex set of changes in myocardium, including cardiomyocyte death and cardiac fibrosis, hypertrophy, and chamber dilation. These changes are termed adverse structural remodeling.

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