Mitochondrial CaMKII causes adverse metabolic reprogramming and dilated cardiomyopathy

Elizabeth D. Luczak (), Yuejin Wu, Jonathan M. Granger, Mei-ling A. Joiner, Nicholas R. Wilson, Ashish Gupta, Priya Umapathi, Kevin R. Murphy, Oscar E. Reyes Gaido, Amin Sabet, Eleonora Corradini, Wen-Wei Tseng, Yibin Wang, Albert J. R. Heck, An-Chi Wei (), Robert G. Weiss and Mark E. Anderson ()
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Elizabeth D. Luczak: The Johns Hopkins University School of Medicine
Yuejin Wu: The Johns Hopkins University School of Medicine
Jonathan M. Granger: The Johns Hopkins University School of Medicine
Mei-ling A. Joiner: University of Iowa Carver College of Medicine
Nicholas R. Wilson: The Johns Hopkins University School of Medicine
Ashish Gupta: The Johns Hopkins University School of Medicine
Priya Umapathi: The Johns Hopkins University School of Medicine
Kevin R. Murphy: The Johns Hopkins University School of Medicine
Oscar E. Reyes Gaido: The Johns Hopkins University School of Medicine
Amin Sabet: The Johns Hopkins University School of Medicine
Eleonora Corradini: Utrecht University
Wen-Wei Tseng: National Taiwan University
Yibin Wang: University of California
Albert J. R. Heck: Utrecht University
An-Chi Wei: The Johns Hopkins University School of Medicine
Robert G. Weiss: The Johns Hopkins University School of Medicine
Mark E. Anderson: The Johns Hopkins University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18165-6

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