Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy
Elizabeth D Luczak,
Jonathan M. Granger,
Mei-ling A Joiner,
Nicholas R Wilson,
Kevin R. Murphy,
Oscar E Reyes Gaido,
Albert JR Heck,
Robert G. Weiss,
Mark E. Anderson
Posted 14 Feb 2020
bioRxiv DOI: 10.1101/2020.02.13.947564 (published DOI: 10.1038/s41467-020-18165-6)
Posted 14 Feb 2020
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 found increased mitochondrial calmodulin kinase II (CaMKII) activation and left ventricular dilation in mice one week after myocardial infarction (MI) surgery. In contrast, mice with genetic mitochondrial CaMKII inhibition were protected from left ventricular dilation and dysfunction after MI. Mice with myocardial and mitochondrial CaMKII over-expression (mtCaMKII) had severe dilated cardiomyopathy and decreased ATP that caused elevated cytoplasmic resting (diastolic) Ca2+ concentration and reduced mechanical performance. We mapped a metabolic pathway that allowed us to rescue disease phenotypes in mtCaMKII mice, providing new 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.
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