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, Mark E. Anderson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number4416
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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