CaMKII determines mitochondrial stress responses in heart

• Published in: Nature (London) Vol. 491; no. 7423; pp. 269 - 273
• Main Authors: Joiner, Mei-ling A., Koval, Olha M., Li, Jingdong, He, B. Julie, Allamargot, Chantal, Gao, Zhan, Luczak, Elizabeth D., Hall, Duane D., Fink, Brian D., Chen, Biyi, Yang, Jinying, Moore, Steven A., Scholz, Thomas D., Strack, Stefan, Mohler, Peter J., Sivitz, William I., Song, Long-Sheng, Anderson, Mark E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.11.2012; Nature Publishing Group
• Subjects: 631/443/319/333; 631/443/592/75/230; 631/80/86/1999; Animals; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Calcium - metabolism; Calcium - pharmacology; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - chemistry; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calmodulin; Cardiology. Vascular system; Cell death; Coronary heart disease; Cyclosporine - pharmacology; Female; Heart; Heart - drug effects; Heart - physiopathology; Heart attacks; Heart cells; Heart failure; Heart Failure - drug therapy; Heart Failure - prevention & control; Homeostasis; Humanities and Social Sciences; letter; Medical sciences; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Mitochondria, Heart - enzymology; Mitochondria, Heart - metabolism; Mitochondria, Heart - pathology; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial myopathies; Mortality; multidisciplinary; Myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - prevention & control; Myocardium - enzymology; Myocardium - metabolism; Myocardium - pathology; Observations; Properties; Protein kinases; Proteins; Reperfusion Injury - enzymology; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Rodents; Science; Serine - metabolism; Stress, Physiological - drug effects; United States; Heart; Myocardial infarction; calmodulin-dependent protein kinase; Enzyme; Transferases; Ischemia reperfusion; Rodentia; Cardiovascular disease; Permeability; Coronary heart disease; Myocardial disease; Stress; Vertebrata; Mitochondria; Mammalia; Mouse; Animal; Ca
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11444

Calcium exchange and cardiac stress Increased mitochondrial calcium entry has been implicated in myocardial death, heart failure and related conditions. Here, the authors show that inhibition of the multifunctional Ca 2+ - and calmodulin-dependent protein kinase II (CaMKII) in a mouse model of ischaemia reperfusion injury reduces infarct size and mitochondrial-triggered cell death and dysfunction. This is due to reduced mitochondrial Ca 2+ entry through the mitochondrial calcium uniporter and enhanced Ca 2+ tolerance of the mitochondrial permeability transition pore. This suggests that CaMKII inhibition could reduce adverse responses to common forms of pathological myocardial stress. Myocardial cell death is initiated by excessive mitochondrial Ca 2+ entry causing Ca 2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm) 1 , 2 . However, the signalling pathways that control mitochondrial Ca 2+ entry through the inner membrane mitochondrial Ca 2+ uniporter (MCU) 3 , 4 , 5 are not known. The multifunctional Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is activated in ischaemia reperfusion, myocardial infarction and neurohumoral injury, common causes of myocardial death and heart failure; these findings suggest that CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current ( I MCU ). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A, an mPTP antagonist with clinical efficacy in ischaemia reperfusion injury 6 , equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to ischaemia reperfusion injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition have reduced I MCU and are resistant to ischaemia reperfusion injury, myocardial infarction and neurohumoral injury, suggesting that pathological actions of CaMKII are substantially mediated by increasing I MCU . Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca 2+ entry in myocardial cell death, and indicate that mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure in response to common experimental forms of pathophysiological stress.