CaMKII determines mitochondrial stress responses in heart

Mei Ling A. Joiner, Olha M. Koval, Jingdong Li, B. Julie He, Chantal Allamargot, Zhan Gao, Elizabeth D. Luczak, Duane D. Hall, Brian D. Fink, Biyi Chen, Jinying Yang, Steven A. Moore, Thomas D. Scholz, Stefan Strack, Peter J. Mohler, William I. Sivitz, Long Sheng Song, Mark E. Anderson

Research output: Contribution to journalArticle

Abstract

Myocardial cell death is initiated by excessive mitochondrial Ca 2+ entry causing Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm). However, the signalling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU) are not known. The multifunctional Ca2+/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, 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)269-273
Number of pages5
JournalNature
Volume491
Issue number7423
DOIs
StatePublished - Nov 8 2012
Externally publishedYes

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    Joiner, M. L. A., Koval, O. M., Li, J., Julie He, B., Allamargot, C., Gao, Z., Luczak, E. D., Hall, D. D., Fink, B. D., Chen, B., Yang, J., Moore, S. A., Scholz, T. D., Strack, S., Mohler, P. J., Sivitz, W. I., Song, L. S., & Anderson, M. E. (2012). CaMKII determines mitochondrial stress responses in heart. Nature, 491(7423), 269-273. https://doi.org/10.1038/nature11444