CaMKII determines mitochondrial stress responses in heart
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 ischa...
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Published in | Nature (London) Vol. 491; no. 7423; pp. 269 - 273 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
08.11.2012
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, Jingdong Li and Peter J. Mohler |
ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/nature11444 |