CaMKII determines mitochondrial stress responses in heart.
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). However, the signalling pathways that control mitochondrial Ca(2+) entry through the inner membrane mitochondrial Ca(2+) uniporter (MCU) 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, 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.
Department of Internal Medicine and Cardiovascular Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. mei-ling-joiner@uiowa.edu
Mei-Ling A
ML
Joiner
Olha M
OM
Koval
Jingdong
J
Li
B Julie
BJ
He
Chantal
C
Allamargot
Zhan
Z
Gao
Elizabeth D
ED
Luczak
Duane D
DD
Hall
Brian D
BD
Fink
Biyi
B
Chen
Jinying
J
Yang
Steven A
SA
Moore
Thomas D
TD
Scholz
Stefan
S
Strack
Peter J
PJ
Mohler
William I
WI
Sivitz
Long-Sheng
LS
Song
Mark E
ME
Anderson
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy / Q000517:prevention & control; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000188:drug therapy / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012694:Serine / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D012694:Serine; D016572:Cyclosporine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium