Myocardial cell death is initiated by excessive mitochondrial Ca2+ entry causing Ca2+ 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 Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU)3,4,5 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 (IMCU). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A, an mPTP antagonist with clinical efficacy in ischaemia reperfusion injury6, 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 IMCU and are resistant to ischaemia reperfusion injury, myocardial infarction and neurohumoral injury, suggesting that pathological actions of CaMKII are substantially mediated by increasing IMCU. 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.
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The authors wish to acknowledge discussions with A. Lee, B. Davidson, K. Campbell and C. Sigmund. This work was funded by: AHA 0635357N (M.A.J.); (NIH R01 HL090905 (L.-S.S.); NIH R01 HL079031, R01 HL62494, R01 HL70250 and R01 HL113001 and supported by a grant from the Fondation Leducq for the Alliance for CaMKII Signaling (M.E.A.); NIH R01 HL084583, R01 HL083422 and Pew Scholars Trust (P.J.M.).
M.E.A. is a named inventor on patents claiming to treat heart disease by CaMKII inhibition. He is a founder and advisor to Allosteros Therapeutics. At present no income derives from these activities.
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Joiner, M., Koval, O., Li, J. et al. CaMKII determines mitochondrial stress responses in heart. Nature 491, 269–273 (2012) doi:10.1038/nature11444
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