Abstract
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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References
Kroemer, G. & Reed, J. C. Mitochondrial control of cell death. Nature Med. 6, 513–519 (2000)
Clapham, D. E. Calcium signaling. Cell 131, 1047–1058 (2007)
Kirichok, Y., Krapivinsky, G. & Clapham, D. E. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360–364 (2004)
Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011)
De Stefani, D., Raffaello, A., Teardo, E., Szabo, I. & Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011)
Piot, C. et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N. Engl. J. Med. 359, 473–481 (2008)
Erickson, J. R. et al. A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133, 462–74 (2008)
Yang, Y. et al. Calmodulin kinase II inhibition protects against myocardial cell apoptosis in vivo. Am. J. Physiol. Heart Circ. Physiol. 291, H3065–H3075 (2006)
Zhang, T. et al. The δC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure. Circ. Res. 92, 912–919 (2003)
Odagiri, K. et al. Local control of mitochondrial membrane potential, permeability transition pore and reactive oxygen species by calcium and calmodulin in rat ventricular myocytes. J. Mol. Cell. Cardiol. 46, 989–997 (2009)
Zhang, R. et al. Calmodulin kinase II inhibition protects against structural heart disease. Nature Med. 11, 409–417 (2005)
García-Rivas, G. J., Carvajal, K., Correa, F. & Zazueta, C. Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br. J. Pharmacol. 149, 829–837 (2006)
Singh, M. V. et al. Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart. J. Clin. Invest. 119, 986–996 (2009)
Hakem, R. et al. Differential requirement for Caspase 9 in apoptotic pathways in vivo. Cell 94, 339–352 (1998)
Olichon, A. et al. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J. Biol. Chem. 278, 7743–7746 (2003)
Wang, W. et al. Superoxide flashes in single mitochondria. Cell 134, 279–290 (2008)
Halestrap, A. P. What is the mitochondrial permeability transition pore? J. Mol. Cell. Cardiol. 46, 821–831 (2009)
Timmins, J. M. et al. Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. J. Clin. Invest. 119, 2925–2941 (2009)
Sharma, V., Abraham, T., So, A., Allard, M. & McNeill, J. Functional effects of protein kinases and peroxynitrite on cardiac carnitine palmitoyltransferase-1 in isolated mitochondria. Mol. Cell. Biochem. 337, 223–237 (2010)
Anderson, M. E., Brown, J. H. & Bers, D. M. CaMKII in myocardial hypertrophy and heart failure. J. Mol. Cell. Cardiol. 51, 468–473 (2011)
Miyawaki, A. et al. Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin. Nature 388, 882–887 (1997)
Saotome, M. et al. Mitochondrial membrane potential modulates regulation of mitochondrial Ca2+ in rat ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 288, H1820–H1828 (2005)
Fong, Y. L., Taylor, W. L., Means, A. R. & Soderling, T. R. Studies of the regulatory mechanism of Ca2+/calmodulin-dependent protein kinase II. Mutation of threonine 286 to alanine and aspartate. J. Biol. Chem. 264, 16759–16763 (1989)
Hanson, P. I., Meyer, T., Stryer, L. & Schulman, H. Dual role of calmodulin in autophosphorylation of multifunctional cam kinase may underlie decoding of calcium signals. Neuron 12, 943–956 (1994)
Koval, O. M. et al. CaV1.2 b-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations. Proc. Natl Acad. Sci. USA 107, 4996–5000 (2010)
Wehrens, X. H. T., Lehnart, S. E., Reiken, S. R. & Marks, A. R. Ca2+/calmodulin-dependent protein kinase II phosphorylation regulates the cardiac ryanodine receptor. Circ. Res. 94, e61–e70 (2004)
Feldman, D. S., Carnes, C. A., Abraham, W. T. & Bristow, M. R. Mechanisms of disease: β-adrenergic receptors—alterations in signal transduction and pharmacogenomics in heart failure. Nature Clin. Pract. Cardiovasc. Med. 2, 475–483 (2005)
Wu, Y., Colbran, R. J. & Anderson, M. E. Calmodulin kinase is a molecular switch for cardiac excitation-contraction coupling. Proc. Natl Acad. Sci. USA 98, 2877–2881 (2001)
Li, J. et al. Calmodulin kinase II inhibition enhances ischemic preconditioning by augmenting ATP-sensitive K+ current. Channels 1, 387–394 (2007)
He, B. J. et al. Oxidation of CaMKII determines the cardiotoxic effects of aldosterone. Nature Med. 17, 1610–1618 (2011)
Herlein, J. A., Fink, B. D., O'Malley, Y. & Sivitz, W. I. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology 150, 46–55 (2009)
Acknowledgements
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.).
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M.A.J. designed the project, carried out experimental work and wrote the manuscript. O.M.K. and L.-S.S. carried out experimental work, analysed data and participated in data interpretation. C.A., Z.G. and E.D.L., carried out experimental work and interpreted data. J.L., B.J.H., D.D.H., B.D.F., B.C. and J.Y. carried out experimental work. S.S. provided critical materials and wrote the manuscript. S.A.M. and T.D.S. interpreted data. P.J.M. supervised the research. W.I.S. supervised the research and wrote the manuscript. M.E.A. conceived the project, supervised the research and wrote the manuscript.
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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, Ml., Koval, O., Li, J. et al. CaMKII determines mitochondrial stress responses in heart. Nature 491, 269–273 (2012). https://doi.org/10.1038/nature11444
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DOI: https://doi.org/10.1038/nature11444
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