CaMKII determines mitochondrial stress responses in heart
| Autor: | Stefan Strack, Mark E. Anderson, Jinying Yang, Thomas D. Scholz, Olha M. Koval, Biyi Chen, Steven A. Moore, Long-Sheng Song, Duane D. Hall, Jingdong Li, B. Julie He, Zhan Gao, William I. Sivitz, Elizabeth D. Luczak, Mei Ling A. Joiner, Peter J. Mohler, Chantal Allamargot, Brian D. Fink |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Myocardial Infarction Apoptosis Mice Transgenic 030204 cardiovascular system & hematology Mitochondrion Mitochondrial Membrane Transport Proteins Article Mitochondria Heart Mice 03 medical and health sciences Mitochondrial membrane transport protein 0302 clinical medicine Stress Physiological Ca2+/calmodulin-dependent protein kinase Cyclosporin a Internal medicine Serine medicine Animals Inner mitochondrial membrane Heart metabolism 030304 developmental biology Heart Failure Membrane Potential Mitochondrial 0303 health sciences Multidisciplinary biology Mitochondrial Permeability Transition Pore Myocardium Heart medicine.disease Mice Inbred C57BL Endocrinology nervous system Mitochondrial permeability transition pore Reperfusion Injury Cyclosporine cardiovascular system biology.protein Calcium Female Calcium-Calmodulin-Dependent Protein Kinase Type 2 Reperfusion injury |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature11444 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|