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Oct 12, 2012

Mitochondrial Enzyme Blockade Protects Against Heart Cell Death

  • Studies in mice suggest that blocking an enzyme involved in transporting calcium ions into mitochondria could help prevent the death of heart cells following a heart attack or other forms of cardiac stress, researchers claim. A University of Iowa Health Care team had previously found that the enzyme, Ca2+/calmodulin-dependent protein kinase II (CaMKII) is overactivated in conditions marked by disturbed intracellular Ca2+ homeostasis, including ischemic reperfusion, myocardial infarction, and neurohumoral injury, and that inhibiting the enzyme has a protective effect. However, the mechanisms involved weren’t clear.

    The team has now found that CaMKII activation promotes opening of the mitochondrial permeability transition pore (mPTP) and dissipates the mitochondrial inner membrane potential, effectively allowing too much calcium to enter the mitochondria, which leads to apopotosis. University of Iowa Carver College of Medicine professor Mark E. Anderson, M.D., and colleagues found that treating mouse models of cardiac injury using a mitochondrial-targeted CaMKII inhibitory protein or the mPTP antagonist cyclosporine A blocked these cell-fatal effects, and protected against ischemic reperfusion injury, myocardial infarction, and neurohomoral injury.

    “Our findings identify CaMKII as a modulator of mitochondrial Ca2+ homeostasis and a crucial component of a final Ca2+-dependent pathway in heart disease due to ischaemia and neurohumoral toxicity,” they write in Nature. “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.”

    The results, published in a paper titled “CaMKII determines mitochondrial stress responses in heart,” could also be relevant to the design of therapeutic approaches for other diseases, Dr. Anderson states. “Because mitochondria also play important roles in other diseases in brain and skeletal muscle, for example, our findings could also have broad implications for understanding and treating noncardiac diseases.”


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