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Cellular Biology Article Discussion “Mitochondrial Death Channels” by Webster, K.A., American Scientist, October 2009 http www.americanscientist.org/issues/feature/2009/5/mitochondrial-death-channels/1
Introduction
Mitochondria are important organelles responsible for cellular respiration and generation of energy in all multicellular organisms. Often referred to as the powerhouse of the cell, the mitochondria produce energy from glucose and oxygen in the form of the high-energy compound, ATP. Thus, mitochondria function in an oxic environment. The presence of thrombosis that is, clogging of a coronary artery by a blood clot leads to ischemia or reduced blood supply to the cardiac tissue, and unhindered ischemia results in heart attack. In many victims of heart attack, reperfusion that is, the resumption of the flow of oxygenated blood leads to further pathogenesis known as reperfusion injury. It is well recognized that mitochondria have an important role to play in the development of reperfusion injury. Against this backdrop, the paper titled, “Mitochondrial Death Channels” by Webster, K.A., addresses the actual mechanism of mitochondrial action of promoting reperfusion injury. The important and individual roles played by two mitochondrial death channels, the mitochondrial permeability transition pore (mPTP) and the mitochondrial apoptosis channel (mAC) in the promotion of infarction are described. It explains in detail, how, during a heart attack, mPTP, under the regulation of calcium and oxidative stress, causes necrotic death while both mPTP and mAC channels are involved in apoptosis.
Discussion
Apoptosis or programmed cell death is an intrinsic cellular process, just as mitosis is. Cell suicides are resorted to in the course of development for example, resorption of the tadpole tail during metamorphosis into a frog, or to destroy cells that represent a threat to the integrity of the organism, or when signals needed for continued survival are lacking. Apoptosis is different from necrosis in that it affects individual cells whereas necrosis affects groups of contiguous cells. Cardiovascular diseases which are the leading cause of death in all developed countries are characterized by the loss of cardiomyocytes due to cell death. Earlier, cell death in myocardial infarction was believed to be caused solely by necrosis. However, recent studies have shown the involvement of apoptosis, too, in the process of myocardial tissue damage subsequent to heart attack (Krijnen et al., 2002). Besides, apoptosis in cardiomyocytes is mediated by mitochondria through the two mitochondrial death channels namely, mPTP and mAC as shown in the current paper.
Mitochondria are known to be important mediators of cardiac injury during ischemia and reperfusion (Chen et al., 2006). The electron transport chain undergoes a blockade due to lack of oxygen during myocardial ischemia (Chen et al., 2006; Webster, 2009) while, during reperfusion, a spurt in reactive oxygen species occurs because of an overwhelmed antioxidant system leading to oxidative stress and initiation of reperfusion injury. Mitochondrial calcium overload is also a central feature of cardiomyocyte death following reperfusion. The free radicals of oxygen together with calcium ions target the first mitochondrial death channel, mPTP causing it to open, triggering cell death.
Conclusion
In conclusion, the fact that the opening of the mitochondrial death channels is associated with both the processes believed to cause reperfusion injury, that is, classical apoptosis and programmed necrosis, has therapeutic implications. Therapies designed to minimize the extent of either could hold promise for acute coronary syndromes. Indeed, some pharmacological compounds are already known (e.g., cyclosporine A, currently used as an immunosuppressant and sildenafil citrate, an approved drug for erectile dysfunction) that have the potential to curtail the opening of the mitochondrial death channels, and thereby reduce tissue damage due to heart attack. Mitochondrial damage is the cause of several other diseases as well. Yet very few therapies that target mitochondria have been developed because of problems associated with delivering the drugs to mitochondria in vivo (Smith et al., 2003).
References
Chen, Q., Camara, A.K.S., Stowe, D.F., Hoppel, C.L. et al., 2006. Modulation of electron
transport protects cardiac mitochondria and decreases myocardial injury during
ischemia and reperfusion. Am J Physiol Cell Physiol 292: C137-C147
Accessed 20 September 2009.
http://ajpcell.physiology.org/cgi/content/full/292/1/C137
Krijnen, P A J., Nijmeijer, R., Meijer, C J L M., Visser, C A et al., 2002. Apoptosis in
myocardial ischaemia and infarction. Journal of Clinical Pathology 55(11): 801–811.
Accessed 19 Sep 2009.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1769793
Smith R.A.J., Porteus, C.M., Gane, A.M., & Murphy, M.P. 2003. Delivery of bioactive
molecules to mitochondria in vivo. PNAS 100(9): 5407-5412.
Accessed 19 September 2009. http://www.pnas.org/content/100/9/5407.full Read More