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Mitochondrial Death Channels

In heart attacks, cells die if they aren’t perfused with fresh oxygen—and kill themselves if they are. Understanding cell suicide may greatly improve outcomes

Keith A. Webster

Coronary artery disease is the leading cause of morbidity and mortality in North America and Europe. More than 12 million people in the United States have coronary artery disease, and more than 7 million have had a myocardial infarction (heart attack). Chronic stable angina (chest pain) is the initial manifestation of coronary artery disease in approximately half of all presenting patients, and about 16.5 million Americans (more than 5 percent) currently have stable angina.

Figure 1. Severe stenosis in a 53-year-oldClick to Enlarge ImageSurgical interventions to prevent or treat acute myocardial infarction are increasing: More than 1.7 million coronary angioplasty and coronary artery bypass procedures were performed in 2006 in the United States. A major goal of clinical cardiac research is to establish treatment criteria that will limit lethal damage to the heart caused by acute myocardial infarction. Research has focused on the multiple stresses that are unleashed by a heart attack and the effects of these stresses on the intracellular structure and function of cardiac muscle.

The mitochondrion, powerhouse of the cell, is the central player in defining the outcome of heart attacks. Mitochondria contain cellular poisons that are normally sequestered in inactive form, but when unleashed and activated they enforce cell suicide. These suicide regulators are released from mitochondria through mitochondrial death channels. Understanding how the death channels work may hold the key to new treatments that could dramatically reduce myocardial injury and improve the outcome for patients who experience acute myocardial infarction.

A heart attack can affect 50 percent or more of the myocardial left ventricle (which takes in freshly oxygenated blood), causing massive tissue loss and scarring, which is known as infarction. Heart attacks begin with thrombosis; a blood clot wedged in a coronary artery causes reduced blood flow to downstream tissue (ischemia). The cardiac muscle becomes hypoxic (short of oxygen) and acidotic, and the energy level falls because the lack of oxygen interrupts mitochondrial metabolism. Cadiac tissue severely affected by ischemia may cease to contract. Ischemia must be relieved in a timely manner or all of the tissue downstream of the blood clot will die. Relief occurs when the flow of oxygenated blood to the tissue recommences, a process known as reperfusion. The amount of tissue salvaged by reperfusion is determined by the amount of time between the onset of ischemia and removal of the clot.

Clot removal usually involves angioplasty. A flexible needle catheter is inserted into the obstructed coronary artery and a balloon is inflated in the region of the obstruction, compressing the clot against the vessel wall. A stent made of stainless steel—or, lately, high-tech shape-memory alloys—is usually deployed by the catheter in the same region to trap the compressed plaque in place and keep the vessel lumen open when the catheter is removed. When reperfusion delivers oxygen back to the tissue, mitochondria become reenergized and contractions resume. If the ischemic period is short, damage to the heart may be minimal at the onset of reperfusion. However, lethal injury spreads insidiously across the formerly ischemic region over the hours, days and sometimes weeks after reperfusion. This damage, known as reperfusion injury, was first described about 20 years ago. For many heart attack victims, it is the greatest threat to survival.

As reperfusion injury develops, heart cells are forced into a wave of suicide known as apoptosis, or programmed cell death. The stimuli for this are a combination of the reoxygenation component of reperfusion and an imbalance of calcium ions and protons that develops during ischemia and which is exacerbated by reperfusion. The targets for both of these stimuli are the mitochondria. Reperfusion injury begins when mitochondrial death channels open and release the suicide activators. We are only now beginning to fully understand what causes the death channels to open and how the suicide process works. With a fuller understanding, it may be possible to design pharmacological procedures that prevent some of the tissue damage (and deaths) caused by heart attacks.

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