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Name: Alex
Status: student
Grade: 9-12
Location: Outside U.S.
Country: Canada
Date: Fall 2012


Question:
When a cell suffers total oxygen deprivation, what causes it to actually die? This might seem like a stupid question at first, but consider the following: if the problem is simply a lack of oxygen, why can't that cell become active again by oxygen being restored to it, like refeuling a car that has run out of gas? What is the process that causes that cell to cross the threshold into permanent cell death and when does this process occur?



Replies:
The basic point here is entropy. Ordered things tend to move to work disorder.

Cells are highly ordered systems. You need to have continuous energy input to maintain order, to maintain life, or homeostasis.

Oxygen is required to break down food into that energy.

Without input of energy the cell cannot maintain order and cell functions will cease. After cell death the disorder continues to increase so the longer the cell is dead the harder it is to return to a living configuration.

This is not just a thermodynamic argument there are also enzymes and other chemical materials that serve to break down cellular components. Without energy input, new components cannot be made to refresh those that are lost.

You could theoretically reassemble all the parts in the exact right way and begin life again however this has proven practically an impossibility.

Hope this helps, Burr


Alex,

This is a great question! One might think that since cells are essentially complex machines, it should be possible to simply 'stop' them when a required input (such as oxygen or glucose) is shut off, and restart it when that input is again resumed. Indeed, for decades researchers have regularly frozen cells and thawed them. Under appropriate conditions, such cells can generally recover to a healthy state, suggesting that your underlying logic is correct. However, this is obviously not the case in the case of oxygen deprivation of human cells. When major organs are deprived of a blood (and thus oxygen) supply for any length of time, they are quickly damaged and can lead to significant amounts of cell death and systemic shutdown. Heart attacks and strokes are two prominent examples of this phenomenon.

The reason why oxygen deprivation is generally not reversible on a cellular scale is because of a complex series of cellular responses that occur during hypoxia (or oxygen deprivation). To understand this, we must examine how molecular oxygen is used in the cell. Its main purpose is in cellular respiration to produce ATP (and thus energy) for the cell. Cells break down glucose in order to produce ATP, and the end of this process consumes oxygen in the mitochondria (for more information on this, see: oxidative phosphorylation). Under hypoxic conditions, the cell cannot make as much ATP as before, as it is forced to rely on inefficient methods of producing ATP that do not use oxygen. A byproduct of this process is the buildup of lactic acid in the cell which itself can be mildly toxic.

Due to the lower than usual ATP levels in the cell, certain energy-intensive cellular processes begin to fail. The major one of interest is a series of ATP-dependent ion pumps on the cell surface. These pumps use the energy liberated by breaking down ATP to pump ions (such as sodium, potassium, and calcium) across the cell membrane in order to provide the appropriate balance of ions inside and outside the cell. These ion gradients are used heavily by cells for internal signalling and other crucial processes (such as muscle contraction and nerve signal propagation). A major result of lower ATP levels, then, is an abnormal increase in calcium ion levels inside the cell. Calcium ions are potent signalling molecules, and high levels can result in the production, release, and activation of a variety of chemical and proteins that are harmful to the cell (among them reactive oxygen species, proteins that degrade other proteins, DNA, and phospholipids that make up the cell membrane, etc.). These harmful chemicals and proteins start to break down critical components of the cell, including the mitochondrial membrane. Inside the mitochondria are even more destructive proteins called caspases that trigger the programmed death of the cell, or apoptosis. Depending on the circumstances, the cells may instead undergo a less organized form of cell death called necrosis, but in either case the basic result is the same: what started as a simple lack of oxygen and enough ATP cascaded into a series of escalating injuries to the integrity of the cell and its components, eventually leading to its death.

There is an additional concern in cases of hypoxia. In cases when a tissue has been deprived of blood supply for a period of time (through, say, a blockage in a blood vessel), when blood supply is restored the cells may be further damaged by a complex process called reperfusion injury. Essentially, as blood returns to the tissue, it can cause a variety of oxidative damage (redox chemical reactions that damage the molecules of the cell) as well as significant inflammation. These processes can further damage the tissue and kill cells that might have survived the primary oxygen deprivation.

The remarkable lesson here is that cells spend a huge proportion of their energy on maintaining the appropriate balance of ions inside and outside the cell, and that disrupting this balance can rapidly lead to cell death. In some cells, ion pumps are responsible for up to 2/3 of the energy expenditure of the entire cell! In a sense, then, the cell's response to a disruption in the ion gradients makes sense. If ion levels inside the cell become abnormal, this is a sign that something is very wrong indeed, possibly with the integrity of the cell membrane. Thus, the cell's machinery sacrifices itself as a lost cause given the damage it presumes it has suffered. It is only through our medical eyes that this process seems premature in the case of hypoxia brought about through a heart attack or stroke.

S. Unterman Ph.D.



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