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Programmed cell death (PCD), or apoptosis, is a normal part of the metabolism of animals. Sometimes this process can happen at the wrong developmental stage, causing disease. Normally, enzymes called caspases are responsible for inducing cell death. An alternative process to bring about PCD is a protein called apoptosis-inducing factor (AIF). This protein is located in the mitochondria and relocates to the nucleus to cause DNA degradation and subsequent cell death.
Apoptosis is a normal part of cellular metabolism. The human body constantly has cells die and then replaces them. If the process is not regulated correctly, it can have severe affects on human physiology. For instance, cancer cells undergo PCD much less frequently than healthy cells and are able to spread and become tumors. Alternatively, if the regulation causes apoptosis to happen too frequently, cells can die off when they are needed for tissue function.
Mitochondria are cellular structures that are separated from the rest of the cell by an outer membrane. They also have an inner membrane. Between these two membranes is a space filled with fluid that contains many proteins, particularly those involved in generating energy for the cells. Apoptosis-inducing factor is found in this space, and functions in the respiratory pathway.
Many of the proteins involved in bringing about the death of cells are caspases, but apoptosis-inducing factor is an entirely different type of protein. This enzyme is a flavoprotein, a specialized protein involved in transferring electrons. It is found in a wide array of eukaryotic cells, ranging from humans to the pond ciliate organism Tetrahymena. Studies of the sequence of the protein and genes that encode the apoptosis-inducing factors have shown that it is an ancient protein and dates back very far in evolution.
When early signals initiate PCD, the outer membrane of the mitochondria becomes leaky. AIF is released from its compartment in the mitochondria and enters the cytosol, the cell’s liquid milieu. From there, it reaches the nucleus. This protein causes the DNA in the nucleus to fragment. In the process, it affects the structural integrity of the nucleus by disrupting chromatin structure, bringing about an early stage of programmed cell death.
The regulation of apoptosis-inducing factor has been studied very thoroughly in animal models. This has led to correlations of AIF activity and the death of neuron cells. Diseases such as Lou Gehrig’s disease have been correlated with such activity in studies with animals.
Many human diseases are known to be due to functional problems with mitochondria. Another type of misregulation can happen to apoptosis-inducing factor while it is still in its mitochondrial location. Genetic studies have correlated mutations that affect AIF while it is localized in its normal cellular compartment to a number of human diseases based on malfunction of the mitochondria.