Huntingtin and Energy Metabolism
Disease Mechanism III: Abnormalities In Energy Metabolism

Cells produce energy through a process called energy metabolism. The food we eat is broken down to different subunits by various enzymes. These subunits undergo a series of reactions that eventually end up in the production of a molecule called ATP, the energy source of the cell. The pathway by which ATP is produced depends on the availability of oxygen in cells. If there is sufficient amount of oxygen, aerobic respiration takes place in the mitochondria and large amounts of ATP are produced. If there is not enough oxygen in cells, anaerobic respiration is instead performed, which produces a smaller amount of ATP. Aerobic respiration is a more efficient process because it captures more of the energy of the food we eat in ATP molecules.

Glycolysis is a series of reactions that begins the process of metabolism in all cells. It takes place in the cytosol (sometimes also called “cytoplasm”) which is the fluid portion of the cell.

The important molecular products of glycolysis are called pyruvate. Pyruvate can undergo either aerobic or anaerobic respiration depending on the availability of oxygen in cells. In this chapter, we’ll go over how the altered huntingtin protein affects glycolysis, aerobic respiration, and, finally, anaerobic respiration.

The exact mechanism of how huntingtin interferes with energy production is unknown, but studies have revealed that it interacts with a variety of key proteins involved in energy metabolism. For example, the altered huntingtin protein has been found to interact with a molecule known as GAPDH (which stands for glyceraldehyde-3-phosphate dehydrogenase), partially inhibiting its ability to function properly. GAPDH is a key enzyme in glycolysis, the early part of metabolism described above. Research suggests that GAPDH interacts preferentially with small subunits of huntingtin protein rather than the full length protein. But this is precisely what the altered huntingtin turns into in persons with HD: the altered huntingtin protein is readily cleaved into small pieces by proteins called caspases. (Click here to read more about caspases, or here for a figure depicting the effects of caspases in a nerve cell.) As HD progresses, cleavage by caspases is enhanced, generating more of the protein fragments. More protein fragments then interact with GAPDH, inhibiting GAPDH activity, leading to lower amounts of ATP available in cells and eventually, cell death.

When there is sufficient oxygen in a cell, pyruvate gets transported to the mitochondria. In the mitochondria, pyruvate molecules undergo a series of sequential reactions that are known collectively as aerobic respiration. Each step helps convert the food we eat from one molecule to another until ATP is produced as the end product.

Aside from interfering with one of the enzymes involved in glycolysis, the altered huntingtin has also been found to interfere with oxidative phosphorylation, the final step in aerobic respiration. Specifically, the altered huntingtin protein decreases the efficiency of the electron transport chain. The electron transport chain is a series of protein complexes that are found in the membrane of the mitochondria and is a vital component of oxidative phosphorylation. The protein complexes are named Complex I, II, III, and IV. As electrons are transported from one complex to another, protons (H+) are pumped out into the space between the inner and outer membrane of the mitochondria. As protons are pumped into the space between the two membranes, a proton gradient forms – more protons are present in the space between the two membranes. The proton gradient is essential in ATP production. The protons that accumulate between the two membranes are then transported through a molecule called the ATP synthase. The ATP synthase then acts to produce the ATP molecules that the cell uses as its source of energy.

Most studies report that HD cells exhibit reduced complex II, III, and IV activity. A few studies have also reported decreased activity in complex I as well. Scientists are still not certain how the huntingtin protein interacts with these protein complexes. They currently speculate that that altered huntingtin protein may be causing an indirect interference by interacting with other molecules involved in the electron transport chain. As the altered huntingtin protein interferes with this step of energy metabolism, the cell experiences more energy deficits, making it more susceptible to damage by substances such as glutamate.

In summary, because of the damage to the mitochondria of people with HD, aerobic respiration is not as efficient as it normally is. Less energy ends up being produced in HD cells. Different compounds that target different parts of the pathways of aerobic respiration are currently being studied in attempts to increase the energy supply available to cells.

Finally, we now turn to anaerobic respiration. As mentioned awhile ago, anaerobic respiration occurs when there is not enough oxygen available to cells. Anaerobic energy producing pathways are called fermentation. Organisms that do not need oxygen in order to grow and survive rely on fermentation as their main source of energy. Examples of such organisms include bacteria. During exercise, our skeletal muscles also rely on fermentation for energy during the few moments when insufficient amounts of oxygen are available. Fermentation produces lower amounts of energy and releases various by-products. In the muscle, the by-products of fermentation include molecules called lactate (also known as lactic acid). The accumulation of lactic acid is what makes our muscles hurt when we exercise. A summary of the steps involved in anaerobic respiration is shown below.

If you remember, the altered huntingtin protein has been found to partially inhibit the activity of the GAPDH enzyme, resulting in impairments in glycolysis. Given that fermentation requires the products of glycolysis in order to occur, how then can fermentation still occur in HD cells? It turns out that partial inhibition of GAPDH still allows some fermentation to occur, although complete inhibition would block glycolysis, and consequently, fermentation.

In summary, the altered huntingtin protein has been found to interfere with an enzyme involved in glycolysis and the electron transport chain. As a consequence, more fermentation occurs relative to aerobic respiration. Studies have reported that people with HD have increased brain lactate levels, indicating the damage to the mitochondria and impaired energy metabolism. Lactate levels are often used in studies to measure the efficiency of a drug or supplement. Lower lactate levels after treatment is seen as an indication of improved energy metabolism in cells.

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-E. Tan, 9-21-01

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Last Modified: 7-14-04

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