Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford

About Abnormalities in Energy Metabolism

The mutant huntingtin protein has been found to disrupt cellular metabolism, the process by which cells make energy. It interacts with key proteins needed to produce energy and causes damage to mitochondria, the ‘energy factory’ of the cell. Mitochondria produce energy in the form of molecules known as ATP (for “adenosine triphosphate”). The amount of ATP available to cells is lower in Huntington’s Disease (HD), which makes cells more susceptible to damage by toxic compounds. Scientists are looking into drugs and supplements that increase the amount of energy available in cells, as they might be possible candidates for treating HD. This article explains how huntingtin affects cellular metabolism, which is important for understanding how these drugs may improve energy production in the cell.

The Basics of Energy Metabolism

J-9: Steps in Metabolism

Energy metabolism is a process by which the food we eat is broken down by various enzymes in order to produce 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 a 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. Thus, aerobic respiration is a more efficient process because it produces more energy from the food we eat.

Fig J-12: Steps in Aerobic Respiration

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 product of glycolysis is called pyruvate, which can undergo either aerobic or anaerobic respiration. If sufficient oxygen is present, pyruvate gets transported to the mitochondria where it undergoes aerobic respiration. Each step of this process helps convert the food we eat from one molecule to another until ATP is produced as the end product.

HD and Cellular Metabolism

Exactly how mutant 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 interacts with a molecule known as GAPDH (which stands for glyceraldehyde-3-phosphate dehydrogenase), a key enzyme in glycolysis, the early part of metabolism described above. Huntingtin’s interaction with GAPDH partially prevents it from working properly. 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 becomes in people 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 protein fragments. These fragments then interact with GAPDH and inhibit its activity, which leads to lower amounts of ATP available in cells and eventually causes cell death.

The mutant huntingtin protein is believed to have a greater impact on cellular metabolism when it has a longer glutamine tail, which happens when an individual’s copy of the HD allele has a longer segment of CAG repeats. Cells engineered to express huntingtin with particularly long polyglutamine tails were significantly worse at making ATP than cells expressing huntingtin with medium-length polyglutamine tails.

Damage to Mitochondria

Fig J-13: Electron Transport Chain

Aside from interfering with one of the enzymes involved in glycolysis, mutant huntingtin also interferes with oxidative phosphorylation, the final step in aerobic respiration. Specifically, mutant huntingtin makes the electron transport chain less efficient. The electron transport chain is a series of protein complexes that are found in the membrane of 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 ATP synthase. ATP synthase then produces ATP molecules that the cell uses as its source of energy.

Most studies report that HD cells exhibit reduced activity in complex II and III. 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 the altered huntingtin protein may indirectly interfere with these complexes by interacting with other molecules involved in the electron transport chain. As the altered huntingtin protein disrupts this step of metabolism, the cell experiences more energy deficits, with some experiments suggesting that neurons in the striatum, a region of the brain heavily affected in HD, make 30% less ATP than non-HD neurons. This makes those brain cells more susceptible to damage by toxic substances such as glutamate.

In summary, because of damage to mitochondria in neurons of people with HD, aerobic respiration is less efficient and therefore produces less energy. Compounds that target different parts of the pathways of aerobic respiration are currently being studied to determine if they increase the energy supply available to cells and may therefore be potential drugs for HD.

Anaerobic Respiration

As mentioned earlier, 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.

Fig J-14: Steps in Anaerobic Respiration

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.

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 damage to 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 metabolism in cells.

The Big Picture

So what do defects in energy metabolism mean for people with HD? Brain scans reveal that people with HD metabolize glucose more slowly in certain parts of the brain. One of those regions, the basal ganglia, is responsible for controlling movements. Patients with particularly impaired metabolism in the basal ganglia have worse motor symptoms and lower functional capacity. Moreover, some scientists think that defective energy metabolism is partly responsible for the weight loss that many people with HD experience, as described in more detail here.

The drugs outlined in this “Abnormalities in Energy Metabolism” section are meant to boost energy, and hopefully reverse some of the effects described in this article.

-E. Tan, 9-21-01, updated M. Hedlin 12.22.11