Your Metabolic efficiency and fuel usage trait focuses on protein called UCP2.

This uncoupling protein acts as a switch for the type of fuel your cells use for energy. UCP2 also plays a role in protection from cell damage.

What are uncoupling proteins?

We’ve encountered uncoupling proteins before in your Metabolic Efficiency and UCP1 trait and readers are strongly encouraged to visit the previous blog for a thorough overview.

To recap briefly, uncoupling proteins (UCPs) are specialized channels found in the inner membranes of mitochondria. Mitochondria are often dubbed the “powerhouses of the cell” because, through a process of cell respiration, they generate our chemical energy currency, ATP (adenosine tri phosphate). ATP can then be used to power all sorts of cell processes such as muscle contraction, transport of molecules and cell growth.

Uncoupling proteins, however, divert or “uncouple” cell respiration from the production of ATP.

Different types of uncoupling proteins

There are 5 types of uncoupling protein that have been identified in humans: UCP1, UCP2, UCP3, UCP4 and UCP5.

These different uncoupling proteins vary in their function and distribution in the body.

For example, as we learned in your previous trait, UCP1 is mainly found in the mitochondria of brown adipose tissue and is involved in generating heat (as part of a process called non-shivering thermogenesis).

By contrast, UCP3 is mainly found in muscle and white adipose tissue, and isn’t thought to be involved in generating heat.

Your Metabolic and fuel usage trait looks at one uncoupling protein in particular: UCP2.

UCP2 is involved in switching your cells' fuel sources, secreting insulin and protecting against cell damage.

KEY POINTS

• Uncoupling proteins are specialized channels found in mitochondria that "uncouple" respiration from the production of ATP - our cells' energy currency
• Your Metabolic Efficiency and fuel usage trait focuses on UCP2.

How do uncoupling proteins work?

Again, if you’re interested in a more detailed explanation of mitochondrial uncoupling, please visit the Metabolic Efficiency and UCP1 blog. We've included a brief explanation below:

Our mitochondria function a bit like mini-batteries.

During the final stage of cell respiration (called the electron transport chain), special complexes in mitochondria pump out hydrogen ions (H+) (also known as protons) from the matrix across their inner mitochondrial membrane into a space called the intermembrane space.

As H+ ions carry an electrical charge, the pumping of H+ ions to one side of the membrane creates a voltage or potential difference – like that observed in a battery. (If you fancy using the more technical term, we actually say that mitochondria create a “protonmotive force”).

After being pumped to one side (by four protein complexes, denoted I - IV), H+ ions are allowed to move back across the inner mitochondrial membrane into the matrix (down a voltage gradient).

Under normal circumstances, the H+ ions are forced to return through a specialized enzyme called ATP synthase. The movement of H+ ions through the ATP synthase enzyme catalyzes the production of ATP – our cells’ energy currency.

In this sense, our mitochondria convert electrical energy (from the movement of charged particles) into chemical energy (in the form of ATP). Similarly, we can describe the ATP synthase enzyme as “coupling” the movement H+ ions to the production of ATP.

Uncoupling proteins (UCPs) are basically channels that provide a shortcut for the passage of H+ ions. They work by allowing H+ ions to return across the mitochondrial membrane without going through the ATP synthase enzyme. They therefore “uncouple” the movement of H+ ions from the production of ATP.

KEY POINTS

• Mitochondria use the electrical energy from the movement of charged particles (H+ ions) to generate ATP.
• Uncoupling proteins are channels that allow the movement of H+ ions without producing ATP.

What is UCP2?

UCP2 stands for uncoupling protein 2.

It is found in the mitochondria of lots of different tissues, including liver, pancreas, adipose tissue, immune cells, spleen, kidney, and the central nervous system (brain and spinal cord).

Unlike UCP1, UCP2 is not thought to play a major role in producing heat (non-shivering thermogenesis). Rather, it protects against cell damage, controls insulin secretion and regulates which fuel we use for respiration.

KEY POINTS

• UCP2 stands for uncoupling protein 2
• UCP2 is not significantly involved in producing heat.
• UCP2 plays a role in protection against cell damage, fuel usage and insulin secretion.

What are the roles of UCP2?

Protection against reactive oxygen species (ROS)

As explained earlier, mitochondria create ATP by first pumping H+ ions to create a voltage difference (or, more accurately, a protonmotive force).

Unfortunately, this process also generates potentially damaging molecules called reactive oxygen species (ROS).

Reactive oxygen species (ROS) are examples of substances termed free radicals – highly reactive atoms or molecules with unpaired electrons. As the name suggests, reactive oxygen species are free radicals derived from oxygen.

Being extremely reactive, ROS can react with and damage important molecules in cells, including proteins, fats and DNA.

In fact, cell damage resulting from the excessive production of ROS is linked to inflammation, ageing and diseases such as diabetes, heart disease and neurodegenerative disorders (e.g. Alzheimer’s disease).

As we’ll shortly find out, UCP2 acts to prevent the build up of reactive oxygen species and therefore protects against cell damage.

KEY POINTS

• Reactive oxygen species (ROS) are highly reactive molecules capable of damaging cells.
• Reactive oxygen species are generated by mitochondria during respiration.
• UCP2 prevents the build up of ROS and protects against cell damage.  

How are reactive oxygen species made?

During aerobic respiration, we consume oxygen to generate ATP and produce water as a waste product.

If we zoomed in on our mitochondria, we would see that oxygen gradually gets converted into water (a process called reduction) in a sequence of steps as mitochondria pump out H+ ions to form a voltage gradient. These processes happen simultaneously in the final stage of respiration – which we call the electron transport chain.

Throughout this process, oxygen gets temporarily converted into intermediate reactive oxygen species (ROS) molecules, including molecules such as superoxide (O2-), hydrogen peroxide (H2O2) and hydroxyl radical (OH). These will eventually get converted into water, as H+ ions are allowed to pass through the ATP synthase enzyme and the voltage gradient dissipates.

If, however, the voltage gradient (or protonmotive force) from pumping H+ becomes too high, then the process of converting oxygen into water starts to get backed up (a bit like a queue).

This then leads to the accumulation of intermediate ROS molecules.

KEY POINTS

• Reactive oxygen species are produced during the electron transport chain of respiration as oxygen is converted into water.
• The pumping of H+ ions to create a voltage difference leads to the build up of ROS.

How does UCP2 prevent the build-up of ROS?

UCP2 allows H+ ions to return through the inner mitochondrial membrane (stage C in the diagram below), thereby dissipating the voltage gradient (or reducing the proton motive force - [stage D]). This is known as uncoupling or proton leak.

Uncoupling relieves the congestion on the electron transport chain, allowing oxygen to be converted into water more freely, and preventing the build up of intermediate ROS molecules (stages B and E in the diagram below).

It’s worth noting that UCP2 likely acts as a “mild uncoupler” – it only allows some H+ ions through, meaning the majority of H+ ions can continue to flow through the ATP synthase enzyme. This permits mitochondria to continue producing ATP, while simultaneously reducing the build up of ROS.

KEY POINTS

• UCP2 dissipates the voltage difference by allowing H+ ions to pass through the inner mitochondrial membrane - this reduces the production of reactive oxygen species.

Changes in fuel usage

Mitochondria are remarkable in that they are capable of using a variety of fuel sources to generate energy (in the form of ATP). These fuel sources include:

• glucose (from the breakdown of carbohydrate)
• fatty acids (from the breakdown of fat)
• amino acids (from the breakdown of proteins).

Studies suggest that one role of UCP2 is to promote the use of fatty acids and amino acids (in particular an amino acid called glutamine) instead of glucose as a fuel source.

In this respect, UCP2 can be considered a type of “metabolic switch” that governs what fuel we use in different circumstances. For example, when we're fasting, our bodies tend to use fatty acids from our fat stores over glucose as an energy source.

KEY POINTS

• UCP2 acts a switch to suppress the use of glucose as a fuel.
• UCP2 promotes the use of fat and protein as a fuel source.

How does UCP2 change fuel usage?

To get an idea of how UCP2 switches fuel usage to fatty acids and amino acids, we first need to understand how cell respiration uses glucose to produce energy.

Cell respiration using glucose takes place in three main stages:

1. Glycolysis
2. The citric acid cycle (TCA) or Kreb’s cycle
3. Electron transport chain

The first stage, glycolysis, involves converting glucose into a molecule called pyruvate (or pyruvic acid). This reaction doesn’t require oxygen and actually yields some ATP, so can be used to provide a limited amount of energy for cells.

In fact, glycolysis is exactly what happens during anaerobic respiration. If you were to sprint for a few seconds, your muscles can be fuelled by ATP produced solely from glycolysis.

If you were to continue running however, you would quickly (excuse the pun) run out of ATP, as glycolysis can only yield a limited amount of ATP.

To overcome this, your body switches to aerobic respiration. Aerobic respiration uses oxygen to further break down glucose and generate even more ATP. This is where your mitochondria play a role.

After glucose has been broken down into pyruvate during glycolysis, your mitochondria convert pyruvate into another molecule, called Acetyl-CoA.

Acetyl-CoA can then enter the last two stages of respiration (the citric acid/ Kreb’s cycle and the electron transport chain) to produce more ATP.

The UCP2 protein, however, acts to inhibit the conversion of pyruvate into Acetyl-CoA. This makes it harder for your cells to use glucose, forcing them to use alternative fuel sources.

Fortunately, your mitochondria are also capable of using fatty acids and amino acids for energy. Through a process called beta-oxidation, fatty acids can be broken down and converted into Acetyl-CoA. This can then enter the citric acid cycle (TCA) to produce ATP.

The amino acid glutamine can also be used for energy. Mitochondria convert glutamine into a molecule called glutamate. Glutamate, in turn, gets converted into one of the molecules in the citric acid cycle and is used to produce ATP.

By suppressing the use of glucose, UCP2 acts to promote the use of fats and amino acids (particularly glutamine) for fuel.

Furthermore, UCP2 gets activated by the presence of fatty acids and glutamine. It therefore may serve to switch on the use of fat and protein for energy when these fuel sources are abundant.

KEY POINTS

• UCP2 suppresses the conversion of pyruvate (formed from the anaerobic breakdown of glucose) into Acetyl-CoA.
• UCP2 promotes the use of fatty acids and amino acids (in particular, glutamine) for energy.

Insulin secretion

UCP2 also plays a critical role in the secretion of insulin and the control of blood sugar levels.

You can find out more about insulin in the Insulin and your blood sugar levels article. If you fancy the cliff notes, though: insulin is a hormone that allows your cells to take up and use glucose. It is secreted by specialized cells in your pancreas, called β cells.

Activation of UCP2 channels reduces the secretion of insulin by β cells. This may further promote the use of fats, rather than glucose, as a fuel source.

KEY POINTS

• UCP2 inhibits the release of insulin by the pancreas

Genetics

We analyze variants of your UCP2 gene, which encodes the UCP2 protein.

Variants of this gene affect how much UCP2 protein you produce. This, in turn, affects your fuel usage, insulin secretion and your production of reactive species molecules.

Individuals with greater production (or expression) of UCP2 are, under various circumstances, more likely to use fat and glutamine as fuel sources over glucose. They are also likely to generate less reactive oxygen species (ROS) during the process of respiration.

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