PIPBEALE

Before I explain what "mitochondrial uncoupling" is, you probably need to know a little something about what mitochondria are in the first place, and what the heck they are doing coupling or uncoupling (or whatever else they aren' t telling their mums about).

Mitochondria are tiny little organelles inside animal (and plant) cells. They have an inner membrane and an outer membrane which separate the inner compartment, called the mitochondrial matrix, from the outer compartment, called the inter-membrane space. They are the powerhouses of the body - quite literally. They are where the energy we eat as food is turned into useful energy for the body - ATP! Adenosine triphosphate (ATP) is a molecule with high energy phosphate bonds. These bonds, when broken down, release the chemical energy that they had stored. It is that energy that allows most of the functions in the body to take place - so ATP is like the energy currency of the body. Used in nearly every transaction!  Perhaps that makes mitochondria more like The Mint? Like other currencies we are mainly interested in how to get more. Making more ATP is called oxidative phosphorylation.

Oxidative phosphorylation is all done by an enzyme called ATP synthase. This enzyme sits within the inner mitochondrial membrane. Basically it just attaches an extra phosphate onto adenosine diphosphate (ADP). BUT, it won't work for free. No sir. ATP synthase will only work when protons are passed through it from the inter-membrane space to the mitochondrial matrix. These protons are moving down an electrochemical gradient. Meaning they try to get from an area where they are in a high concentration (inter-membrane space), to an area with a low concentration (mitochondrial matrix). This electrochemical gradient is set up by a series of proteins called the electron transport chain.

Essentially these proteins take in substrates broken down from food (which come from another physiologic process called the Krebs cycle) then pass electrons along from one protein to the next. As they pass electrons along they use up oxygen and pump protons from the mitochondrial matrix into the inter-membrane space thus setting up the electrochemical gradient required to make ATP synthase work.

The amount of oxygen used up per the amount of ATP produced is what "coupling" is referring to. When this process is efficient the mitochondria are more coupled and less oxygen is used up in making ATP. When they are "uncoupled" they are using up more oxygen to make less ATP. There are lots of things that can uncouple mitochondria! Often these things involve making the inner mitochondrial membrane more leaky to protons. This means they cheat the system by reentering the mitochondrial matrix without passing through ATP synthase. The result is that the electron transport chain has to work much harder to maintain the electrochemical gradient. It uses up more substrate and more oxygen in doing this - it is literally burning fuel - this generates heat as well!

Some things that cause mitochondrial uncoupling:

1. Uncoupling Proteins: The uncoupling proteins are inserted into the inner mitochondrial membrane. They are essentially channels that give the protons a path to go from the inter-membrane space into the mitochondrial matrix. They dissipate the electrochemical gradient. These proteins are especially up regulated in a tissue called brown adipose tissue (BAT) when animals are cold and want to make more body heat.

2. Uncoupling Agents: the chemical properties of come compounds allow them to enter the mitochondria and bounce around through the inner mitochondrial membrane. The compounds are usually weak acids, which means hydrogen ions (which are the same as protons) can easily attach or dissociate. So the compounds bounce around inside the mitochondria picking up protons on one side of the membrane and dropping them off on the other. Again this results in dissipation of the electrochemical gradient. At least this is how one well known example works - the drug DNP, used as a weight loss drug until people literally became too hot! UPDATE: while the video below depicts an uncoupler (the banana) bouncing around within the membrane, we now know that it should pass through the membrane. I will update the animation when I can contain myself from eating delicious fruit for long enough! 

3. Protein slip: sometimes the proteins in the electron transport chain slip a bit. They mess up. We all do it from time to time right? But of course this makes things in the mitochondria less efficient.