Uncoupling proteins in mitochondria provide a paradoxical safety valve.
One of the great insights of biochemistry in the last century was the chemiosmotic theory, which finally described the nature of power flows in the mitochondrion. Everyone knew that energetic electrons were spun off the metabolism (burning) of food via the electron transport chain, ending up re-united with oxygen (creating the CO2 we breathe out). But how was that power transmitted to ATP? The key turned out to be a battery-like state across the mitochondrial membrane, where protons are pumped out by the electron transport chain, and then come back in while turning the motor of the ATP synthase to phosphorylate ADP into ATP. It is the (proton) concentration and charge difference (that is, the chemiosmotic gradient) across the inner mitochondrial membrane that stores and transmits this power- a clever and flexible system for energizing the mitochondrion and, indirectly, the rest of the cell.
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| Schematic view of the electron transport chain proteins, as well as the consumer of its energy, the ATP synthase. The inside of the mitochondrial matrix is at top, where core metabolism takes place to generate electrons, resulting in protons pumped out towards the bottom. Protons return through the ATP synthase (right) to power the phosphorylation (so-called oxidative phosphorylation) of ADP to ATP. |
Chemiosmotic theory taught us that mitochondria are always charged up, keeping a balance of metabolism and ATP production going, all dependent on the tightness of the inner mitochondrial membrane, which was the "plate" that keeps the protons and other ions sealed apart. But over the years, leaks kept cropping up. In the human genome, there are at least six uncoupling proteins, or UCPs, which let protons through this membrane, on purpose. What is the deal with that?
One use of these proteins is easy enough to understand- the generation of heat in brown fat. Brown fat is brown because it has a lot of mitochondria, which are brown because of the many metal- and iron-hosting enzymes that operate at the core of metabolism. UCP1 is present in brown fat to generate heat by letting the engine run free, as it were. It is as simple as that. But most of the time, inefficiency is not really the point. The other UCP proteins have very different roles. On the whole, however, it is estimated that proton leaks from all sources eat up about a fourth of our metabolic energy, and thus evidently play a role in making us warm blooded, even apart from specialized brown fat.
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| A more general schematic that adds UCP proteins to the view above. Leaks also happen through other channels, such as the membrane itself, and also the ANT protein, at low and non-regulated rates.. |
One big problem of mitochondria is that they are doing some quite dangerous chemistry. The electrons liberated from metabolism of food have a lot of energy, and the electron transport chain is really more like a high voltage power station. The proteins in this chain are all structured to squeeze all the power they can out of the electrons and into the proton gradient. But that runs the risk of squeezing too hard. If there is a holdup anywhere, things can back up and electrons leak out. If that happens, they are likely to combine with oxygen in an uncontrolled way that generates compounds like peroxide, superoxide, and hydroxy radicals. These are highly reactive (customarily termed ROS, for reactive oxygen species) and can do a great deal of damage in the cell. ROS is used in some signaling systems, such as the pathway by which glucose stimulates insulin secretion in the pancreas, but generally, ROS is very bad for the cell and rises exponentially with the severity of blockages in the electron transport chain. Many theories relating to aging and how to address it revolve around the ongoing damage from ROS.
Thus the more important role for the other UCP proteins is to function as a safety valve for overall power flow through mitochondrial metabolism- a metaphorical steam valve. UCP proteins are known to be inducible by ROS, and when activated, allow protons to run back into the matrix, which relieves the pressure upstream on all the electron transport chain proteins, which are furiously pumping out protons in response to the overall metabolic rate of fat/sugar usage. While metabolism is regulated at innumerable points, it is evident that, on a moment-to-moment basis, an extra level of regulation, i.e. relief, is needed at this UCP level to keep the system humming with minimal chemical damage to the rest of the cell.
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