Uncoupling in Cellular Respiration

Written By Vaishnavi Kolluru

Idea creds @survivalaren. 

The mitochondrion is the site of cellular respiration. Below is the anatomy (note the double-membraned structure, and the distinction between the mitochondrial matrix and intermembrane space):

Embedded on the inner membrane of the mitochondrion are various proteins, diagrammed below. Each protein that spans the entire width of the membrane is a proton pump; when activated, it pumps protons from the mitochondrial matrix to the intermembrane space. 

Roman numerals indicate complexes (complex I, complex II, etc). ATP synthase not shown.

When electron carriers like FADH2 and NADH drop their electrons into complex I, the electron transport chain (ETC) begins. Electrons are passed from protein to protein, and with each pass, the electrons lose energy. These electron transfers are used to actively pump protons into the intermembrane space, making it more acidic than the matrix. The energy comes from the highly electronegative proteins' thermodynamically favorable acceptance of the electron. Once the electrons reach the end of the ETC, they have very low energy and can no longer be used to pump protons across the inner membrane. These low-energy electrons pair with hydrogen and oxygen atoms in the matrix, forming H2O. This is why oxygen is known as the terminal electron acceptor; it accepts electrons at the very end (terminus) of the ETC. Without oxygen, these electrons will be trapped in the electron transport chain and accumulate within complex IV, effectively halting future progress of the ETC.

Following successful electron transport through the ETC's complexes is ADP phosphorylation via ATP synthase. Accumulated protons in the intermembrane space flow through ATP synthase according to their concentration gradient, which provides the energy needed to spin the rotors of ATP synthase and phosphorylate ADP to form ATP. (Important note: flow through ATP synthase is an example of passive facilitated diffusion, as proton flow goes down the concentration gradient through a channel. The proton pumps of the ETC are active transport, which flows protons against their concentration gradient, and consumes energy.) Below is an image of ATP synthase:

Let's quickly review. Electron carriers like NADH and FADH2 dropped their electrons off in the ETC. These electrons were passed from protein to protein, while pumping H+ from the matrix into the intermembrane space using the energy produced from the thermodynamically-favorable acceptance of electrons by the next electronegative protein in the ETC. Once electrons reach the end of the chain, they complex with hydrogen and oxygen to form water, which is released back into the matrix. The accumulated protons in the intermembrane space flow back down their concentration gradient into the matrix which provides the energy to phosphorylate ADP, forming ATP. 

This process is very intricate, so we can screw it up in various ways. One example of a screwup of traditional ETC function occurs in brown fat, which helps newborns thermoregulate (babies that young can't shiver yet). This nonshivering heat-generating process is called nonshivering thermogenesis, which utilizes uncoupling protein (thermogenin) to generate heat. Instead of ATP synthase, protons from the intermembrane space flow passively down into the matrix by way of thermogenin; however, instead of this movement producing ATP, it produces heat (recall that "wasted" energy in chemical reactions becomes thermal energy; this is an example of this kind of "waste" energy being put to use). Thus, uncoupling protein dissipates the proton gradient to produce heat, so we can no longer produce ATP until the ETC creates another proton gradient via more electron transport.

Nonshivering thermogenesis is a textbook example to demonstrate the general principle of mitochondrial uncoupling, which is defined as a separation between the proton-motive force-generation of the ETC and the ATP-producing capabilities of ATP synthase. In simple terms, the ETC cannot occur at the same time as ATP generation (due to the proton gradient being dissipated every time it is created), so the proton gradient produced by the ETC cannot be used by ATP synthase to make ATP. 

Nonshivering thermogenesis occurs in a physiologically-controlled manner, so it doesn't halt ATP production so much that the cell nears death. Other things, such as drugs, can also uncouple electron transport from ATP generation. Oftentimes these drugs are very harmful, and can kill cells. One example of an uncoupling drug is dinitrophenol, once marketed as a weight-loss drug (now illegal in most places for human consumption), as it burned calories through respiration but didn't make ATP, so it was like the fat was evaporating off the body instead of being used in metabolism (so you didn't have to work out to lose weight). 

A consequence of uncoupling is excess oxygen consumption. Imagine this: the electron transport chain has been working hard to create the proton gradient for use by ATP synthase. The uncoupling agent is modifying the system such that the gradient cannot be used to make ATP. The ETC needs to move faster and create more proton gradients to keep up with cellular ATP demands (otherwise, the cell will die). Oxygen is needed to keep the cycle going, as oxygen is the terminal electron acceptor that allows the electron transport chain to keep working to increase the proton gradient between the intermembrane space and matrix. So there will be excess oxygen consumption as a recovery mechanism.

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Vaishnavi Kolluru
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