Electron transport chain and oxidative phosphorylation
Definitions & Key takeaways
The electron transport chain and oxidative phosphorylation are two biochemical processes that occur in the mitochondria of cells. The electron transport chain is a series of proteins that transfer electrons from donors to acceptors, and oxidative phosphorylation is the process by which the energy released by these electrons is used to generate ATP, which is the cellular currency of energy. The electron transport chain and oxidative phosphorylation are important for generating energy in all cells, but they are especially important in muscle cells, because muscles use a lot of energy.
Your heart is constantly working. Whether you’re swimming or taking a nap, your heart is always on the go.
The main form of energy that keeps our heart cells, and really all of our body cells, going is adenosine triphosphate, or ATP.
In most cells, the main ATP producing factory is the mitochondria, which has an inner and an outer membrane, and it’s along the inner membrane where a process called oxidative phosphorylation occurs.
“Oxidative” refers to oxidation - which is when a molecule donates its electron, and “phosphorylation” which refers to the addition of a phosphate group to adenosine diphosphate, or ADP, to form ATP.
So oxidative phosphorylation is the process of making ATP by donating electrons to complexes embedded within the inner mitochondrial membrane.
These complexes are proteins or lipids coupled with metals like iron and copper that facilitate the movement of electrons.
Together, they form the electron transport chain. During the electron transport chain, electrons are passed on from complex to complex, and finally to oxygen, creating a proton gradient that will be used to make ATP.
The electron transport chain begins with two key molecules that want to donate their electrons: nicotinamide adenine dinucleotide, or NADH, and flavin adenine dinucleotide, or FADH2, both of which get oxidized in the electron transport chain.
NADH and FADH2 are primarily generated in the citric acid cycle which occurs in the mitochondria, but it can also come directly from glycolysis - which is the breakdown of glucose in the cytoplasm, or fatty acid oxidation, which is the breakdown of fats in the mitochondria.
Enzymes called dehydrogenases help generate the electron-rich NADH and FADH2. And when those molecules are coming from the cytoplasm they can only enter the mitochondria using a specific shuttle.
When using the malate-aspartate shuttle, electrons enter the electron transport chain as NADH. When using the glycerol-3-phosphate shuttle, electrons enter electron transport chain as FADH2.
There are two entry points into the electron transport chain. The first point of entry, is where NADH gives its electrons to Complex I.
Complex I contains flavin mononucleotide - a derivative of riboflavin or Vitamin B2 - and iron-sulfur centers called FeS.
NADH gives its electron to flavin mononucleotide, and it gets turned back to NAD+, and can then be re-used by dehydrogenases to make more NADH.
The second point of entry, is where FADH2 gives its electron to Complex II, which is also called succinate dehydrogenase - the exact same enzyme that takes part in the citric acid cycle!
That means that citric acid cycle and electron transport chain actually share a step, so their activity rises and falls together.
Ultimately, electrons from complexes I and II flow directly to Coenzyme Q, which is also called ubiquinone. Coenzyme Q is actually a cholesterol derivative and therefore the only lipid in the electron transport chain.
Next coenzyme Q passes on the electrons to a series of cytochromes, which are proteins that contain heme groups. Heme groups contain iron, which is able to grab an electron and go from Fe3+ to Fe2+.
The heme iron can then release the electron to the next cytochrome in the chain and go back to Fe3+, so that it’s ready to grab another electron.
It’s a bit like factory chain workers relaying the electrons between one another! Complex III is made up of cytochrome b and cytochrome c1, and then electrons move over to cytochrome c, and from there the electrons get passed to complex IV, which is composed of cytochromes a and a3, which are together referred to as cytochrome oxidase.
Now, if a cell doesn’t receive enough oxygen, like in hypoxia, which is the most common cellular injury, then electron transport chain gets interrupted and ATP synthesis doesn’t happen.
So the complexes are responsible for the “oxidative” part of oxidative phosphorylation - and you can think of the electron transport chain as a game of hot potato - with the complexes rapidly passing electrons off to one another, creating an electrical current.
That electrical current creates energy that drives complexes I, III, and IV to pump positively charged protons out of the mitochondria and into the space between the inner and outer mitochondrial membrane, creating a proton gradient across the inner mitochondrial membrane.
That’s because complexes I, III, and IV are the only ones to span the inner mitochondrial membrane. In fact, as the electrons are hopping through, the complexes are changing their conformation to push protons across.
It’s a bit like how electrons hop wires in a home, and that energy can be used to do work - like plugging in a vacuum to suck up dirt.
In this case, the little complexes would be the vacuums, sucking up protons. Now, this gradient is considered unstable because the protons are always trying to equilibrate across the inner mitochondrial membrane, even though it’s totally impermeable to them.
To get across, protons have to use a special proton channel called F0, that’s attached to an enzyme called F1. F1 is an ATP synthase that uses the proton gradient to phosphorylate an ADP molecule and make ATP - so ATP synthase is in charge of the “phosphorylation” step of oxidative phosphorylation.
Sometimes it’s called Complex V of electron transport chain. Since ATP is formed in the mitochondria, it uses an ATP/ADP antiport to get pumped out of the mitochondria and into the cytoplasm, and that way the mitochondria gets a new ADP molecule, which it uses to make the next ATP.
You can think of it as an ATP shuttle! Approximately 1 NADH molecule that donates its electron to the electron transport chain generates a proton gradient strong enough to make 3 ATP molecules, since NADH activates 3 proton pumps - complexes I, III and IV.
whereas, 1 FADH2 molecule only makes 2 ATP molecules, because FADH2 skips complex 1, and starts at complex 2, activating only 2 proton pumps - complexes III and IV.
Since both NADH and FADH2 require an oxygen molecule to ultimately accept their electrons, these values are called the phosphate to oxygen ratio or P/O ratio, which is the ratio of ATP produced per oxygen consumed for each molecule.
Again, these are just approximate ratios. Electron transport chain isn’t controlled hormonally, rather it’s controlled by the energy level within the cell itself.
When ATP builds up within a cell, a sign of high energy, electron transport chain slows down, and when ADP builds up, a sign of low energy, electron transport chain speeds up.
Now, it turns out that drugs and chemicals can effectively “break” oxidative phosphorylation in two ways - uncoupling and inhibition.
Let’s start with uncoupling. Normally, the electron transport chain is coupled with ATP synthesis, meaning that they happen together.
Uncoupling agents break that link. They do this by inserting their own proton channels, called ionophores, into the inner mitochondrial membrane or by simply carrying the protons back into the mitochondrial matrix, thereby allowing them to bypass the F0 subunit of the ATP synthase enzyme.
Uncoupling agents dissipate the proton gradient created by the complexes. And because the protons enter back into the mitochondria with the uncoupling agent instead of through the F0 component of ATP synthase, F1 isn’t able to phosphorylate ADP to make ATP.
Now it’s important to note that the electrons are still flowing from complex to complex all the way to the final electron recipient, oxygen.
So red blood cells keep delivering oxygen to the tissues so that it can be the electron recipient. Also, as the cell’s ADP levels rise, the body tries to increase its metabolic rate to make more electron donors like NADH and FADH2.
But this electron flow is useless, because no matter how large of a proton gradient there is, the protons just go back with the uncoupling agent instead of going through F0.
Because some of the electron’s energy is not used up in moving protons across the inner mitochondrial membrane, more of it is available to turn into heat energy.
There are some endogenous uncoupling agents like thermogenin, which is a protein found in the brown adipose tissue of babies, used to generate heat.
Funnily enough, thermogenin is also found in hibernating animals - so yeah, we’re kind of like polar bears when we’re babies.
Uncoupling is kind of like a car with a hot, hard working engine, but despite that, the car isn’t moving. Another example of a medication that can be an uncoupling agent in high doses is aspirin.
The uncoupling can lead to a really high metabolic rate, which can lead to a metabolic acidosis, and if ATP levels start to fall too low to allow the respiratory centers and respiratory muscles to work, then it can lead to a respiratory acidosis as well.
A combined metabolic and respiratory acidosis quickly becomes life-threatening. Okay, the other way that oxidative phosphorylation can go awry is by inhibition, meaning that some chemicals and drugs inhibit components of the electron transport chain.
Unlike uncoupling, inhibition stops the flow of electrons through the electron transport chain, and that leads to a decrease in ATP synthesis.
Because electron flow is put to a stop, electron donors such as NADH and FADH2 build up, so the body doesn’t feel the need to make more, and the metabolic rate falls.
Inhibition is like turning off the car engine, which of course means that the car won’t move. And not surprisingly, poisons that work by inhibiting electron transport chain can lead to death pretty quickly.
Examples of inhibiting agents include carbon monoxide and cyanide, both of which inhibit complex IV of the electron transport chain.
Barbiturates, which are GABA agonists that can be effective for seizure disorders, inhibit complex I at high doses. Oligomycin, which is an antibiotic too toxic for human use, inhibits the F0 component of ATP synthase.
Statins, which are a class of lipid-lowering medications don’t inhibit electron transport chain, but they can decrease the synthesis of coenzyme Q.
That reduction in coenzyme Q can result in decreased ATP production and lead to muscle pains and cramps - and rarely can even cause rhabdomyolysis, which is when there’s severe muscle breakdown resulting in kidney failure from the myoglobin released.
Alright, a quick recap. Oxidative phosphorylation is a mitochondrial process where electrons are transported across various complexes of the electron transport chain.
NADH and FADH2 are the main electron donors, and oxygen is the crucial final electron acceptor. This movement of electrons helps establish a proton gradient is that drives ATP synthase to complete the “phosphorylation” of ADP into ATP.
Uncouplers like thermogenin disrupt oxidative phosphorylation by dissipating the proton gradient, while inhibitors like carbon monoxide put an end to the electron transport by inhibiting electron flow.
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