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Oxidative Phosphorylation: The major energy provider of the cell

There are a lot of different ways organisms acquire food. Just think about how sharks, bees, plants, and bacteria eat. Almost all aerobic organisms (organisms that require oxygen to live) use oxidative phosphorylation, in one way or another, to produce the basic energy currency of the cell needs to function: ATP (adenosine triphosphate). Oxidative phosphorylation is the fourth step of cellular respiration, and produces the most of the energy in cellular respiration.
Where does oxidative phosphorylation fit into cellular respiration?
1. Glycolysis, where the simple sugar glucose is broken down, occurs in the cytosol.
2. Pyruvate, the product from glycolysis, is transformed into acetyl CoA in the mitochondria for the next step.
3. The citric acid cycle, where acetyl CoA is modified in the mitochondria to produce energy precursors in preparation for the next step.
4. Oxidative phosphorylation, the process where electron transport from the energy precursors from the citric acid cycle (step 3) leads to the phosphorylation of ADP, producing ATP. This also occurs in the mitochondria.

What is oxidative phosphorylation?

Oxidative phosphorylation is the process where energy is harnessed through a series of protein complexes embedded in the inner-membrane of mitochondria (called the electron transport chain and ATP synthase) to create ATP. Oxidative phosphorylation can be broken down into two parts: 1) Oxidation of NADH and FADHstart text, end text, start subscript, 2, end subscript, and 2) Phosphorylation.
Figure of the electron transport chain (complexes 1-4)

1. Oxidation of NADH and FADH$\text{}_{2}$start text, end text, start subscript, 2, end subscript - losing electrons via high energy molecules

Step 1
Oxidative phosphorylation starts with the arrival of 3 NADH and 1 FADHstart text, end text, start subscript, 2, end subscript from the citric acid cycle, which shuttle high energy molecules to the electron transport chain. NADH transfers its high energy molecules to protein complex 1, while FADHstart text, end text, start subscript, 2, end subscript transfers its high energy molecules to protein complex 2. Shuttling high energy molecules causes a loss of electrons from NADH and FADHstart text, end text, start subscript, 2, end subscript, called oxidation (other molecules are also capable of being oxidized).
The opposite of oxidation is reduction, where a molecule gains electrons (which is seen in the citric acid cycle). Here’s an easy way to remember which process gains or loses electrons:
LEO the lion says GER
Lose Electrons Oxidation (LEO)
Gain Electrons Reduction (GER)
Figure of oxidation of NADH and FADH2
Step 2 - Hitting the gym to pump some serious hydrogens
The process of NADH oxidation leads to the pumping of protons (single positively-charged hydrogen atoms denoted as Hstart superscript, start text, plus, end text, end superscript) through protein complex 1 from the matrix to the intermembrane space. The electrons that were received by protein complex 1 are given to another membrane-bound electron carrier called ubiquinone or Q.
This process of transferring electrons drives the pumping of protons, which is seen as unfavorable. Electron transfer driving proton pumping is repeated in complexes 3 and 4 (which we will discuss in steps 2 - 5). As this action is repeated, protons will accumulate in the intermembrane space. This accumulation of protons is how the cell temporarily stores transformed energy.
Note - FADHstart text, end text, start subscript, 2, end subscript has a slightly different route than NADH. After its arrival at protein complex 2, its high energy electrons are directly transferred to Q, to form reduced Q, or QHstart text, end text, start subscript, 2, end subscript. There is no hydrogen pumping for the exchange of the FADHstart text, end text, start subscript, 2, end subscript electrons here.
Figure of electrons being transferred from FADH2 and NADH to ubiquinone
Step 3
The rest of the steps are now the same for the high energy molecules from NADH and FADHstart text, end text, start subscript, 2, end subscript in earlier steps. Inside the nonpolar region of the phospholipid bilayer, UQHstart text, end text, start subscript, 2, end subscript (which is also a nonpolar compound) transports the electrons to protein complex 3. UQHstart text, end text, start subscript, 2, end subscript also carries protons. When UQHstart text, end text, start subscript, 2, end subscript delivers electrons to protein complex 3, it also donates its protons to be pumped.
Figure of UQH2 transporting electrons to protein complex 3
Step 4
The electrons that arrived at protein complex 3 are picked up by cytochrome C (or “cyt C”), the last electron carrier. This action also causes protons to be pumped into the intermembrane space.
Figure electrons being transferred from protein complex 3 to cytochrome C
Step 5
Cytochrome C carries the electrons to the final protein complex, protein complex 4. Once again, energy released via electron shuttling allows for another proton to be pumped into the intermembrane space. The electrons are then drawn to oxygen, which is the final electron acceptor. Its important to note that oxygen must be present for oxidative phosphorylation to occur. Water is formed as oxygen receives the electrons from protein complex 4, and combines with protons on the inside of the cell.
Figure of cytochrome C carrying electrons to protein complex 2
In summary
• +1 FADHstart text, end text, start subscript, 2, end subscript
• +3 Hydrogen protons (Hstart superscript, start text, plus, end text, end superscript)
• -2 Hydrogen protons (Hstart superscript, start text, plus, end text, end superscript)
• -½ Ostart text, end text, start subscript, 2, end subscript
• +1 Hstart text, end text, start subscript, 2, end subscriptO

2. Phosphorylation - the production of ATP

Step 6
As a result of part 1 (Oxidation of NADH and FADHstart text, end text, start subscript, 2, end subscript), an electrochemical gradient is created, meaning there is a difference in electrical charge between the two sides of the inner mitochondrial membrane. The outside, or exterior, of the mitochondrial membrane is positive because of the accumulation of the protons (Hstart superscript, start text, plus, end text, end superscript), and the inside is negative due to the loss of the protons. A chemical concentration gradient has also developed on either side of the membrane. The electrochemical gradient is how the cell transfers the stored energy from the reduced NADH and FADHstart text, end text, start subscript, 2, end subscript.
Figure showing electrochemical gradient
Step 7
When there is a high concentration of protons on the outside of the mitochondrial membrane, protons are pushed through ATP synthase. This movement of protons causes ATP synthase to spin, and bind ADP and Pi, producing ATP. Finally, ATP is made!
In summary
• -Pi
• +ATP
Figure of protons being pushed through mitochondrial membrane producing ATP

Consider the following:

In oxidative phosphorylation, oxygen must be present to receive electrons from the protein complexes. This allows for more electrons and high energy molecules to be passed along, and maintains the hydrogen pumping that produces ATP. What happens if we run out of oxygen? How do we break down our food to make energy? The body has a plan B for this situation called fermentation. It happens all the time in athletes, like runners, when they use all their oxygen and produce lactic acid. Fermentation starts after glycolysis, replacing the citric acid cycle and oxidative phosphorylation. During glycolysis, only two ATP molecules are produced. NADH is then oxidized to transform the pyruvates made in glycolysis into lactic acid.

Want to join the conversation?

• Are these protons, actually protons or just short hand for +H30?
• They are actually protons (H+), and not H3O+. If you consider these protein carriers are highly specific (form = function), they only bind single protons. They do not bind water, and do not transport water.
• Are electron transport system same as the oxidative phosphorylation?
• Yes it is. Just watch the next video and Sal clarifies this.
• I understand that Oxygen must be present for the cycle to work because it accepts the electrons at the end of the chain of proteins. But, what exactly about accepting those electrons makes it necessary? Is it that a build up of electrons at that protein are harmful? Do they change the energy of the system so that more electrons wouldn't then flow towards that lower-energy protein? What, chemically, would happen if Oxygen didn't take them??
• It would back up. The whole system is predicated upon rolling energetically downhill and passing the electrons to a more readily reduced molecule. If this molecule (oxygen) isn't there then complex 4 has nowhere to dump them (you can't just eject electrons from a molecule without some solid energy investments). As complex 4 already has electrons in this case, it loses the great ability to be reduced that made it a good place for cytochrome C (from complex 3) to dump it electrons from earlier in the chain. This causes complex 3 to back up etc., until the whole chain is effectively clogged with electrons until they can be unloaded onto an O2.
• i just wanna know specificly how many H+ are pumped in the the space : for each NADH one or two h+ are pumped out ?
• Charles is right. The most recent research points out that complex I pumps out 4 H+, Complex III pumps out 4 H+, and complex IV pumps out 2 H+. Therefore, NADH results in 10 H+ being pumped out, but FADH2 results in 6H+ being pumped out since it bypasses complex I.

The current research estimates that ATP synthase makes 1 ATP for every 4 H+ that pass through it, thus, the 10 H+ coming from the energy of one NADH would lead to the creation of 10/4 or 2.5 ATP.
• If the inner membrane is impermeable to NADH, how does the NAD+ and FAD go from the citric acid cycle to the matrix in the electron transport chain?
• The citric acid cycle happens in the matrix of mitochondria, so NADH and FADH2 (from the reduction of NAD+ and FAD in the citric acid cycle) already have access to the ETC. Keep in mind that the citric acid cycle occurs in the mitochondrial matrix, and that the protons from NADH and FADH2 are pumped from the matrix of mitochondria across their inner membranes into the intermembrane space.
• It would be much better if we recognized NAD+ accepts what is essentially a hydride anion, and FAD accepts what is essentially a hydrogen diatom
• I agree, that is a good way of thinking about it! :)
(1 vote)
• What is the difference between ATP synthase and ATP synthetase? I have seen different sources interchange these words.
(1 vote)
• ATP synthetase is real, much like synthase, it's an enzyme that helps form covalent bonds however:
synTHase = without much energy input, and
synTHETase = with energy input
So an example of this would be in the Krebs cycle, at the beginning, when forming citrate, it uses citrate synthase, which is pretty much without ATP usage. However, later on in the cycle, when forming succinate, the reaction actually takes GDP and produces GTP, so it uses energy - succinyl-CoA synthetase