Question

How can an organism generate ATP from Acetyl-CoA directly (not via electron transfer chains indirectly)? Describe the chemistry involved.

Answer 1

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 FADH₂ and 2) Phosphorylation.

Step 1
Oxidative phosphorylation starts with the arrival of 3 NADH and 1 FADH₂ 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 FADH₂ transfers its high energy molecules to protein complex 2. Shuttling high energy molecules causes a loss of electrons from NADH and FADH₂, called oxidation (other molecules are also capable of being oxidized).

The opposite of oxidation is the 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)

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 H⁺ 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 - FADH₂ 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 QH₂. There is no hydrogen pumping for the exchange of the FADH₂ electrons here.

Step 3
The rest of the steps are now the same for the high energy molecules from NADH and FADH₂ in earlier steps. Inside the nonpolar region of the phospholipid bilayer, UQH₂ (which is also a nonpolar compound) transports the electrons to protein complex 3. UQH₂ also carries protons. When UQH₂ delivers electrons to protein complex 3, it also donates its protons to be pumped.

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.

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.

In summary

• +3 NADH
• +1 FADH₂
• +3 Hydrogen protons (H⁺)
• -2 Hydrogen protons (H⁺)
• -½ O₂
• +1 H₂O

Step 6
As a result of part 1 (Oxidation of NADH and FADH₂), 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 (H⁺), 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 FADH₂

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

• -ADP
• -Pi
• +ATP