8.3 Citric acid cycle and electron transport chain

The citric acid cycle and the electron transport chain represent the final stages of aerobic respiration, where the bulk of ATP is actually produced. The citric acid cycle oxidizes acetyl-CoA and generates electron carriers (NADH and FADH2), while the electron transport chain uses those carriers to build a proton gradient that drives ATP synthesis. Together, these processes account for roughly 90% of the ATP your cells get from glucose.

Citric Acid Cycle

The citric acid cycle (also called the Krebs cycle) takes place in the mitochondrial matrix. It's the metabolic hub where acetyl-CoA, derived from carbohydrates, fats, and amino acids, gets fully oxidized. Each turn of the cycle produces electron carriers (NADH and FADH2) that feed directly into the electron transport chain, plus a small amount of ATP (or GTP) through substrate-level phosphorylation.

Steps of the Citric Acid Cycle

1. Citrate synthase combines acetyl-CoA (2C) with oxaloacetate (4C) to form citrate (6C). This is the committed step of the cycle.
2. Aconitase converts citrate to isocitrate through a dehydration followed by a rehydration, essentially rearranging the molecule.
3. Isocitrate dehydrogenase oxidizes isocitrate to α-ketoglutarate (5C), reducing $\text{NAD}^+$ to $\text{NADH}$ and releasing $\text{CO}_2$. This is the first carbon lost as $\text{CO}_2$.
4. The α-ketoglutarate dehydrogenase complex converts α-ketoglutarate to succinyl-CoA (4C), producing another $\text{NADH}$ and releasing a second $\text{CO}_2$.
5. Succinyl-CoA synthetase converts succinyl-CoA to succinate, generating GTP (or ATP) via substrate-level phosphorylation. This is the only step that directly produces a high-energy phosphate.
6. Succinate dehydrogenase (which is also Complex II of the ETC) oxidizes succinate to fumarate, reducing $\text{FAD}$ to $\text{FADH}_2$. This is the only step that produces $\text{FADH}_2$ instead of $\text{NADH}$.
7. Fumarase hydrates fumarate to form malate.
8. Malate dehydrogenase oxidizes malate back to oxaloacetate, producing the third $\text{NADH}$ of the cycle. Oxaloacetate is now regenerated and ready to accept another acetyl-CoA.

Per turn of the cycle, the net products are: 3 $\text{NADH}$, 1 $\text{FADH}_2$, 1 GTP (or ATP), and 2 $\text{CO}_2$. Since each glucose produces 2 acetyl-CoA, you double these numbers per glucose molecule.

Electron Transport Chain and Oxidative Phosphorylation

The electron transport chain (ETC) is embedded in the inner mitochondrial membrane. Its job is to transfer electrons from NADH and FADH2 to oxygen while pumping protons ($\text{H}^+$) across the membrane. That proton gradient then drives ATP synthase to produce the vast majority of ATP in aerobic respiration.

Organization of the Electron Transport Chain

The ETC consists of four protein complexes plus two mobile electron carriers:

• Complex I (NADH dehydrogenase) accepts electrons from $\text{NADH}$, transfers them to ubiquinone (coenzyme Q), and pumps $\text{H}^+$ into the intermembrane space.
• Complex II (succinate dehydrogenase) accepts electrons from $\text{FADH}_2$, transfers them to ubiquinone, but does not pump protons. This is why $\text{FADH}_2$ yields fewer ATP than $\text{NADH}$.
• Ubiquinone (Q) is a mobile carrier that shuttles electrons from Complexes I and II to Complex III.
• Complex III (cytochrome bc1 complex) transfers electrons from ubiquinol ($\text{QH}_2$) to cytochrome c, pumping $\text{H}^+$ in the process.
• Cytochrome c is a small mobile protein that carries electrons from Complex III to Complex IV.
• Complex IV (cytochrome c oxidase) transfers electrons to the final electron acceptor, $\text{O}_2$, reducing it to $\text{H}_2\text{O}$. It also pumps $\text{H}^+$.

The overall electron flow is: $\text{NADH} \rightarrow \text{Complex I} \rightarrow \text{Q} \rightarrow \text{Complex III} \rightarrow \text{Cyt c} \rightarrow \text{Complex IV} \rightarrow \text{O}_2$. Oxygen is the final electron acceptor, which is exactly why you need to breathe.

Process of Oxidative Phosphorylation

The proton pumping by Complexes I, III, and IV creates a steep $\text{H}^+$ concentration gradient across the inner mitochondrial membrane (high in the intermembrane space, low in the matrix). ATP synthase (sometimes called Complex V) harnesses this gradient:

1. Protons flow down their electrochemical gradient through the F0 subunit of ATP synthase, which is the channel portion embedded in the membrane.
2. This proton flow causes the F0 subunit to rotate, which in turn spins the central stalk connected to the F1 subunit in the matrix.
3. The mechanical rotation of F1 drives conformational changes that catalyze the synthesis of ATP from $\text{ADP} + \text{P}_i$.
4. ATP is released into the mitochondrial matrix and then transported out to the cytoplasm (via the ATP-ADP translocase) for use throughout the cell.

The driving force behind this process is the proton motive force, which has two components: the $\Delta\text{pH}$ (difference in proton concentration) and the $\Delta\Psi$ (membrane potential from charge separation). Both contribute to the energy available for ATP synthesis.

Concept of Chemiosmosis

Chemiosmosis is the principle that links the ETC to ATP production. Peter Mitchell proposed this model, and it explains how energy from redox reactions gets converted to ATP without a direct chemical intermediate.

The core idea: the ETC pumps protons across a membrane, storing energy as an electrochemical gradient. ATP synthase then taps that stored energy as protons flow back down their gradient. This coupling of electron transport (redox chemistry) to phosphorylation (ATP synthesis) through a proton gradient is what "chemiosmosis" means.

Think of it as a dam. The ETC is the pump that moves water uphill (protons into the intermembrane space). ATP synthase is the turbine that captures energy as water flows back downhill.

Energy Yield Comparisons in Respiration

The total ATP yield depends on whether oxygen is available and which electron acceptors are used:

Aerobic respiration ($\text{O}_2$ as final electron acceptor): 30-32 ATP per glucose

• Glycolysis: 2 ATP (substrate-level phosphorylation)
• Citric acid cycle: 2 ATP/GTP (substrate-level phosphorylation)
• Oxidative phosphorylation: 26-28 ATP (from NADH and FADH2)

The range of 30-32 exists because the NADH produced in glycolysis (in the cytoplasm) must be shuttled into the mitochondria, and different shuttle systems yield slightly different amounts of ATP.

Anaerobic respiration (alternative electron acceptors, used by some prokaryotes):

• Nitrate respiration: ~20-25 ATP per glucose
• Sulfate respiration: ~15-20 ATP per glucose

These yield less because the alternative electron acceptors have less favorable reduction potentials than $\text{O}_2$, so less energy is released during electron transport.

Fermentation: 2 ATP per glucose

• Lactic acid fermentation (e.g., muscle cells under oxygen debt) and ethanol fermentation (e.g., yeast) both produce only the 2 ATP from glycolysis.
• Fermentation does not use the citric acid cycle or ETC. Its purpose is to regenerate $\text{NAD}^+$ so glycolysis can continue when oxygen is unavailable.