Citric Acid Cycle and Oxidative Phosphorylation

Core Concepts

Pyruvate oxidation: the doorway to the cycle

Before the cycle, each pyruvate is converted in the matrix by the pyruvate dehydrogenase complex:

Pyruvate + CoA + NAD⁺ → acetyl-CoA + CO₂ + NADH

One carbon leaves as CO₂ (this is why we exhale carbon derived from food). Per glucose: 2 pyruvate → 2 acetyl-CoA, 2 CO₂, 2 NADH.

The citric acid cycle: a molecular carousel

The cycle runs in the mitochondrial matrix. Simplified, per turn:

1. Entry: acetyl-CoA (2 C) combines with oxaloacetate (4 C) to form citrate (6 C).
2. Spin: through a series of enzyme-catalyzed steps, the molecule is oxidized, losing 2 CO₂ (one carbon at a time).
3. Harvest: each turn produces 3 NADH, 1 FADH₂, and 1 ATP (via GTP).
4. Regeneration: the four-carbon oxaloacetate is regenerated, ready for the next acetyl-CoA.

Per glucose (two turns): 6 NADH, 2 FADH₂, 2 ATP (GTP), 4 CO₂. Notice that all the carbon atoms of glucose are now released as CO₂ — the cycle is where the "burning" of carbon actually completes.

The electron transport chain: a downhill electron relay

The ETC is a series of protein complexes (traditionally numbered I–IV) and mobile carriers (ubiquinone/coenzyme Q and cytochrome c) in the inner mitochondrial membrane:

• NADH donates electrons at complex I; FADH₂ enters later at complex II (so NADH contributes more energy — its electrons start higher up the chain).
• Electrons pass from complex to complex, each step releasing a little energy, which is used to pump H⁺ out of the matrix into the intermembrane space.
• The final step: O₂ + electrons + H⁺ → H₂O. Oxygen's job is to accept the spent electrons — it is the "garbage collector" that keeps the chain from backing up. This is a model of the process; the precise molecular details (proton stoichiometry, supercomplex organization) are an active research area.

Chemiosmosis: the proton gradient turns the turbine

The pumping creates a proton gradient — many H⁺ in the intermembrane space, few in the matrix — the proton-motive force. Protons flow back into the matrix only through ATP synthase, a rotary enzyme:

H⁺ flow through ATP synthase → ADP + Pᵢ → ATP

Because ATP synthesis is coupled to electron transport (which depends on oxidation), this stage is called oxidative phosphorylation. It is the cell's main ATP factory.

Putting the tally together (reference figures)

A commonly taught accounting per glucose:

The 10 NADH and 2 FADH₂ feed the ETC, yielding roughly 28–34 ATP (exact numbers depend on the shuttle system that moves cytosolic NADH into mitochondria and on textbook conventions; total commonly taught as ~36–38 ATP per glucose). The key point: most ATP comes from oxidative phosphorylation, not from glycolysis or the cycle directly.

Worked Example: A Glucose Molecule's Journey Through the Mitochondria

Follow one glucose's worth of carbon and energy:

1. Glycolysis (cytosol): 1 glucose → 2 pyruvate, net 2 ATP, 2 NADH.
2. Across the membrane: pyruvate enters the matrix; each becomes acetyl-CoA, releasing 2 CO₂ and making 2 NADH.
3. Two turns of the cycle: the two acetyl-CoA each join oxaloacetate → citrate → ... → oxaloacetate. Each turn releases 2 CO₂ (4 CO₂ total for the pair) and produces 3 NADH, 1 FADH₂, 1 ATP — so 6 NADH, 2 FADH₂, 2 ATP for the pair.
4. Oxidative phosphorylation: the 10 NADH and 2 FADH₂ deliver electrons to the ETC, pumping protons out; the gradient drives ATP synthase; oxygen catches the electrons and makes water. This step yields the bulk of the ATP — roughly 28–34 ATP depending on counting conventions.
5. Tally: ~36–38 ATP per glucose (textbook-dependent), most from oxidative phosphorylation, plus 6 CO₂ exhaled and water formed.

Common Confusions