Cellular Respiration

Core Review

Overview of Glucose Catabolism

Cellular respiration is the process by which cells extract energy from glucose. The overall reaction: C₆H₁₂O₆ + 6 O₂ → 6 CO₂ + 6 H₂O + energy (ATP + heat)

The process occurs in four stages. The first (glycolysis) is cytoplasmic; the remaining three occur in the mitochondria.

Stage 1: Glycolysis (Cytoplasm)

Glycolysis ("sugar splitting") converts one 6-carbon glucose into two 3-carbon pyruvate molecules. It consists of an energy investment phase (2 ATP consumed) and an energy payoff phase (4 ATP produced, 2 NADH generated). Net yield per glucose: 2 ATP (substrate-level phosphorylation), 2 NADH, and 2 pyruvate. Oxygen is NOT required — glycolysis occurs in both aerobic and anaerobic conditions.

Key enzymes to know: hexokinase (phosphorylates glucose, trapping it in the cell), phosphofructokinase (PFK, the committed and rate-limiting step — regulated by ATP and citrate inhibition), and pyruvate kinase.

Stage 2: Pyruvate Oxidation (Mitochondrial Matrix)

Each pyruvate enters the mitochondrial matrix via active transport. Pyruvate dehydrogenase complex catalyzes: Pyruvate + CoA + NAD⁺ → Acetyl-CoA + CO₂ + NADH Per glucose (2 pyruvates): 2 NADH, 2 CO₂, 2 acetyl-CoA. This is an irreversible, oxidative decarboxylation step linking glycolysis to the Krebs cycle.

Stage 3: The Krebs Cycle (Citric Acid Cycle) — Matrix

Acetyl-CoA (2C) combines with oxaloacetate (4C) to form citrate (6C), catalyzed by citrate synthase. Through a series of redox and decarboxylation reactions, citrate is progressively oxidized back to oxaloacetate. Per turn (per acetyl-CoA):

• 2 CO₂ released
• 3 NADH produced
• 1 FADH₂ produced
• 1 GTP produced (equivalent to ATP via substrate-level phosphorylation)

Per glucose (2 turns): 4 CO₂, 6 NADH, 2 FADH₂, 2 GTP.

Stage 4: Oxidative Phosphorylation (Inner Mitochondrial Membrane)

Electron Transport Chain (ETC): NADH and FADH₂ donate electrons to protein complexes in the inner membrane. Electrons pass through Complexes I–IV, losing energy at each step, which is used to pump protons (H⁺) from the matrix into the intermembrane space. The final electron acceptor is molecular oxygen (O₂), which is reduced to H₂O. NADH enters at Complex I (pumping more protons → more ATP), while FADH₂ enters at Complex II (pumping fewer protons → less ATP).

Chemiosmosis: The proton gradient (proton-motive force) drives H⁺ back into the matrix through ATP synthase (Complex V). This flow powers the phosphorylation of ADP to ATP — the mechanism is called chemiosmosis, proposed by Peter Mitchell.

ATP Yield Estimates:

• Glycolysis: 2 ATP + 2 NADH (→ ~3–5 ATP depending on shuttle)
• Pyruvate oxidation: 2 NADH (→ ~5 ATP)
• Krebs cycle: 2 GTP + 6 NADH (→ ~15 ATP) + 2 FADH₂ (→ ~3 ATP)
• Total: approximately 30–32 ATP per glucose. (The theoretical maximum of ~36–38 is lower in eukaryotes due to the cost of transporting NADH from the cytoplasm into the mitochondria.)

Anaerobic Respiration: Fermentation

When oxygen is unavailable, NADH cannot be reoxidized by the ETC. Fermentation regenerates NAD⁺ so glycolysis can continue.

Lactic Acid Fermentation (animals, some bacteria): Pyruvate + NADH → Lactic acid + NAD⁺ Occurs in human muscle cells during intense exercise when oxygen delivery lags behind demand. Produces only 2 ATP per glucose.

Ethanol Fermentation (yeast, some bacteria): Pyruvate → Acetaldehyde + CO₂, then Acetaldehyde + NADH → Ethanol + NAD⁺ Produces 2 ATP per glucose. Used in baking (CO₂ makes dough rise) and brewing (ethanol is the alcohol).

Aerobic vs. Anaerobic Comparison

Common Traps

• "Glycolysis requires oxygen": False. Glycolysis is strictly anaerobic. The confusion arises because aerobic organisms run glycolysis and then feed pyruvate into aerobic pathways.
• "Fermentation makes ATP": It does NOT directly — glycolysis makes the ATP. Fermentation simply regenerates NAD⁺ so glycolysis can continue.
• "The Krebs cycle uses oxygen": The Krebs cycle itself does not directly use O₂. The ETC uses O₂, but since the Krebs cycle depends on NAD⁺ regeneration by the ETC, it stops without O₂ indirectly.