12.6 Cellular Respiration & Fermentation

12.6 Cellular Respiration & Fermentation

Quick Answer: Cellular respiration extracts energy from glucose in four stages: glycolysis (cytosol, nets 2 ATP + 2 NADH), pyruvate oxidation (2 acetyl-CoA + 2 NADH), the citric acid cycle (6 NADH + 2 FADH₂ + 2 ATP + 4 CO₂), and the electron transport chain + oxidative phosphorylation (inner mitochondrial membrane, ~30–32 ATP total). Oxygen is the final electron acceptor, reduced to water. Without oxygen, cells regenerate NAD⁺ by fermentation: homolactic (pyruvate → lactate) in muscle and many bacteria, or alcoholic (pyruvate → ethanol + CO₂) in yeast.

Fermentation and Anaerobic Respiration

When oxygen is unavailable or mitochondria are absent (e.g., mature mammalian RBCs), glycolysis must continue by regenerating NAD⁺, otherwise glycolysis stalls at glyceraldehyde-3-phosphate dehydrogenase. Fermentation solves this:

• Homolactic fermentation: pyruvate + NADH → lactate + NAD⁺ (lactate dehydrogenase). Occurs in muscle under heavy exertion and in Lactobacillus.
• Alcoholic fermentation: pyruvate → acetaldehyde (pyruvate decarboxylase, releases CO₂) → ethanol (alcohol dehydrogenase, consumes NADH). Used by yeast and some plants under anaerobic conditions.

Anaerobic respiration (distinct from fermentation) uses an electron transport chain but with a terminal acceptor other than O₂ (e.g., nitrate, sulfate, fumarate). Fermentation yields only the 2 ATP from glycolysis; anaerobic respiration, with its ETC, can yield more. The key distinction on the PA-CAT: fermentation regenerates NAD⁺ via substrate-level reactions and produces no ATP beyond glycolysis; anaerobic respiration still uses an ETC and oxidative phosphorylation.

Aerobic Respiration Overview

Aerobic respiration oxidizes glucose completely:

C₆H₁₂O₆ + 6 O₂ → 6 CO₂ + 6 H₂O + ~30–32 ATP

It occurs in three compartments: cytosol (glycolysis), mitochondrial matrix (pyruvate oxidation, citric acid cycle), and inner mitochondrial membrane (ETC, ATP synthase).

Glycolysis

Glycolysis splits one glucose (6C) into two pyruvate (3C) molecules in ten enzyme-catalyzed steps, all in the cytosol. The payoff phase yields 4 ATP (substrate-level phosphorylation) and 2 NADH; the investment phase consumes 2 ATP, so the net is 2 ATP + 2 NADH per glucose. Key regulatory enzyme: phosphofructokinase-1 (PFK-1), inhibited by ATP and citrate, activated by AMP and fructose-2,6-bisphosphate. Under aerobic conditions, the 2 NADH feed electrons into the mitochondrial ETC (via the malate-aspartate or glycerol-3-phosphate shuttle).

Oxidation of Pyruvate

Pyruvate enters the mitochondrial matrix and is decarboxylated by the pyruvate dehydrogenase complex:

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

This happens twice per glucose, yielding 2 acetyl-CoA, 2 CO₂, and 2 NADH. Acetyl-CoA is the entry substrate for the citric acid cycle and a central hub: fatty acids and several amino acids also feed in here.

Citric Acid Cycle (Krebs Cycle)

Per turn (one acetyl-CoA): 3 NADH, 1 FADH₂, 1 ATP (or GTP), 2 CO₂. Per glucose (two turns): 6 NADH, 2 FADH₂, 2 ATP, 4 CO₂. The cycle begins when acetyl-CoA (2C) condenses with oxaloacetate (4C) to form citrate (6C); successive oxidations and decarboxylations regenerate oxaloacetate. Key enzymes: citrate synthase, isocitrate dehydrogenase (rate-limiting, inhibited by ATP/NADH), and α-ketoglutarate dehydrogenase.

Electron Transport Chain and Oxidative Phosphorylation

The ETC sits in the inner mitochondrial membrane. Electrons from NADH enter complex I (NADH dehydrogenase); electrons from FADH₂ enter complex II (succinate dehydrogenase). Electrons pass through ubiquinone (CoQ) → complex III (cytochrome bc₁) → cytochrome c → complex IV (cytochrome c oxidase), where they reduce O₂ to H₂O. Complexes I, III, and IV pump protons from the matrix to the intermembrane space, establishing an electrochemical proton gradient (proton-motive force).

ATP synthase (complex V) lets protons flow back, using the energy to phosphorylate ADP → ATP: this is oxidative phosphorylation. Modern P/O ratios give ~2.5 ATP per NADH and ~1.5 ATP per FADH₂. Total yield per glucose:

Grand total ~30–32 ATP per glucose, depending on the shuttle used and the ATP cost of mitochondrial transport.

Catabolism of Proteins and Fats

Fatty acids are activated to acyl-CoA in the cytosol, then transported into the matrix via the carnitine shuttle and oxidized by β-oxidation, which cleaves two-carbon units as acetyl-CoA and produces NADH and FADH₂ each cycle. A 16-carbon palmitate yields 8 acetyl-CoA, 7 NADH, 7 FADH₂ → ~106 ATP, more than twice the energy per gram of glucose.

Amino acids are deaminated (removal of the amino group, excreted as urea in mammals via the urea cycle), and their carbon skeletons enter at pyruvate, acetyl-CoA, or one of the citric acid cycle intermediates (α-ketoglutarate, succinyl-CoA, fumarate, oxaloacetate), depending on the amino acid. These entry points are termed glucogenic (form pyruvate or TCA intermediates, can support gluconeogenesis) or ketogenic (form acetyl-CoA or acetoacetate, cannot support gluconeogenesis).

Why This Matters for the PA-CAT

The PA-CAT Bulletin of Information (rev. 20240815) lists Cellular Respiration within General Biology. Expect questions that (a) identify the location and net products of each stage, (b) distinguish substrate-level from oxidative phosphorylation, (c) explain why oxygen is the final electron acceptor and what happens in its absence (fermentation regenerates NAD⁺), (d) compare ATP yield from NADH vs FADH₂, and (e) place β-oxidation and amino acid carbon skeletons into the correct entry point of the central metabolic pathway.