Difficulty: Intermediate | Prerequisites: Basic chemistry (bonds, electrons, redox), Chapter 6–7 notes on metabolism and enzymes.
Cellular respiration breaks glucose (and other fuel molecules) into CO2 and water, capturing the released energy as ATP. The process runs through three main stages: glycolysis, the Krebs cycle, and oxidative phosphorylation. Electrons are stripped from fuel molecules at each stage, carried by NADH and FADH2 to the electron transport chain, and ultimately handed to oxygen.
Glycolysis
The splitting of one glucose molecule (6 carbons) into two pyruvate molecules (3 carbons each) in the cytoplasm. Produces a small net gain of ATP and NADH. Does not require oxygen.
In simple terms: the first stage of breaking down sugar for energy, happening outside the mitochondria.
Pyruvate
The three-carbon end product of glycolysis. In the presence of oxygen it is converted to acetyl CoA and enters the mitochondria.
Think of it as the handoff molecule between glycolysis and the rest of respiration.
Acetyl CoA
A two-carbon acetyl group attached to coenzyme A, formed from pyruvate (or from fatty acid beta-oxidation). Feeds directly into the Krebs cycle.
In simple terms: the universal fuel ticket that enters the Krebs cycle regardless of whether the original fuel was carbohydrate, fat, or protein.
Krebs cycle (citric acid cycle / TCA cycle)
A cyclic series of reactions in the mitochondrial matrix that oxidises acetyl CoA to CO2, generating NADH, FADH2, and a small amount of ATP (as GTP).
Think of it as the stage where carbon atoms leave as CO2 and electrons are loaded onto carriers.
Oxidative phosphorylation
The process by which NADH and FADH2 donate electrons to the electron transport chain (ETC) in the inner mitochondrial membrane. The energy released pumps protons across the membrane, and ATP synthase uses that proton gradient to produce the bulk of the cell's ATP. Oxygen is the final electron acceptor, forming water.
In simple terms: the big payoff stage where most ATP is made, and where oxygen is consumed.
NADH / FADH2
Electron carriers. NAD+ and FAD are oxidised forms that pick up electrons (and protons) during glycolysis and the Krebs cycle, becoming NADH and FADH2. They deliver those electrons to the ETC.
Think of them as shuttle buses carrying high-energy electrons to the power plant.
Electron transport chain (ETC)
A series of protein complexes (I, II, III, IV) embedded in the inner mitochondrial membrane. Electrons pass along the chain, releasing energy used to pump H+ ions into the intermembrane space.
ATP synthase
The enzyme (Complex V) that lets protons flow back down their concentration gradient, using the energy to phosphorylate ADP into ATP. This is chemiosmosis.
Beta-oxidation
The breakdown of fatty acids into two-carbon acetyl CoA units. This is how fats enter respiration, bypassing glycolysis and feeding straight into the Krebs cycle.
Deamination
The removal of an amino group from an amino acid, allowing the remaining carbon skeleton to enter the Krebs cycle or other metabolic pathways. This is how proteins contribute to ATP production.
Hexokinase
The enzyme catalysing step 1 of glycolysis (glucose to glucose-6-phosphate). A key regulatory point.
Phosphofructokinase (PFK)
The enzyme catalysing step 3 of glycolysis (fructose-6-phosphate to fructose-1,6-bisphosphate). The most important regulatory enzyme of glycolysis, inhibited by ATP and citrate, activated by AMP and ADP.
Citrate synthase
The enzyme catalysing the first step of the Krebs cycle (acetyl CoA + oxaloacetate to citrate). Regulatory checkpoint.
Isocitrate dehydrogenase
The enzyme catalysing step 3 of the Krebs cycle (isocitrate to alpha-ketoglutarate). Another regulatory checkpoint, stimulated by ADP and inhibited by ATP and NADH.
Carbohydrates (e.g. bread, fries, sugar in a soft drink): digested to glucose, which enters at glycolysis. Glucose is split into pyruvate, then converted to acetyl CoA, and proceeds through the Krebs cycle and oxidative phosphorylation.
Fats (e.g. cheese, cooking oil): broken down by beta-oxidation into acetyl CoA units. These skip glycolysis entirely and feed into the Krebs cycle, then oxidative phosphorylation.
Proteins (e.g. meat): amino acids are deaminated (the amino group is removed). The remaining carbon skeletons enter at various points, typically the Krebs cycle, then proceed to oxidative phosphorylation.
The flow of electrons through cellular respiration:
Glucose is oxidised to pyruvate (glycolysis), releasing electrons picked up by NAD+ to form NADH.
Pyruvate is converted to acetyl CoA (pyruvate oxidation), releasing CO2 and producing more NADH.
Acetyl CoA enters the Krebs cycle, where further oxidation releases CO2 and loads electrons onto NAD+ (forming NADH) and FAD (forming FADH2).
NADH and FADH2 deliver electrons to the electron transport chain on the inner mitochondrial membrane.
Electrons pass through Complexes I, II, III, and IV, releasing energy that pumps H+ ions across the membrane.
At Complex IV, electrons are finally handed to O2, the terminal electron acceptor, forming H2O.
The proton gradient drives ATP synthase (Complex V) to produce ATP from ADP + Pi.
Stage | Inputs | Outputs |
|---|---|---|
Glycolysis | Glucose, 2 NAD+, 2 ADP + 2 Pi | 2 Pyruvate, 2 NADH, 2 ATP (net) |
Krebs cycle | 2 Acetyl CoA, 6 NAD+, 2 FAD, 2 ADP + 2 Pi | 4 CO2, 6 NADH, 2 FADH2, 2 ATP (as GTP) |
Oxidative phosphorylation | 10 NADH, 2 FADH2, O2, ~34 ADP + Pi | NAD+, FAD, ~34 ATP, H2O |
Glycolysis regulation:
Step 1, hexokinase: phosphorylates glucose, trapping it in the cell. Inhibited by its own product (glucose-6-phosphate).
Step 3, phosphofructokinase (PFK): the committed step. Inhibited by ATP and citrate (signals of energy abundance). Activated by AMP and ADP (signals of energy need).
Krebs cycle regulation:
Step 1, citrate synthase: inhibited by ATP, NADH, and citrate.
Step 3, isocitrate dehydrogenase: stimulated by ADP, inhibited by ATP and NADH.
The pattern across both pathways: when the cell has plenty of ATP, the pathway slows down. When ATP is depleted (high AMP/ADP), the pathway speeds up.
Several compounds disrupt oxidative phosphorylation:
Cyanide and carbon monoxide (CO): bind to Complex IV of the ETC, blocking electrons from reaching oxygen. The entire chain backs up and ATP production halts.
Azide: also inhibits Complex IV, similar mechanism to cyanide.
Oligomycin: blocks the proton channel in ATP synthase. Protons cannot flow back, so the gradient builds up and eventually the ETC stalls.
Dinitrophenol (DNP): an uncoupler. It carries protons across the inner membrane without going through ATP synthase, dissipating the gradient as heat. The ETC runs (oxygen is still consumed) but no ATP is made from the gradient.
This statement captures the mass balance of metabolism:
Weight gain: food enters through the mouth. Macronutrients provide carbon skeletons and energy. When energy intake exceeds expenditure, excess is stored (as glycogen or fat), adding mass.
Weight loss: when stored fuels are broken down via respiration, the carbon leaves the body as CO2 (exhaled through the nose and mouth) and hydrogen leaves as H2O (exhaled as vapour and excreted). The atoms that made up the stored fat or glycogen literally leave as gas.
Overall equation for aerobic respiration:
C_6H_{12}O_6 + 6O_2 \rightarrow 6CO_2 + 6H_2O + \text{ATP (approx. 30--38)}Simplified pathway summary:
Glucose → (glycolysis) → 2 Pyruvate → (pyruvate oxidation) → 2 Acetyl CoA → (Krebs cycle) → CO2 + electron carriers → (ETC / oxidative phosphorylation) → ATP + H2O
ATP yield per glucose (approximate):
Glycolysis: 2 ATP (net, by substrate-level phosphorylation)
Krebs cycle: 2 ATP (as GTP, by substrate-level phosphorylation)
Oxidative phosphorylation: ~30-34 ATP (via chemiosmosis)
Total: ~30-38 ATP per glucose (the range depends on the shuttle used to transport cytoplasmic NADH into the mitochondria)
Cyanide poisoning is lethal precisely because it blocks Complex IV of the ETC, shutting down aerobic ATP production in minutes. This is why cyanide antidote kits work by freeing up that complex.
DNP was once sold as a weight-loss drug because it uncouples oxidative phosphorylation: the body burns fuel without making ATP, releasing energy as heat. It was banned because the uncontrolled heat generation can be fatal.
The idea that "you lose weight through your nose" has real clinical relevance. Studies tracking labelled carbon atoms in fat show that roughly 84% of a fat molecule's mass leaves the body as exhaled CO2.
Students often think oxygen is used in the Krebs cycle. It is not. Oxygen is consumed only at the very end, at Complex IV of the electron transport chain. The Krebs cycle is aerobic only in the sense that it depends on NAD+ and FAD being regenerated by the ETC, which does require oxygen.
Students sometimes believe glycolysis happens inside the mitochondria. It does not. Glycolysis takes place in the cytoplasm.
A common error is thinking that most ATP comes from glycolysis or the Krebs cycle. In fact, the vast majority (roughly 30-34 of the ~38 ATP per glucose) comes from oxidative phosphorylation.
Students confuse the electron transport chain with ATP synthase. The ETC (Complexes I-IV) moves electrons and pumps protons. ATP synthase (Complex V) is a separate enzyme that uses the resulting proton gradient to make ATP. They are coupled but distinct.
Know the inputs and outputs of all three stages cold. This is a classic table question.
Be able to trace electrons from glucose all the way to water, naming every carrier and transfer point.
Understand which regulatory enzymes control each pathway and what activates or inhibits them (PFK is the most commonly tested).
Know the respiratory poisons, which complex or enzyme each one targets, and whether it blocks the ETC or uncouples it (DNP uncouples; cyanide, CO, and azide block Complex IV; oligomycin blocks ATP synthase).
The "gain weight through your mouth, lose weight through your nose" concept ties mass balance to respiration and is a favourite discussion-section question.
Be ready to explain how fats and proteins enter respiration at different points than carbohydrates.
True or False: Glycolysis occurs inside the mitochondria. (False, it occurs in the cytoplasm.)
Fill in the blank: The final electron acceptor in the electron transport chain is ______. (Oxygen / O2)
True or False: Fats enter cellular respiration at the glycolysis stage. (False, fats enter as acetyl CoA via beta-oxidation.)
Fill in the blank: The enzyme ______ is the most important regulatory enzyme of glycolysis. (Phosphofructokinase / PFK)
True or False: Cyanide works by uncoupling oxidative phosphorylation. (False, cyanide blocks Complex IV of the ETC. DNP is the uncoupler.)
Q: Jane Doe eats a cheeseburger, fries, and a regular Coke. Name three molecules from this meal that provide energy and describe how each enters respiration.
A: Carbohydrates (glucose from the bread, fries, and Coke) enter at glycolysis, are converted to pyruvate, then acetyl CoA, and proceed through the Krebs cycle and oxidative phosphorylation. Fats (from the cheese) undergo beta-oxidation to form acetyl CoA, then enter the Krebs cycle and oxidative phosphorylation. Proteins (from the meat) are deaminated, and the carbon skeletons enter the Krebs cycle and proceed to oxidative phosphorylation.
Q: Trace the path of electrons from glucose to oxygen in cellular respiration.
A: Glucose is oxidised through glycolysis and the Krebs cycle. At each stage, electrons are transferred to NAD+ and FAD, forming NADH and FADH2. These carriers deliver electrons to the electron transport chain in the inner mitochondrial membrane. Electrons pass through Complexes I-IV, releasing energy that pumps protons. At Complex IV, electrons are transferred to O2, forming H2O.
Q: What is the role of oxygen in cellular respiration?
A: Oxygen serves as the final electron acceptor at the end of the electron transport chain (Complex IV). Without oxygen, electrons cannot be passed off, the chain backs up, NADH and FADH2 cannot be recycled, and aerobic ATP production stops.
Q: How does dinitrophenol (DNP) differ from cyanide in its effect on oxidative phosphorylation?
A: Cyanide blocks Complex IV of the ETC, preventing electron flow entirely. DNP is an uncoupler: it does not block the ETC but instead carries protons across the inner membrane, bypassing ATP synthase. The ETC keeps running and oxygen is still consumed, but the proton gradient is dissipated as heat rather than being used to make ATP.
Q: Explain why you "lose weight through your nose."
A: When stored fuels (fat, glycogen) are broken down via respiration, the carbon atoms are released as CO2 and the hydrogen atoms as H2O. CO2 is exhaled through the lungs (nose and mouth). The mass of the stored fuel literally leaves the body as exhaled gas and water vapour.
Respiration is the mirror image of photosynthesis: photosynthesis captures light energy to build glucose from CO2 and H2O, while respiration breaks glucose back down, releasing that stored energy as ATP. Understanding one helps you understand the other.
Enzyme regulation in respiration (allosteric inhibition and activation, feedback loops) connects directly to the broader topic of enzyme kinetics and metabolic control covered earlier in the course.
The chemiosmotic mechanism (proton gradient driving ATP synthase) is the same principle used in chloroplasts during the light reactions of photosynthesis, so this concept bridges both energy chapters.
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