In 1961 the British biochemist Peter Mitchell proposed an odd idea: mitochondria make ATP not through a high-energy chemical intermediate, which most researchers were searching for, but by pumping protons across a membrane and letting them flow back. Many biochemists were skeptical for years. The evidence built up, and in 1978 Mitchell received the Nobel Prize in Chemistry. His idea, chemiosmosis, is where cellular respiration ends. Let's look closer at how a cell gets there from one molecule of glucose (AP Biology Unit 3).
The map
Cellular respiration releases the energy stored in glucose and other organic molecules a little at a time:
- Glycolysis in the cytosol
- Pyruvate oxidation and the Krebs (citric acid) cycle in the mitochondrial matrix
- The electron transport chain and ATP synthase in the inner mitochondrial membrane
You don't need to memorize the steps, intermediates or enzyme names of glycolysis or the Krebs cycle; the course leaves them out. You do need to know what goes in, what comes out, and where.
Glycolysis
One glucose is split into 2 pyruvate. The cell spends 2 ATP and makes 4, a net gain of 2 ATP, and reduces NAD⁺ to 2 NADH. No oxygen is needed, and nearly all living organisms carry out glycolysis.
Pyruvate oxidation and the Krebs cycle
Pyruvate moves into the mitochondrion. Each one loses a carbon as CO₂ and becomes acetyl-CoA, which enters the Krebs cycle. Over two turns per glucose, the remaining carbons leave as CO₂, a little ATP is made, and lots of electrons are loaded onto carriers: NAD⁺ becomes NADH and FAD becomes FADH₂.
Look closer at the bookkeeping. By the end of the Krebs cycle, glucose is fully oxidized, but only a net 4 ATP have been made. Most of the energy is now held in NADH and FADH₂.
The electron transport chain
NADH and FADH₂ hand their electrons to a series of proteins in the inner membrane. Each transfer is a redox reaction, and the energy released is used to pump H⁺ from the matrix into the intermembrane space. That builds an electrochemical gradient: the intermembrane space has more H⁺, so its pH is lower than the matrix.
At the end of the chain, oxygen is the terminal electron acceptor. It takes the electrons, picks up H⁺ and becomes water. Anaerobic prokaryotes use a different molecule as the final acceptor. The inner membrane is folded into cristae, which gives it more surface area for more chains and more ATP synthase.
ATP synthase and chemiosmosis
H⁺ ions flow back into the matrix mainly through ATP synthase. As they flow down their gradient, the enzyme joins ADP and inorganic phosphate into ATP. This is oxidative phosphorylation, and it makes most of the cell's ATP. Textbooks give different totals per glucose (often around 30 to 32), because the exact count depends on the cell and on assumptions about the membrane.
When the gradient leaks
If H⁺ leaks back without passing ATP synthase, electron transport continues but the energy is released as heat instead of being stored in ATP. Brown fat, found in newborns and hibernating mammals, does this on purpose with a protein that lets protons leak. It's one way endotherms keep warm.
Without oxygen: fermentation
With no oxygen to accept electrons, the chain stops and NADH piles up. Glycolysis needs NAD⁺, so cells regenerate it by fermentation:
- Lactic acid fermentation: pyruvate becomes lactate (muscle cells short of oxygen; bacteria that make yogurt).
- Alcohol fermentation: pyruvate becomes ethanol and CO₂ (yeast; the CO₂ makes bread dough rise).
Fermentation itself makes no extra ATP. The cell lives on the 2 ATP from glycolysis.
Common mistakes students make
- "Plants don't respire." They do, day and night, in their mitochondria.
- "Oxygen becomes CO₂." Oxygen becomes water. The carbon in CO₂ comes from glucose.
- "The electron transport chain makes the ATP." The chain builds the gradient; ATP synthase makes the ATP.
- "Fermentation makes ATP." Its job is to regenerate NAD⁺ so glycolysis can keep making 2 ATP.
Frequently asked questions
What are the stages of cellular respiration in order?
Glycolysis, pyruvate oxidation, the Krebs cycle, then the electron transport chain with oxidative phosphorylation.
Why is oxygen needed for cellular respiration?
Oxygen is the final electron acceptor. Without it, electrons stop flowing, the proton gradient runs down and ATP synthase makes far less ATP.
Where is the proton gradient in the mitochondrion?
Across the inner membrane: H⁺ is concentrated in the intermembrane space and flows back into the matrix through ATP synthase.
What is the difference between aerobic respiration and fermentation?
Aerobic respiration uses oxygen and the electron transport chain to make many ATP per glucose. Fermentation uses only glycolysis, making 2 ATP, and regenerates NAD⁺ by turning pyruvate into lactate or ethanol.
Try it
Say each answer before you flip the card. Then predict: what would you expect to see if you mixed yeast with sugar and warm water in a sealed bag, and then with plain warm water in a second bag?
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