Respiration and ATP synthesis

Q: What are the three main stages of cellular respiration and where does each take place?

The three stages are glycolysis in the cytosol, the citric acid cycle in the mitochondrial matrix, and the electron transport chain in the mitochondrial inner membrane.

Q: What is the primary biological purpose of fermentation in anaerobic environments?

Fermentation oxidizes \(\text{NADH}\) back to \(\text{NAD}^+\) in the cytosol so that glycolysis can continue producing ATP in the absence of oxygen.

Q: What is the difference between alcoholic fermentation and lactic acid fermentation regarding chemical products and \(\text{CO}_2\) release?

Alcoholic fermentation converts pyruvate (\(\text{C}_3\)) into ethanol (\(\text{C}_2\)) and releases \(\text{CO}_2\) , whereas lactic acid fermentation converts pyruvate directly into lactic acid (\(\text{C}_3\)) with no \(\text{CO}_2\) produced.

Biology · Common Test for University Admissions · 9 min read · Updated: 22 Oct 2026

Chapter 1: Overview of Respiration and ATP Synthesis

Hello to all of you studying biology! When you hear the word "respiration," you might picture breathing in and out with your lungs. However, in biology, cellular respiration (internal respiration) refers to the series of chemical reactions that break down organic substances (mainly glucose) inside cells to extract ATP (adenosine triphosphate)—the vital energy currency of living organisms.

At first, with all the names of chemical reactions and substances moving around, you might feel like "this looks tough...", but don't worry! In short, respiration is simply the process of "gradually dismantling a large block called glucose and exchanging its energy into convenient pocket money called ATP." Let's understand the whole story by breaking it down into three stages.

Overall Reaction Equation for Respiration

The overall chemical reaction of respiration can be summarized by the following equation:

\(\text{C}_6\text{H}_{12}\text{O}_6 + 6\text{O}_2 + 6\text{H}_2\text{O} \longrightarrow 6\text{CO}_2 + 12\text{H}_2\text{O} + \text{エネルギー（最大38ATP）}\)

* Note: The number of ATP molecules produced is expressed as up to 38 (or 36–38) depending on conditions. Notice that \(6\text{H}_2\text{O}\) is also included on the left side of the equation (this is because water is used in the citric acid cycle).

The Three Major Stages of Respiration

Respiration is divided into the following three stages based on where each takes place and what role it plays:

1. Glycolysis: Takes place in the cytosol. Splits glucose in half without using oxygen.
2. Citric Acid Cycle: Takes place in the mitochondrial matrix. Completely dismantles the fragments and releases carbon dioxide.
3. Electron Transport Chain: Takes place in the mitochondrial inner membrane. Uses oxygen to synthesize a large amount of ATP.

[Key Point]
Memorizing the locations correctly is your first step toward acing the Common Test! Make sure you firmly memorize the sequence: "Cytosol → Matrix → Inner Membrane."

Chapter 2: Stage 1 — "Glycolysis"

Where and What Happens?

Glycolysis takes place in the cell's cytosol. The most important feature of this pathway is that it does not require oxygen (\(\text{O}_2\)). It is considered an extremely ancient metabolic pathway, handed down from primitive life forms in the distant past when there was virtually no oxygen on Earth.

Flow of Reactions (Step-by-Step)

1. Activation of Glucose: One molecule of glucose with 6 carbons (\(\text{C}_6\)) is first energized by consuming 2 ATP molecules from within the cell (an investment), attaching phosphate groups to make it easier to split.
2. Splitting in Two: It splits into two 3-carbon (\(\text{C}_3\)) compounds.
3. Oxidation and ATP Synthesis: Hydrogen is removed (dehydrogenation) and transferred to the dehydrogenation coenzyme \(\text{NAD}^+\), producing \(\text{NADH}\). At the same time, 4 molecules of ATP are produced via substrate-level phosphorylation.
4. Production of Pyruvate: Ultimately, two molecules of 3-carbon pyruvate (\(\text{C}_3\text{H}_4\text{O}_3\)) are formed.

Balance Sheet for Glycolysis

Per 1 glucose molecule:
・ ATP consumed: \(2\text{ATP}\)
・ ATP produced: \(4\text{ATP}\)
・ Net gain: \(2\text{ATP}\)
・ Products: \(2\text{ピルビン酸} + 2\text{NADH} + 2\text{H}^+\)

Reaction equation: \(\text{C}_6\text{H}_{12}\text{O}_6 + 2\text{NAD}^+ + 2\text{ADP} + 2\text{Pi} \longrightarrow 2\text{C}_3\text{H}_4\text{O}_3 + 2\text{NADH} + 2\text{H}^+ + 2\text{ATP}\)
(* \(\text{Pi}\) represents inorganic phosphate)

[Common Mistake]
Be careful not to jump to the conclusion that "only 2 ATP molecules are made in total in glycolysis"! It is: "4 are produced and 2 are consumed, resulting in a net profit of 2." Read test questions carefully to see whether they are asking for the "total amount synthesized" or the "net gain."

Chapter 3: Stage 2 — "The Citric Acid Cycle"

Moving to the Mitochondria

When oxygen is present, the pyruvate produced in glycolysis is transported into the internal compartment of the mitochondrion, the matrix.

Preparatory Reaction: Formation of Acetyl-CoA

As soon as pyruvate (\(\text{C}_3\)) enters the matrix, it is oxidized, releasing one molecule of carbon dioxide (\(\text{CO}_2\)) and transferring hydrogen to \(\text{NAD}^+\) to form \(\text{NADH}\). The resulting 2-carbon (\(\text{C}_2\)) activated acetate combines with coenzyme A (\(\text{CoA}\)) to become acetyl-CoA.

Turning of the Citric Acid Cycle (The Spinning Breakdown Factory)

Acetyl-CoA (\(\text{C}_2\)) combines with oxaloacetate (\(\text{C}_4\)) waiting in the cycle to form citric acid (\(\text{C}_6\)). This is why it is called the "citric acid cycle."

After that, the carbon skeleton sequentially transforms into various organic acids:
Citric acid (\(\text{C}_6\)) \(\longrightarrow\) \(\alpha\)-ketoglutaric acid (\(\text{C}_5\)) \(\longrightarrow\) succinic acid (\(\text{C}_4\)) \(\longrightarrow\) fumaric acid (\(\text{C}_4\)) \(\longrightarrow\) malic acid (\(\text{C}_4\)) \(\longrightarrow\) oxaloacetate (\(\text{C}_4\))

During this cyclic process, the following events occur:
・ Decarboxylation reactions: Carbons are cleaved off as carbon dioxide (\(\text{CO}_2\)). Most of the carbon dioxide in our breath comes from this citric acid cycle (and its preparatory step).
・ Dehydrogenation reactions: Released hydrogens are transferred to hydrogen carriers \(\text{NAD}^+\) and \(\text{FAD}\), turning them into \(\text{NADH}\) and \(\text{FADH}_2\).
・ Substrate-level phosphorylation: \(2\text{ATP}\) are directly synthesized per 1 glucose molecule (equivalent to 2 pyruvate molecules).
・ Consumption of water: Water molecules (\(\text{H}_2\text{O}\)) are taken in during the pathway.

Balance Sheet for the Citric Acid Cycle (2 Pyruvate Molecules = 1 Glucose Molecule)

・ Consumed: \(6\text{H}_2\text{O}\)
・ Released: \(6\text{CO}_2\)
・ Synthesized: \(2\text{ATP}\)
・ Reduced coenzymes produced: \(8\text{NADH} + 8\text{H}^+\) (a total of 10 NADH if including the 2 molecules from the preparatory step), \(2\text{FADH}_2\)

[Did You Know?]
The citric acid cycle is also called the "Krebs cycle," named after its discoverer, or the "TCA cycle," because it involves acids with three carboxyl groups. On the Common Test, the term "citric acid cycle" is standard.

Chapter 4: Stage 3 — "Electron Transport Chain" and ATP Synthesis

The Powerhouse That Generates Massive ATP

Up to this point through glycolysis and the citric acid cycle, a total of only 4 ATP molecules have been directly made from 1 glucose molecule (2 in glycolysis, 2 in the citric acid cycle). You might wonder, "Wait, aren't we supposed to get up to 38?" In fact, most of the energy is still stored in the electrons (hydrogens) held by \(\text{NADH}\) and \(\text{FADH}_2\). Harnessing these electrons to produce a huge amount of ATP is the job of the electron transport chain located in the inner membrane of the mitochondria!

How Electron Transport Works (A Bucket Brigade)

1. \(\text{NADH}\) and \(\text{FADH}_2\) hand over their electrons (\(e^-\)) to protein complexes embedded in the inner membrane. They are oxidized back into \(\text{NAD}^+\) and \(\text{FAD}\), which are reused in glycolysis and the citric acid cycle.
2. Like a bucket brigade, the electrons are passed along multiple electron carriers (such as cytochromes) lined up in the inner membrane, moving from higher energy levels to lower energy levels.
3. Using the energy released as electrons flow, the complexes pump protons (\(\text{H}^+\)) from the matrix into the intermembrane space (between the outer and inner membranes).
4. The electrons reaching the end of the relay are transferred to the oxygen (\(\text{O}_2\)) we inhaled through respiration, where they combine with protons (\(\text{H}^+\)) to form water (\(\text{H}_2\text{O}\)).
\(\text{O}_2 + 4\text{H}^+ + 4e^- \longrightarrow 2\text{H}_2\text{O}\)

Chemiosmotic Hypothesis and ATP Synthase (The Hydroelectric Dam Model)

As protons are continuously pumped into the intermembrane space, the intermembrane space becomes high in \(\text{H}^+\) concentration (acidic and positively charged), while the matrix side remains low. This creates a proton concentration gradient (electrochemical gradient) across the inner membrane. Think of this just like a reservoir full of water behind a dam.

ATP synthase embedded in the inner membrane acts like the spillway/turbines of this dam. When protons rush through the channel of ATP synthase down their concentration gradient back into the matrix, part of the enzyme rotates like a motor. Using the mechanical energy of this rotation, massive amounts of \(\text{ATP}\) are synthesized from \(\text{ADP}\) and inorganic phosphate. This mechanism is known as the chemiosmotic hypothesis (oxidative phosphorylation).

ATP Yield in the Electron Transport Chain

・ From the \(\text{NADH}\) and \(\text{FADH}_2\) derived from 1 glucose molecule, up to 34 ATP molecules are synthesized.
・ 2 ATP from glycolysis + 2 ATP from the citric acid cycle + up to 34 ATP from the electron transport chain = up to 38 ATP.

[Key Point]
If you are asked, "Why is oxygen necessary?", make sure you can answer: "To act as the final electron acceptor in the electron transport chain and form water." Without oxygen, electron flow backs up into a complete traffic jam, halts, and ATP can no longer be made.

Chapter 5: Metabolism Without Oxygen — "Fermentation"

Something you must never overlook when studying respiration is fermentation, which operates in environments where oxygen cannot be used. It is closely linked to glycolysis.

Why Does Even Glycolysis Stop Without Oxygen?

For glycolysis to keep running, \(\text{NAD}^+\) is indispensable as a hydrogen acceptor. Normally, the electron transport chain takes electrons from \(\text{NADH}\) and regenerates \(\text{NAD}^+\). But without oxygen, the electron transport chain halts, and cellular \(\text{NAD}^+\) quickly runs out.
To prevent this, "fermentation" serves as an emergency backup system that works entirely within the cytosol without using mitochondria; it forces the hydrogens from \(\text{NADH}\) onto substances like pyruvate to regenerate \(\text{NAD}^+\), keeping glycolysis barely running to scrape together \(2\text{ATP}\).

1. Alcoholic Fermentation (Yeasts, etc.)

\(\text{CO}_2\) is removed from pyruvate (\(\text{C}_3\)) to form acetaldehyde (\(\text{C}_2\)), which is then reduced by \(\text{NADH}\) to produce ethanol (\(\text{C}_2\text{H}_5\text{OH}\)).

Reaction equation: \(\text{C}_6\text{H}_{12}\text{O}_6 \longrightarrow 2\text{C}_2\text{H}_5\text{OH} + 2\text{CO}_2 + 2\text{ATP}\)

2. Lactic Acid Fermentation (Lactic acid bacteria, muscles during vigorous exercise, etc.)

Pyruvate (\(\text{C}_3\)) is directly reduced by \(\text{NADH}\) to produce lactic acid (\(\text{C}_3\text{H}_6\text{O}_3\)). No \(\text{CO}_2\) is generated.

Reaction equation: \(\text{C}_6\text{H}_{12}\text{O}_6 \longrightarrow 2\text{C}_3\text{H}_6\text{O}_3 + 2\text{ATP}\)

[Common Mistake]
Many students mistakenly assume that "lactic acid fermentation also releases carbon dioxide"! In alcoholic fermentation, \(\text{CO}_2\) is produced because the number of carbons drops from 3 (pyruvate) \(\to\) 2 (ethanol), but in lactic acid fermentation, the carbon number stays at 3 (pyruvate) \(\to\) 3 (lactic acid), so no \(\text{CO}_2\) is released at all. Make sure you distinguish between the two clearly.

Summary: Common Test Final Review!

Finally, let's wrap up with a comparison summary of the three stages of respiration.

・ Glycolysis
Location: Cytosol
Oxygen required?: Not required
Net ATP yield: \(+2\text{ATP}\)
Fate of carbon: Glucose (\(\text{C}_6\)) \(\longrightarrow\) Pyruvate (\(\text{C}_3\)) \(\times 2\)
Coenzymes: \(2\text{NADH}\) produced

・ Citric Acid Cycle
Location: Mitochondrial matrix
Oxygen required?: Indirectly required (stops if the electron transport chain stops)
Net ATP yield: \(+2\text{ATP}\)
Fate of carbon: Pyruvate (\(\text{C}_3\)) \(\longrightarrow\) completely released as \(6\text{CO}_2\)
Coenzymes: \(8\text{NADH}\) (10 NADH including the preparatory step), \(2\text{FADH}_2\) produced (6 water molecules consumed)

・ Electron Transport Chain
Location: Mitochondrial inner membrane
Oxygen required?: Directly required (final electron acceptor)
Net ATP yield: Up to \(+34\text{ATP}\)
Fate of carbon: Not involved (oxygen is reduced to form \(12\text{H}_2\text{O}\))
Coenzymes: All \(\text{NADH}\) and \(\text{FADH}_2\) are oxidized and become reusable

Once you connect how respiration works in your head, your understanding of "photosynthesis" (the reverse flow of energy) that you'll study next will be so much easier. First, make sure you firmly sort out these three locations and their roles!

Quick check

Can you answer these now?

Open each question to check the key ideas from this chapter.

What is cellular respiration, and what is its overall chemical reaction equation?

Cellular respiration is the breakdown of organic molecules such as glucose to synthesize ATP, summarized as: \(\text{C}_6\text{H}_{12}\text{O}_6 + 6\text{O}_2 + 6\text{H}_2\text{O} \longrightarrow 6\text{CO}_2 + 12\text{H}_2\text{O} + \text{energy (up to 38 ATP)}\).

What are the three main stages of cellular respiration and where does each take place?

The three stages are glycolysis in the cytosol, the citric acid cycle in the mitochondrial matrix, and the electron transport chain in the mitochondrial inner membrane.

What occurs during the process of glycolysis, and what is its net energy yield?

One molecule of glucose (\(\text{C}_6\)) is split into two pyruvate molecules (\(\text{C}_3\)), consuming 2 ATP and generating 4 ATP, resulting in a net gain of 2 ATP and 2 NADH.

How is pyruvate converted into acetyl-CoA before entering the citric acid cycle?

In the mitochondrial matrix, pyruvate (\(\text{C}_3\)) undergoes decarboxylation to release \(\text{CO}_2\) and oxidation to form \(\text{NADH}\), combining with coenzyme A to form acetyl-CoA (\(\text{C}_2\)).

How does the citric acid cycle operate, and what are its main products per glucose molecule?

Acetyl-CoA (\(\text{C}_2\)) combines with oxaloacetate (\(\text{C}_4\)) to form citric acid (\(\text{C}_6\)); per glucose molecule, the cycle yields \(6\text{CO}_2\), \(2\text{ATP}\), \(8\text{NADH}\) (10 including the preparatory step), and \(2\text{FADH}_2\), while consuming \(6\text{H}_2\text{O}\).

How does the electron transport chain transfer electrons and create a proton gradient?

Electrons from \(\text{NADH}\) and \(\text{FADH}_2\) pass along inner-membrane carriers to pump \(\text{H}^+\) from the matrix into the intermembrane space, ultimately being accepted by \(\text{O}_2\) to form \(\text{H}_2\text{O}\).

What is the chemiosmotic hypothesis and how does ATP synthase generate ATP?

Protons stored in the intermembrane space flow down their concentration gradient through ATP synthase back into the matrix, driving the rotary synthesis of ATP from ADP and inorganic phosphate.

What is the primary biological purpose of fermentation in anaerobic environments?

Fermentation oxidizes \(\text{NADH}\) back to \(\text{NAD}^+\) in the cytosol so that glycolysis can continue producing ATP in the absence of oxygen.

What is the difference between alcoholic fermentation and lactic acid fermentation regarding chemical products and \(\text{CO}_2\) release?

Alcoholic fermentation converts pyruvate (\(\text{C}_3\)) into ethanol (\(\text{C}_2\)) and releases \(\text{CO}_2\), whereas lactic acid fermentation converts pyruvate directly into lactic acid (\(\text{C}_3\)) with no \(\text{CO}_2\) produced.

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