What you’ll learn to do: Identify the reactants and products of cellular respiration and where these reactions occur in a cell

Figure 1. A hummingbird needs energy to maintain prolonged flight. The bird obtains its energy from taking in food and transforming the energy contained in food molecules into forms of energy to power its flight through a series of biochemical reactions. (credit: modification of work by Cory Zanker)

Virtually every task performed by living organisms requires energy. Energy is needed to perform heavy labor and exercise, but humans also use energy while thinking, and even during sleep. In fact, the living cells of every organism constantly use energy.

Nutrients and other molecules are imported into the cell, metabolized (broken down) and possibly synthesized into new molecules, modified if needed, transported around the cell, and possibly distributed to the entire organism. For example, the large proteins that make up muscles are built from smaller molecules imported from dietary amino acids. Complex carbohydrates are broken down into simple sugars that the cell uses for energy.

Just as energy is required to both build and demolish a building, energy is required for the synthesis and breakdown of molecules as well as the transport of molecules into and out of cells. In addition, processes such as ingesting and breaking down pathogenic bacteria and viruses, exporting wastes and toxins, and movement of the cell require energy. From where, and in what form, does this energy come? How do living cells obtain energy, and how do they use it? This chapter will discuss different forms of energy and the physical laws that govern energy transfer. This chapter will also describe how cells use energy and replenish it, and how chemical reactions in the cell are performed with great efficiency.

In the process of photosynthesis, plants and other photosynthetic producers create glucose, which stores energy in its chemical bonds. You will actually study photosynthesis in more detail a bit later. But once photosynthesis has created glucose to store energy, both plants and consumers, such as animals, undergo a series of metabolic pathways, collectively called cellular respiration, to use that energy. Cellular respiration extracts the energy from the bonds in glucose and converts it into a form that all living things can use. Now let’s take a more detailed look at how all eukaryotes—which includes humans!—make use of this stored energy.

Glycolysis

Even exergonic, energy-releasing reactions require a small amount of activation energy to proceed. However, consider endergonic reactions, which require much more energy input because their products have more free energy than their reactants. Within the cell, where does energy to power such reactions come from? The answer lies with an energy-supplying molecule called adenosine triphosphate, or ATP. ATP is a small, relatively simple molecule, but within its bonds contains the potential for a quick burst of energy that can be harnessed to perform cellular work. This molecule can be thought of as the primary energy currency of cells in the same way that money is the currency that people exchange for things they need. ATP is used to power the majority of energy-requiring cellular reactions.

ATP in Living Systems

A living cell cannot store significant amounts of free energy. Excess free energy would result in an increase of heat in the cell, which would denature enzymes and other proteins, and thus destroy the cell. Rather, a cell must be able to store energy safely and release it for use only as needed. Living cells accomplish this using ATP, which can be used to fill any energy need of the cell. How? It functions as a rechargeable battery.

When ATP is broken down, usually by the removal of its terminal phosphate group, energy is released. This energy is used to do work by the cell, usually by the binding of the released phosphate to another molecule, thus activating it. For example, in the mechanical work of muscle contraction, ATP supplies energy to move the contractile muscle proteins.

ATP Structure and Function

Figure 2. The structure of ATP shows the basic components of a two-ring adenine, five-carbon ribose, and three phosphate groups.

At the heart of ATP is a molecule of adenosine monophosphate (AMP), which is composed of an adenine molecule bonded to both a ribose molecule and a single phosphate group (Figure 2). Ribose is a five-carbon sugar found in RNA and AMP is one of the nucleotides in RNA. The addition of a second phosphate group to this core molecule results in adenosine diphosphate (ADP); the addition of a third phosphate group forms adenosine triphosphate (ATP).

The addition of a phosphate group to a molecule requires a high amount of energy and results in a high-energy bond. Phosphate groups are negatively charged and thus repel one another when they are arranged in series, as they are in ADP and ATP. This repulsion makes the ADP and ATP molecules inherently unstable. The release of one or two phosphate groups from ATP, a process called hydrolysis, releases energy.

Glycolysis

You have read that nearly all of the energy used by living things comes to them in the bonds of the sugar, glucose. Glycolysis is the first step in the breakdown of glucose to extract energy for cell metabolism. Many living organisms carry out glycolysis as part of their metabolism. Glycolysis takes place in the cytoplasm of most prokaryotic and all eukaryotic cells.

Glycolysis begins with the six-carbon, ring-shaped structure of a single glucose molecule and ends with two molecules of a three-carbon sugar called pyruvate. Glycolysis consists of two distinct phases. In the first part of the glycolysis pathway, energy is used to make adjustments so that the six-carbon sugar molecule can be split evenly into two three-carbon pyruvate molecules. In the second part of glycolysis, ATP and nicotinamide-adenine dinucleotide (NADH) are produced (Figure 3).

Figure 3. In glycolysis, a glucose molecule is converted into two pyruvate molecules.

If the cell cannot catabolize the pyruvate molecules further, it will harvest only two ATP molecules from one molecule of glucose. For example, mature mammalian red blood cells are only capable of glycolysis, which is their sole source of ATP. If glycolysis is interrupted, these cells would eventually die.

Citric Acid Cycle and Oxidative Phosphorylation

The Citric Acid Cycle

In eukaryotic cells, the pyruvate molecules produced at the end of glycolysis are transported into mitochondria, which are sites of cellular respiration. If oxygen is available, aerobic respiration will go forward. In mitochondria, pyruvate will be transformed into a two-carbon acetyl group (by removing a molecule of carbon dioxide) that will be picked up by a carrier compound called coenzyme A (CoA), which is made from vitamin B₅. The resulting compound is called acetyl CoA. (Figure 4). Acetyl CoA can be used in a variety of ways by the cell, but its major function is to deliver the acetyl group derived from pyruvate to the next pathway in glucose catabolism.

Figure 4. Pyruvate is converted into acetyl-CoA before entering the citric acid cycle.

Like the conversion of pyruvate to acetyl CoA, the citric acid cycle in eukaryotic cells takes place in the matrix of the mitochondria. Unlike glycolysis, the citric acid cycle is a closed loop: The last part of the pathway regenerates the compound used in the first step. The eight steps of the cycle are a series of chemical reactions that produces two carbon dioxide molecules, one ATP molecule (or an equivalent), and reduced forms (NADH and FADH₂) of NAD⁺ and FAD⁺, important coenzymes in the cell. Part of this is considered an aerobic pathway (oxygen-requiring) because the NADH and FADH₂ produced must transfer their electrons to the next pathway in the system, which will use oxygen. If oxygen is not present, this transfer does not occur.

Two carbon atoms come into the citric acid cycle from each acetyl group. Two carbon dioxide molecules are released on each turn of the cycle; however, these do not contain the same carbon atoms contributed by the acetyl group on that turn of the pathway. The two acetyl-carbon atoms will eventually be released on later turns of the cycle; in this way, all six carbon atoms from the original glucose molecule will be eventually released as carbon dioxide. It takes two turns of the cycle to process the equivalent of one glucose molecule. Each turn of the cycle forms three high-energy NADH molecules and one high-energy FADH₂ molecule. These high-energy carriers will connect with the last portion of aerobic respiration to produce ATP molecules. One ATP (or an equivalent) is also made in each cycle. Several of the intermediate compounds in the citric acid cycle can be used in synthesizing non-essential amino acids; therefore, the cycle is both anabolic and catabolic.

Oxidative Phosphorylation

You have just read about two pathways in glucose catabolism—glycolysis and the citric acid cycle—that generate ATP. Most of the ATP generated during the aerobic catabolism of glucose, however, is not generated directly from these pathways. Rather, it derives from a process that begins with passing electrons through a series of chemical reactions to a final electron acceptor, oxygen. These reactions take place in specialized protein complexes located in the inner membrane of the mitochondria of eukaryotic organisms and on the inner part of the cell membrane of prokaryotic organisms. The energy of the electrons is harvested and used to generate a electrochemical gradient across the inner mitochondrial membrane. The potential energy of this gradient is used to generate ATP. The entirety of this process is called oxidative phosphorylation.

The electron transport chain (Figure 5a) is the last component of aerobic respiration and is the only part of metabolism that uses atmospheric oxygen. Oxygen continuously diffuses into plants for this purpose. In animals, oxygen enters the body through the respiratory system. Electron transport is a series of chemical reactions that resembles a bucket brigade in that electrons are passed rapidly from one component to the next, to the endpoint of the chain where oxygen is the final electron acceptor and water is produced. There are four complexes composed of proteins, labeled I through IV in Figure 5c, and the aggregation of these four complexes, together with associated mobile, accessory electron carriers, is called the electron transport chain. The electron transport chain is present in multiple copies in the inner mitochondrial membrane of eukaryotes and in the plasma membrane of prokaryotes. In each transfer of an electron through the electron transport chain, the electron loses energy, but with some transfers, the energy is stored as potential energy by using it to pump hydrogen ions across the inner mitochondrial membrane into the intermembrane space, creating an electrochemical gradient.

Figure 5. (a) The electron transport chain is a set of molecules that supports a series of oxidation-reduction reactions. (b) ATP synthase is a complex, molecular machine that uses an H+ gradient to regenerate ATP from ADP. (c) Chemiosmosis relies on the potential energy provided by the H+ gradient across the membrane.

Electrons from NADH and FADH₂ are passed to protein complexes in the electron transport chain. As they are passed from one complex to another (there are a total of four), the electrons lose energy, and some of that energy is used to pump hydrogen ions from the mitochondrial matrix into the intermembrane space. In the fourth protein complex, the electrons are accepted by oxygen, the terminal acceptor. The oxygen with its extra electrons then combines with two hydrogen ions, further enhancing the electrochemical gradient, to form water. If there were no oxygen present in the mitochondrion, the electrons could not be removed from the system, and the entire electron transport chain would back up and stop. The mitochondria would be unable to generate new ATP in this way, and the cell would ultimately die from lack of energy. This is the reason we must breathe to draw in new oxygen.

In the electron transport chain, the free energy from the series of reactions just described is used to pump hydrogen ions across the membrane. The uneven distribution of H⁺ ions across the membrane establishes an electrochemical gradient, owing to the H⁺ ions’ positive charge and their higher concentration on one side of the membrane.

Hydrogen ions diffuse through the inner membrane through an integral membrane protein called ATP synthase (Figure 5b). This complex protein acts as a tiny generator, turned by the force of the hydrogen ions diffusing through it, down their electrochemical gradient from the intermembrane space, where there are many mutually repelling hydrogen ions to the matrix, where there are few. The turning of the parts of this molecular machine regenerate ATP from ADP. This flow of hydrogen ions across the membrane through ATP synthase is called chemiosmosis.

Chemiosmosis (Figure 5c) is used to generate 90 percent of the ATP made during aerobic glucose catabolism. The result of the reactions is the production of ATP from the energy of the electrons removed from hydrogen atoms. These atoms were originally part of a glucose molecule. At the end of the electron transport system, the electrons are used to reduce an oxygen molecule to oxygen ions. The extra electrons on the oxygen ions attract hydrogen ions (protons) from the surrounding medium, and water is formed. The electron transport chain and the production of ATP through chemiosmosis are collectively called oxidative phosphorylation.

ATP Yield

The number of ATP molecules generated from the catabolism of glucose varies. For example, the number of hydrogen ions that the electron transport chain complexes can pump through the membrane varies between species. Another source of variance stems from the shuttle of electrons across the mitochondrial membrane. The NADH generated from glycolysis cannot easily enter mitochondria. Thus, electrons are picked up on the inside of the mitochondria by either NAD⁺ or FAD⁺. Fewer ATP molecules are generated when FAD⁺ acts as a carrier. NAD⁺ is used as the electron transporter in the liver and FAD⁺ in the brain, so ATP yield depends on the tissue being considered.

Another factor that affects the yield of ATP molecules generated from glucose is that intermediate compounds in these pathways are used for other purposes. Glucose catabolism connects with the pathways that build or break down all other biochemical compounds in cells, and the result is somewhat messier than the ideal situations described thus far. For example, sugars other than glucose are fed into the glycolytic pathway for energy extraction. Other molecules that would otherwise be used to harvest energy in glycolysis or the citric acid cycle may be removed to form nucleic acids, amino acids, lipids, or other compounds. Overall, in living systems, these pathways of glucose catabolism extract about 34 percent of the energy contained in glucose.

Summary

Cellular respiration is a process that all living things use to convert glucose into energy. Autotrophs (like plants) produce glucose during photosynthesis. Heterotrophs (like humans) ingest other living things to obtain glucose. While the process can seem complex, this page takes you through the key elements of each part of cellular respiration.

Let’s Review

Cellular respiration is a collection of three unique metabolic pathways: glycolysis, the citric acid cycle, and the electron transport chain. Glycolysis is an anaerobic process, while the other two pathways are aerobic. In order to move from glycolysis to the citric acid cycle, pyruvate molecules (the output of glycolysis) must be oxidized in a process called pyruvate oxidation.

Glycolysis

Glycolysis is the first pathway in cellular respiration. This pathway is anaerobic and takes place in the cytoplasm of the cell. This pathway breaks down 1 glucose molecule and produces 2 pyruvate molecules. There are two halves of glycolysis, with five steps in each half. The first half is known as the “energy requiring” steps. This half splits glucose, and uses up 2 ATP. If the concentration of pyruvate kinase is high enough, the second half of glycolysis can proceed. In the second half, the “energy releasing: steps, 4 molecules of ATP and 2 NADH are released. Glycolysis has a net gain of  2 ATP molecules and 2 NADH.

Some cells (e.g., mature mammalian red blood cells) cannot undergo aerobic respiration, so glycolysis is their only source of ATP. However, most cells undergo pyruvate oxidation and continue to the other pathways of cellular respiration.

Pyruvate Oxidation

In eukaryotes, pyruvate oxidation takes place in the mitochondria. Pyruvate oxidation can only happen if oxygen is available. In this process, the pyruvate created by glycolysis is oxidized. In this oxidation process, a carboxyl group is removed from pyruvate, creating acetyl groups, which compound with coenzyme A (CoA) to form acetyl CoA. This process also releases CO₂.

Citric Acid Cycle

The citric acid cycle (also known as the Krebs cycle) is the second pathway in cellular respiration, and it also takes place in the mitochondria. The rate of the cycle is controlled by ATP concentration. When there is more ATP available, the rate slows down; when there is less ATP the rate increases. This pathway is a closed loop: the final step produces the compound needed for the first step.

The citric acid cycle is considered an aerobic pathway because the NADH and FADH₂ it produces act as temporary electron storage compounds, transferring their electrons to the next pathway (electron transport chain), which uses atmospheric oxygen. Each turn of the citric acid cycle provides a net gain of CO₂, 1 GTP or ATP, and 3 NADH and 1 FADH₂.

Electron Transport Chain

Most ATP from glucose is generated in the electron transport chain. It is the only part of cellular respiration that directly consumes oxygen; however, in some prokaryotes, this is an anaerobic pathway. In eukaryotes, this pathway takes place in the inner mitochondrial membrane. In prokaryotes it occurs in the plasma membrane.

The electron transport chain is made up of 4 proteins along the membrane and a proton pump. A cofactor shuttles electrons between proteins I–III. If NAD is depleted, skip I: FADH₂ starts on II. In chemiosmosis, a proton pump takes hydrogens from inside mitochondria to the outside; this spins the “motor” and the phosphate groups attach to that. The movement changes from ADP to ATP, creating 90% of ATP obtained from aerobic glucose catabolism.

Let’s Practice

Now that you’ve reviewed cellular respiration, this practice activity will help you see how well you know cellular respiration:

Click here for a text-only version of the activity.