Topic 7 Reading

9
KEY CONCEPTS
Cellular Respiration
and Fermentation
9.1 Catabolic pathways yield energy by

oxidizing organic fuels p. 165
9.2 Glycolysis harvests chemical energy by

oxidizing glucose to pyruvate p. 170
9.3 After pyruvate is oxidized, the citric acid

cycle completes the energy-yielding
oxidation of organic molecules p. 171
9.4 During oxidative phosphorylation,

chemiosmosis couples electron
transport to ATP synthesis p. 174
9.5 Fermentation and anaerobic

respiration enable cells to produce ATP
without the use of oxygen p. 179
9.6 Glycolysis and the citric acid cycle Figure 9.1 This hoary marmot (Marmota caligata) obtains energy for its cells by
connect to many other metabolic feeding on plants. In the process of cellular respiration, mitochondria in the cells
pathways p. 182 of animals, plants, and other organisms break down organic molecules, generating
ATP and waste products: carbon dioxide, water, and heat. Note that energy flows
Study Tip one way, but chemicals are recycled.
Make a visual study guide: Draw a cell
with a large mitochondrion, labeling
the parts of the mitochondrion. As you
How is the chemical energy stored in food used to
go through the generate ATP, the molecule that drives most cellular work?
Mitochondrion chapter, add key
reactions for each
stage of cellular
respiration, Light
linking the stages energy
together. Label the
carbon molecule(s)
with the most
used in generates
energy and the carbon molecule(s) with
Photosynthesis
the least energy. Your cell can be a simple
sketch, as shown here. Organic
CO2 + H2O + O2
molecules
Go to Mastering Biology
generates used in
For Students (in eText and Study Area)
• Get Ready for Chapter 9
• BioFlix® Animation: Cellular Respiration
• Figure 9.12 Walkthrough: Free-Energy
Change During Electron Transport Cellular respiration in mitochondria
For Instructors to Assign (in Item Library)
breaks down organic
• BioFlix® Tutorial: Glycolysis
molecules,generating
• BioFlix® Tutorial: Cellular Respiration:
Inputs and Outputs
Ready-to-Go Teaching Module Plant cell powers most Animal cell
ATP
(in Instructor Resources) cellular work
• Oxidative Phosphorylation (Concept 9.4)
Heat
164
CONCEPT 9.1 However, it originated as a synonym for aerobic respiration
because of the relationship of that process to organismal
Catabolic pathways yield energy respiration, in which an animal breathes in oxygen. Thus,
cellular respiration is often used to refer to the aerobic process,
by oxidizing organic fuels a practice we follow in most of this chapter.
Living cells require transfusions of energy from outside sources Although very different in mechanism, aerobic respira-
to perform their many tasks—for example, assembling poly- tion is in principle similar to the combustion of gasoline in
mers, pumping substances across membranes, moving, and an automobile engine after oxygen is mixed with the fuel
reproducing. The outside source of energy is food, and the (hydrocarbons). Food provides the fuel for respiration, and
energy stored in the organic molecules of food ultimately comes the exhaust is carbon dioxide and water. The overall process
from the sun. As shown in Figure 9.1, energy flows into an eco- can be summarized as follows:
system as sunlight and exits as heat; in contrast, the chemical
Organic Carbon
elements essential to life are recycled. Photosynthesis generates + Oxygen S + Water + Energy
compounds dioxide
oxygen, as well as organic molecules used by the mitochondria
of eukaryotes as fuel for cellular respiration. Respiration breaks Carbohydrates, fats, and proteins from food can all be pro-
this fuel down, using oxygen (O2) and generating ATP. The cessed and consumed as fuel. In animal diets, a major source
waste products of this type of respiration, carbon dioxide (CO2) of carbohydrates is starch, a storage polysaccharide that can
and water (H2O), are the raw materials for photosynthesis. be broken down into glucose (C6H12O6) subunits. Here, we
will learn the steps of cellular respiration by tracking the
Mastering Biology Animation: Energy Flow degradation of the sugar glucose:
and Chemical Recycling
C6H12O6 + 6 O2 S 6 CO2 + 6 H2O + Energy (ATP + heat)
Let’s consider how cells harvest the chemical energy stored
Mastering Biology BioFlix® Animation: Introduction to
in organic molecules and use it to generate ATP, the molecule
Cellular Respiration
that drives most cellular work. Metabolic pathways that release
stored energy by breaking down complex molecules are called This breakdown of glucose is exergonic, having a free-
catabolic pathways (see Concept 8.1). Transfer of electrons energy change of -686 kcal (-2,870 kJ) per mole of glucose
from food molecules (like glucose) to other molecules plays a decomposed (∆G = - 686 kcal/mol). Recall that a negative
major role in these pathways. In this section, we consider these ∆G1 ∆G 6 02 indicates that the products of the chemical
processes, which are central to cellular respiration. process store less energy than the reactants and that the reac-
tion can happen spontaneously—in other words, without an
input of energy (see Concept 8.2).
Catabolic Pathways and Production of ATP Catabolic pathways do not directly move flagella, pump
Organic compounds possess potential energy as a result solutes across membranes, polymerize monomers, or per-
of the arrangement of electrons in the bonds between form other cellular work. Catabolism is linked to work by a
their atoms. Compounds that can participate in exergonic chemical drive shaft—ATP (see Concept 8.3). To keep work-
reactions can act as fuels. Through the activity of enzymes ing, the cell must regenerate its supply of ATP from ADP and
(see Concept 8.4), a cell systematically degrades complex ~P i (see Figure 8.12). To understand how cellular respiration
organic molecules that are rich in potential energy to accomplishes this, let’s examine the fundamental chemical
simpler waste products that have less energy. Some of the processes known as oxidation and reduction.
energy taken out of chemical storage can be used to do work;
the rest is dissipated as heat.
One catabolic process, fermentation, is a partial degra- Redox Reactions: Oxidation and Reduction
dation of sugars or other organic fuel that occurs without the How do the catabolic pathways that decompose glucose
use of oxygen. However, the most efficient catabolic pathway and other organic fuels yield energy? The answer is based on
is aerobic respiration, in which oxygen is consumed as the transfer of electrons during the chemical reactions. The
a reactant along with the organic fuel (aerobic is from the relocation of electrons releases energy stored in organic mol-
Greek aer, air, and bios, life). The cells of most eukaryotic and ecules, and this energy ultimately is used to synthesize ATP.
many prokaryotic organisms can carry out aerobic respira-
tion. Some prokaryotes use substances other than oxygen as The Principle of Redox
reactants in a similar process that harvests chemical energy In many chemical reactions, there is a transfer of one or more
without oxygen; this process is called anaerobic respiration (the electrons (e - ) from one reactant to another. These electron
prefix an- means “without”). Technically, the term cellular transfers are called oxidation-reduction reactions, or redox
respiration includes both aerobic and anaerobic processes. reactions for short. In a redox reaction, the loss of electrons
CHAPTER 9 Cellular Respiration and Fermentation 165

from one substance is called oxidation, and the addition of . Figure 9.2 Methane combustion as an energy-yielding redox
electrons to another substance is known as reduction. (Note reaction. The reaction releases energy to the surroundings because the
electrons lose potential energy when they end up being shared unequally,
that adding electrons is called reduction; adding negatively
spending more time near electronegative atoms such as oxygen.
charged electrons to an atom reduces the amount of positive
charge of that atom.) Reactants Products
To take a simple, nonbiological example, consider the becomes oxidized
reaction between the elements sodium (Na) and chlorine (Cl)
that forms table salt: CH4 + 2 O2 CO2 + Energy + 2 H2O
becomes oxidized becomes reduced

(loses electron) H
Na 1 Cl Na+ 1 Cl–
H C H O O O C O H O H
becomes reduced
(gains electron)
H
We could generalize a redox reaction this way: Methane Oxygen Carbon dioxide Water
(reducing (oxidizing
becomes oxidized agent) agent)
–
Xe 1 Y X 1 Ye – VISUAL SKILLS Is the carbon atom oxidized or reduced during this
becomes reduced reaction? Explain.
Mastering Biology Animation: Redox Reactions
In the generalized reaction, substance Xe -, the electron donor,
is called the reducing agent; it reduces Y, which accepts the burning (oxidation) of methane, therefore releases chemical
donated electron. Substance Y, the electron acceptor, is the energy that can be put to work.
oxidizing agent; it oxidizes Xe - by removing its electron.
Because an electron transfer requires both an electron donor and Oxidation of Organic Fuel Molecules
an acceptor, oxidation and reduction always go hand in hand. During Cellular Respiration
Not all redox reactions involve the complete transfer of elec- The oxidation of methane by O2 is the main combustion
trons from one substance to another; some change the degree reaction that occurs at the burner of a gas stove. The com-
of electron sharing in covalent bonds. Methane combustion, bustion of gasoline in an automobile engine is also a redox
shown in Figure 9.2, is an example. The covalent electrons in reaction; the energy released pushes the pistons. But the
methane are shared nearly equally between the bonded atoms energy-yielding redox process of greatest interest to biologists
because carbon and hydrogen have about the same affinity for is respiration: the oxidation of glucose and other molecules in
valence electrons; they are about equally electronegative (see food. Examine again the summary equation for cellular respi-
Concept 2.3). But when methane reacts with O2, forming CO2, ration, but this time think of it as a redox process:
electrons end up shared less equally between the carbon atom becomes oxidized
and its new covalent partners, the oxygen atoms, which are C6H12O6 1 6 O2 6 CO2 1 6 H2O 1 Energy
very electronegative. In effect, the carbon atom has partially
becomes reduced
“lost” its shared electrons; thus, methane has been oxidized.
Now let’s examine the fate of the reactant O2. The two As in the combustion of methane or gasoline, the fuel (glu-
atoms of O2 share their electrons equally. But after the reac- cose) is oxidized and O2 is reduced. The electrons lose poten-
tion with methane, when each O atom is bonded to two H tial energy along the way, and energy is released.
atoms in H2O, the electrons of those covalent bonds spend In general, organic molecules that have an abundance of
more time near the oxygen (see Figure 9.2). In effect, each O hydrogen are excellent fuels because their bonds are a source
atom has partially “gained” electrons, so the oxygen molecule of “hilltop” electrons, whose energy may be released as these
(O2) has been reduced. Because the O atom is so electronega- electrons “fall” down an energy gradient during their transfer
tive, O2 is one of the most powerful of all oxidizing agents. to oxygen. The summary equation for respiration indicates
Energy must be added to pull an electron away from an that hydrogen is transferred from glucose to the O atoms in
atom, just as energy is required to push a ball uphill. The more O2. But the important point, not visible in the summary equa-
electronegative the atom (the stronger its pull on electrons), tion, is that the energy state of the electron changes as hydro-
the more energy is required to take an electron away from it. gen (with its electron) is transferred to oxygen. In respiration,
An electron loses potential energy when it shifts from a less the oxidation of glucose transfers electrons to a lower energy
electronegative atom toward a more electronegative one, just state, liberating energy that becomes available for ATP syn-
as a ball loses potential energy when it rolls downhill. A redox thesis. So, in general, we see fuels with multiple C ¬ H bonds
reaction that moves electrons closer to an O atom, such as the oxidized into products with multiple C ¬ O bonds.
166 UNIT TWO The Cell

The main energy-yielding foods—carbohydrates and fats— from the substrate (glucose, in the preceding example),
are reservoirs of electrons associated with hydrogen, often in thereby oxidizing it. The enzyme delivers the 2 electrons
the form of C ¬ H bonds. Only the barrier of activation energy along with 1 proton to its coenzyme, NAD + , forming NADH
holds back the flood of electrons to a lower energy state (Figure 9.3). The other proton is released as a hydrogen ion
(see Figure 8.13). Without this barrier, a food substance like (H + ) into the surrounding solution:
glucose would combine almost instantaneously with O2.
Dehydrogenase
If we supply the activation energy by igniting glucose, it burns H C OH 1 NAD+ C O 1 NADH 1 H+
in air, releasing 686 kcal (2,870 kJ) of heat per mole of glucose
(about 180 g). Body temperature is not high enough to initi- By receiving 2 negatively charged electrons but only 1 posi-
ate burning, of course. Instead, if you swallow some glucose, tively charged proton, the nicotinamide portion of NAD + has
enzymes in your cells will lower the barrier of activation its charge neutralized when NAD + is reduced to NADH. The
energy, allowing the sugar to be oxidized in a series of steps. name NADH shows the hydrogen that has been received in
the reaction. NAD + is the most versatile electron acceptor in
Stepwise Energy Harvest via NAD∙ cellular respiration and functions in several of the redox steps
and the Electron Transport Chain during the breakdown of glucose.
If energy is released from a fuel all at once, it cannot be Electrons lose very little of their potential energy when
harnessed efficiently for constructive work. For example, they are transferred from glucose to NAD + . Each NADH mol-
if a gasoline tank explodes, it cannot drive a car very far. ecule formed during respiration represents stored energy that
Cellular respiration does not oxidize glucose (or any other can be tapped to make ATP when the electrons complete their
organic fuel) in a single explosive step either. Rather, glucose “fall” down an energy gradient from NADH to O2.
is broken down in a series of steps, each one catalyzed by an How do electrons that are extracted from glucose and
enzyme. At key steps, electrons are stripped from the glucose. stored as potential energy in NADH finally reach oxygen?
As is often the case in oxidation reactions, each electron It will help to compare the redox chemistry of cellular res-
travels with a proton—thus, as a hydrogen atom. The hydro- piration to a much simpler reaction: the reaction between
gen atoms are not transferred directly to O2, but instead are hydrogen and oxygen to form water (Figure 9.4a). Mix H2
usually passed first to an electron carrier, a coenzyme called and O2, provide a spark for activation energy, and the gases
nicotinamide adenine dinucleotide, a derivative of the vita- combine explosively. In fact, combustion of liquid H2 and
min niacin. This coenzyme is well suited as an electron carrier O2 is harnessed to help power the rocket engines that boost
because it can cycle easily between its oxidized form, NAD1, satellites into orbit and launch spacecraft. The explosion
and its reduced form, NADH. As an electron acceptor, NAD + represents a release of energy as the electrons of hydrogen
functions as an oxidizing agent during respiration. “fall” closer to the electronegative oxygen atoms. Cellular
How does NAD + trap electrons from glucose and the other respiration also brings hydrogen and oxygen together to
organic molecules in food? Enzymes called dehydrogenases form water, but there are two important differences. First, in
remove a pair of hydrogen atoms (2 electrons and 2 protons) cellular respiration, the hydrogen that reacts with oxygen
2 e– + 2 H+
2 e– + H+
NAD+ NADH H+
Dehydrogenase
H O O
Reduction of NAD+ H H
C NH2 + 2H C NH2 + H+
(from food) Oxidation of NADH
N+ Nicotinamide N Nicotinamide VISUAL SKILLS
(oxidized form) (reduced form) Describe the structural
O CH2
O differences between
O P O–
the oxidized form and
O H H the reduced form of
– HO OH
nicotinamide.
O P O NH2
O CH2 N
N
H m Figure 9.3 NAD∙ as an electron shuttle. The full name for NAD + ,
N N H nicotinamide adenine dinucleotide, describes its structure—the molecule consists
O of two nucleotides joined together at their phosphate groups (shown in yellow).
(Nicotinamide is a nitrogenous base, although not one that is present in DNA or
H H RNA; see Figure 5.23.) The enzymatic transfer of 2 electrons and 1 proton (H+ ) from
HO OH an organic molecule in food to NAD + reduces the NAD + to NADH: Most of the
electrons removed from food are transferred initially to NAD + , forming NADH.

is derived from organic molecules rather than H2. Second, pulls electrons down the chain in an energy-yielding tumble
instead of occurring in one explosive reaction, respiration analogous to gravity pulling objects downhill.
uses an electron transport chain to break the fall of electrons In summary, during cellular respiration, most electrons
to oxygen into several energy-releasing steps (Figure 9.4b). travel the following “downhill” route: glucose S NADH S
An electron transport chain consists of a number of electron transport chain S oxygen. Later in this chapter, you
molecules, mostly proteins, built into the inner membrane will learn more about how the cell uses the energy released
of the mitochondria of eukaryotic cells (and the plasma from this exergonic electron fall to regenerate its supply of
membrane of respiring prokaryotes). Electrons removed ATP. For now, having covered the basic redox mechanisms of
from glucose are shuttled by NADH to the “top,” higher- cellular respiration, let’s look at the entire process by which
energy end of the chain. At the “bottom,” lower-energy end, energy is harvested from organic fuels.
O2 captures these electrons along with hydrogen nuclei (H + ),
forming water. (Anaerobically respiring prokaryotes have The Stages of Cellular Respiration: A Preview
an electron acceptor at the end of the chain that is different The harvesting of energy from glucose by cellular respiration is
from O2.) a cumulative function of three metabolic stages. We list them
Electron transfer from NADH to oxygen is an exergonic reac- here along with a color-coding scheme we will use throughout
tion with a free-energy change of -53 kcal/mol (-222 kJ/mol). the chapter to help you keep track of the big picture:
Instead of this energy being released and wasted in a single
explosive step, electrons cascade down the chain from one car- 1. GLYCOLYSIS (color-coded blue throughout the chapter)
rier molecule to the next in a series of redox reactions, losing a 2. PYRUVATE OXIDATION (light orange) and the
small amount of energy with each step until they finally reach CITRIC ACID CYCLE (dark orange)
oxygen, the terminal electron acceptor, which has a very great 3. OXIDATIVE PHOSPHORYLATION: Electron transport and
affinity for electrons. Each “downhill” carrier has a greater affin- chemiosmosis (purple)
ity for electrons than, and is thus capable of accepting electrons
from (oxidizing), its “uphill” neighbor, with O2 at the bottom Biochemists usually reserve the term cellular respiration for
of the chain. Therefore, the electrons transferred from glucose stages 2 and 3 together. In this text, however, we include gly-
to NAD +, reducing it to NADH, fall down an energy gradient colysis as a part of cellular respiration because most respiring
in the electron transport chain to a far more stable location in cells deriving energy from glucose use glycolysis to produce
an electronegative oxygen atom from O2. Put another way, O2 the starting material for the citric acid cycle.
As diagrammed in Figure 9.5, gly-
. Figure 9.4 An introduction to electron transport chains. colysis and then pyruvate oxidation
and the citric acid cycle are the catabolic
(a) Uncontrolled reaction. (b) Cellular respiration. In cellular respiration, the
The one-step exergonic reaction same reaction occurs in stages: An electron pathways that break down glucose and
of hydrogen with oxygen to transport chain breaks the “fall” of electrons in this other organic fuels. Glycolysis, which
form water releases a large reaction into a series of smaller steps and stores occurs in the cytosol, begins the degrada-
amount of energy in the form some of the released energy in a form that can be
of heat and light: an explosion. used to make ATP. (The rest of the energy is tion process by breaking glucose into two
released as heat.) molecules of a compound called pyruvate.
In eukaryotes, pyruvate enters the mito-
H2 + 1/2 O2 2H + 1
/2 O2 chondrion and is oxidized to a compound
(from food via NADH) called acetyl CoA, which enters the citric
Controlled acid cycle. There, the breakdown of
release of
+
2H + 2e – glucose to carbon dioxide is completed.
energy for
synthesis of (In prokaryotes, these processes take place
ATP ATP in the cytosol.) Thus, the carbon dioxide
Elec
Free energy, G
Free energy, G
produced by respiration represents frag-

tron ain
Explosive ATP
release of ments of oxidized organic molecules.
ch
tran
heat and light ATP Some of the steps of glycolysis and

energy the citric acid cycle are redox reactions in
spor
2 e– which dehydrogenases transfer electrons

t
12 O from substrates to NAD + or the related

+ 2
2H electron carrier FAD, forming NADH or
FADH2. (You’ll learn more about FAD and
H 2O H2O FADH2 later.) In the third stage of respira-
tion, the electron transport chain accepts

c Figure 9.5 An overview of cellular
respiration. During glycolysis, each glucose
molecule is broken down into two molecules Electrons carried Electrons carried
of pyruvate. In eukaryotic cells, as shown via NADH via NADH
here, the pyruvate enters the mitochondrion. and FADH2
There it is oxidized to acetyl CoA, which will
be further oxidized to CO2 in the citric acid
cycle. The electron carriers NADH and FADH2 PYRUVATE OXIDATIVE
GLYCOLYSIS
transfer electrons derived from glucose to OXIDATION CITRIC PHOSPHORYLATION
electron transport chains. During oxidative ACID
phosphorylation, electron transport chains Glucose Pyruvate Acetyl CoA CYCLE (Electron transport
convert the chemical energy to a form and chemiosmosis)
used for ATP synthesis in the process called
chemiosmosis. (During earlier steps of cellular CYTOSOL MITOCHONDRION
respiration, a few molecules of ATP are
synthesized in a process called substrate-level
phosphorylation.) To visualize these processes
in their cellular context, see Figure 6.32b. ATP ATP ATP
Mastering Biology Animation: Overview

of Cellular Respiration Substrate-level Substrate-level Oxidative
phosphorylation phosphorylation phosphorylation
electrons from NADH or FADH2 generated during the first two occurs when an enzyme transfers a phosphate group from a
stages and passes these electrons down the chain. At the end of substrate molecule to ADP, rather than adding an inorganic
the chain, the electrons are combined with molecular oxygen phosphate to ADP as in oxidative phosphorylation. “Substrate
(O2) and hydrogen ions (H +), forming water (see Figure 9.4b). molecule” here refers to an organic molecule generated as
The energy released at each step of the chain is stored in a form an intermediate during the catabolism of glucose. You’ll see
the mitochondrion (or prokaryotic cell) can use to make ATP examples of substrate-level phosphorylation later in the chap-
from ADP. This mode of ATP synthesis is called oxidative ter, in both glycolysis and the citric acid cycle.
phosphorylation because it is powered by the redox You can think of the whole process this way: When you
reactions of the electron transport chain. withdraw a relatively large sum of money from an ATM, it is not
In eukaryotic cells, the inner membrane of the mitochon- delivered to you in a single bill of a large denomination. Instead,
drion is the site of electron transport and another process the machine dispenses a number of smaller-denomination
called chemiosmosis, together making up oxidative phosphory- bills that you can spend more easily. This is analogous to ATP
lation. (In prokaryotes, these processes take place in the plasma production during cellular respiration. For each molecule of
membrane.) Oxidative phosphorylation accounts for almost glucose degraded to CO2 and H2O by respiration, the cell makes
90% of the ATP generated by respiration. A smaller amount up to about 32 molecules of ATP, each with 7.3 kcal/mol of free
of ATP is formed directly in a few reactions of glycolysis and energy. Respiration cashes in the large denomination of energy
the citric acid cycle by a mechanism called substrate-level banked in a single molecule of glucose (686 kcal/mol under
phosphorylation (Figure 9.6). This mode of ATP synthesis standard conditions) for the small change of many molecules of
ATP, which is more practical for the cell to spend on its work.
This preview has introduced you to how glycolysis, the
. Figure 9.6 Substrate-level phosphorylation. Some ATP is
made by direct transfer of a phosphate group from an organic citric acid cycle, and oxidative phosphorylation fit into the
substrate to ADP by an enzyme. (For examples in glycolysis, see process of cellular respiration so you can keep the big pic-
Figure 9.8, steps 7 and 10.) ture in mind as you take a closer look at each of these three
stages of respiration. As you read about the chemical reac-
tions, remember that each reaction is catalyzed by a specific
Enzyme Enzyme enzyme, some of which are shown in Figure 6.32b.
ADP
CONCEPT CHECK 9.1
P
ATP 1. Compare and contrast aerobic and anaerobic respiration,
Substrate including the processes involved.
Product 2. WHAT IF? If the following redox reaction occurred, which
compounds would be oxidized? Reduced?
MAKE CONNECTIONS Review Figure 8.9. In the reaction shown
above, is the potential energy higher for the reactants or for the C 4H6O5 + NAD + S C 4H4O5 + NADH + H+
products? Explain. For suggested answers, see Appendix A.

. Figure 9.7 The inputs and outputs of glycolysis.
CONCEPT 9.2
Glycolysis harvests chemical energy Mastering Biology

Animation: Glycolysis
by oxidizing glucose to pyruvate GLYCOLYSIS
PYRUVATE CITRIC
ACID
OXIDATIVE
PHOSPHORY-
OXIDATION
CYCLE LATION
The word glycolysis means “sugar splitting,” and that is
exactly what happens during this pathway. Glucose, a six-
carbon sugar, is split into two three-carbon sugars. These GLYCOLYSIS: ATP
smaller sugars are then oxidized and their remaining atoms Energy Investment Phase
rearranged to form two molecules of pyruvate. (Pyruvate is
Glucose
the ionized form of pyruvic acid.)
As summarized in Figure 9.7, glycolysis can be divided
into two phases: the energy investment phase and the energy 2 ATP used 2 ADP + 2 P
payoff phase. During the energy investment phase, the cell
actually spends ATP. This investment is repaid with inter-
Energy Payoff Phase
est during the energy payoff phase, when ATP is produced
by substrate-level phosphorylation and NAD + is reduced to
4 ADP + 4 P 4 ATP formed
NADH by electrons released from the oxidation of glucose.
The net energy yield from glycolysis, per glucose molecule, is
2 ATP plus 2 NADH. The ten steps of the glycolytic pathway 2 NAD+ + 4 e– + 4 H+ 2 NADH + 2 H+
are shown in Figure 9.8.
All of the carbon originally present in glucose is 2 Pyruvate + 2 H2O
accounted for in the two molecules of pyruvate; no carbon is
released as CO2 during glycolysis. Glycolysis occurs whether Net Inputs and Outputs
or not O2 is present. However, if O2 is present, the chemi- Glucose 2 Pyruvate + 2 H2O
cal energy stored in pyruvate and NADH can be extracted
4 ATP formed – 2 ATP used 2 ATP
by pyruvate oxidation, the citric acid cycle, and oxidative
phosphorylation. 2 NAD+ + 4 e– + 4 H+ 2 NADH + 2 H+
. Figure 9.8 The steps of glycolysis. Glycolysis, a source of ATP and NADH, takes place in
PYRUVATE CITRIC OXIDATIVE the cytosol. Two of the enzymes (in steps 1 and 3 ) are shown in Figure 6.32b.
GLYCOLYSIS ACID PHOSPHORY-
OXIDATION
CYCLE LATION
GLYCOLYSIS: Energy Investment Phase
WHAT IF? What would happen if you removed the dihydroxyacetone

ATP
phosphate generated in step 4 as fast as it was produced?
Glyceraldehyde
3-phosphate (G3P)
HC O
ATP Glucose Fructose ATP Fructose CHOH
Glucose 6-phosphate 6-phosphate 1,6-bisphosphate
ADP ADP CH2O P
CH2OH CH2O P CH2O P CH2OH P OCH2 CH2O P
O O O Isomerase
H H O H H H H
OH H OH H
H HO H HO 5
OH HO OH H OH H OH
HO Hexokinase Phosphogluco- Phospho- Aldolase
HO H HO H
Dihydroxyacetone
isomerase fructokinase
H OH
1 H OH
4 phosphate (DHAP)
2 3 CH2O P
Hexokinase transfers Glucose 6- Phosphofructokinase Aldolase cleaves C O

a phosphate group phosphate is transfers a phosphate the sugar CH2OH
from ATP to glucose, converted to group from ATP to the molecule into
making it more fructose opposite end of the two different Conversion between DHAP
chemically reactive. 6-phosphate. sugar, investing a second three-carbon and G3P: This reaction
The charged molecule of ATP. This is sugars. never reaches equilibrium;
phosphate also traps a key step for regulation G3P is used in the next step
the sugar in the cell. of glycolysis. as fast as it forms.

CONCEPT CHECK 9.2 . Figure 9.9 Oxidation of pyruvate to acetyl CoA, the step
before the citric acid cycle. Pyruvate enters the mitochondrion
1. VISUAL SKILLS During the redox reaction in glycolysis (see through a transport protein and is processed by a complex of
step 6 in Figure 9.8), which one of the molecules acts as the several enzymes known as pyruvate dehydrogenase (shown in
oxidizing agent? The reducing agent? the computer-generated image based on cryo-EMs). This complex
For suggested answers, see Appendix A. catalyzes the three numbered steps, which are described in the
text. The CO2 molecule will diffuse out of the cell. The NADH will
be used in oxidative phosphorylation. The acetyl group of acetyl
CONCEPT 9.3 CoA will enter the citric acid cycle. (Coenzyme A is abbreviated
S-CoA when it is attached to a molecule, emphasizing its sulfur
After pyruvate is oxidized, atom, S.)
the citric acid cycle completes

the energy-yielding oxidation
of organic molecules GLYCOLYSIS
PYRUVATE
OXIDATION
CITRIC
ACID
CYCLE
OXIDATIVE
PHOSPHORY-
LATION
Glycolysis releases less than a quarter of the chemical energy in 10 nm

glucose that can be harvested by cells; most of the energy remains Pyruvate dehydrogenase
stockpiled in the two molecules of pyruvate. When O2 is present,
the pyruvate in eukaryotic cells enters a mitochondrion, where MITOCHONDRION
CYTOSOL
the oxidation of glucose is completed. In aerobically respiring Coenzyme A
CO2
prokaryotic cells, this process occurs in the cytosol. (Later in the
O– 1 3
chapter, we’ll examine other fates for pyruvate—for example, S-CoA
when O2 is unavailable or in a prokaryote that is unable to use O2.) C O
Pyruvate dehydrogenase C O
C O
2 CH3
Oxidation of Pyruvate to Acetyl CoA CH3
NAD + NADH + H +
Acetyl CoA
Pyruvate
Upon entering the mitochondrion via active transport, pyru-
vate is first converted to a compound called acetyl coenzyme Transport protein
A, or acetyl CoA (Figure 9.9). This step, linking glycolysis and
the citric acid cycle, is carried out by a multienzyme complex
that catalyzes three reactions: 1 Pyruvate’s carboxyl group Mastering Biology BioFlix® Animation: Acetyl CoA
The energy payoff phase occurs after glucose is split into two three-carbon
sugars. Thus, the coefficient 2 precedes all molecules in this phase.
GLYCOLYSIS: Energy Payoff Phase
2 ATP 2 ATP
2 NADH 2 H 2O
2 ADP
2 NAD + + 2 H+ 2 ADP 2 2 2 2
O– O– O– O–
2
P OC O C O C O C O C O
CHOH CHOH H CO P CO P C O
Triose Phospho- Phospho- Enolase Pyruvate
phosphate 2 Pi CH2O P glycerokinase CH2 O P glyceromutase CH2OH CH2 kinase CH3
dehydrogenase 9
1,3-Bisphospho- 7 3-Phospho- 8 2-Phospho- Phosphoenol- 10 Pyruvate
6 glycerate glycerate glycerate pyruvate (PEP)
Two sequential reactions: The phosphate group is This enzyme Enolase causes a The phosphate
(1) G3P is oxidized by the transferred to ADP relocates the double bond to form group is transferred
transfer of electrons to (substrate-level remaining in the substrate by from PEP to ADP
NAD+, forming NADH. phosphorylation) in an phosphate extracting a water (a second example
(2) Using energy from this exergonic reaction. The group. molecule, yielding of substrate-level
exergonic redox reaction, carbonyl group of G3P phosphoenolpyruvate phosphorylation),
a phosphate group is has been oxidized to (PEP), a compound forming pyruvate.
attached to the oxidized the carboxyl group with a very high
substrate, making a (—COO–) of an organic potential energy.
high-energy product. acid (3-phosphoglycerate).
Mastering Biology BioFlix®
Animation: Glycolysis

( ¬ COO-), already somewhat oxidized and thus carrying little pyruvate is broken down to three CO2 molecules, includ-
chemical energy, is now fully oxidized and given off as a mol- ing the molecule of CO2 released during the conversion
ecule of CO2. This is the first step in which CO2 is released dur- of pyruvate to acetyl CoA. The cycle generates 1 ATP per
ing respiration. 2 Next, the remaining two-carbon fragment turn by substrate-level phosphorylation, but most of the
is oxidized and the electrons transferred to NAD +, storing chemical energy is transferred to NAD + and FAD during
energy in the form of NADH. 3 Finally, coenzyme A (CoA), the redox reactions. The reduced coenzymes, NADH and
a sulfur-containing compound derived from a B vitamin, is FADH2, shuttle their cargo of high-energy electrons into
attached via its sulfur atom to the two-carbon intermediate, the electron transport chain. The citric acid cycle is also
forming acetyl CoA. Acetyl CoA has a high potential energy, called the tricarboxylic acid cycle or the Krebs cycle, the
which is used to transfer the acetyl group to a molecule in the latter honoring Hans Krebs. Krebs was the German-British
citric acid cycle, a reaction that is therefore highly exergonic. scientist largely responsible for working out the pathway
in the 1930s.
Now let’s look at the citric acid cycle in more detail.
The Citric Acid Cycle The cycle has eight steps, each catalyzed by a specific
The citric acid cycle functions as a metabolic furnace enzyme. You can see in Figure 9.11 that for each turn of
that further oxidizes organic fuel derived from pyru- the citric acid cycle, two carbons (red) enter in the relatively
vate. Figure 9.10 summarizes the inputs and outputs as reduced form of an acetyl group (step 1 ), and two differ-
ent carbons (blue) leave in the completely oxidized form of
. Figure 9.10 An overview of pyruvate oxidation and the
citric acid cycle. The inputs and outputs per pyruvate molecule are CO2 molecules (steps 3 and 4 ). The acetyl group of acetyl
shown with a focus on the carbon atoms involved. To calculate on CoA joins the cycle by combining with the compound
a per-glucose basis, multiply by 2 because each glucose molecule is oxaloacetate, forming citrate (step 1 ). Citrate is the ion-
split during glycolysis into two pyruvate molecules.
ized form of citric acid, for which the cycle is named. The
CYTOSOL next seven steps decompose the citrate back to oxaloac-
etate. It is this regeneration of oxaloacetate that makes the
Pyruvate
(from glycolysis, process a cycle.
2 molecules per glucose) GLYCOLYSIS
PYRUVATE
OXIDATION
CITRIC
ACID
OXIDATIVE
PHOSPHORY- Referring to Figure 9.11, we can tally the energy-rich
CYCLE LATION
C C C molecules produced by the citric acid cycle. For each ace-
tyl group entering the cycle, 3 NAD + are reduced to NADH
ATP (steps 3 , 4 , and 8 ). In step 6 , electrons are transferred
not to NAD + , but to FAD, which accepts 2 electrons and
C C C PYRUVATE OXIDATION 2 protons to become FADH2. In many animal tissue cells,
the reaction in step 5 produces a guanosine triphosphate
C CO2 (GTP) molecule by substrate-level phosphorylation. GTP is
NAD+
CoA a molecule similar to ATP in its structure and cellular func-
NADH tion. This GTP may be used to make an ATP molecule (as
+ H+ shown) or directly power work in the cell. In the cells of
Acetyl CoA
C C plants, bacteria, and some animal tissues, step 5 forms an
CoA
ATP molecule directly by substrate-level phosphorylation.
NADH
CoA The output from step 5 represents the only ATP generated
+ H+
during the citric acid cycle. Recall that each glucose gives
rise to two molecules of acetyl CoA that enter the cycle.
NAD +
Because the numbers noted earlier are obtained from a sin-
CITRIC C C gle acetyl group entering the pathway, the total yield per
ACID
CYCLE 2 CO2 glucose from the citric acid cycle turns out to be doubled,
or 6 NADH, 2 FADH2, and the equivalent of 2 ATP.
FADH2 2 NAD+ Most of the ATP produced by respiration is generated later,
2 NADH from oxidative phosphorylation, when the NADH and FADH2
FAD produced by the citric acid cycle and earlier steps relay the
+ 2 H+
ADP + P i electrons extracted from food to the electron transport chain.
In the process, they supply the necessary energy for the phos-
ATP
MITOCHONDRION phorylation of ADP to ATP. We will explore this process in
the next section.
Mastering Biology Animation: The Citric Acid Cycle

. Figure 9.11 A closer look at the citric each other.) Notice that the carbon atoms their ionized forms, as ¬ COO–, because the
acid cycle. In the chemical structures, red that enter the cycle from acetyl CoA do not ionized forms prevail at the pH within the
type traces the fate of the two carbon atoms leave the cycle in the same turn. They remain mitochondrion. In eukaryotic cells, all
that enter the cycle via acetyl CoA (step 1 ), in the cycle, occupying a different location the citric acid cycle enzymes are located
and blue type indicates the two carbons that in the molecules on their next turn, after in the mitochondrial matrix except for the
exit the cycle as CO2 in steps 3 and 4 . (The another acetyl group is added. Therefore, enzyme that catalyzes step 6 , which resides
red type goes only through step 5 because the oxaloacetate regenerated at step 8 is in the inner mitochondrial membrane. (The
the succinate molecule is symmetrical; the made up of different carbon atoms each time enzyme that catalyzes step 3 , isocitrate
two ends cannot be distinguished from around. Carboxylic acids are represented in dehydrogenase, is shown in Figure 6.32b.)
CITRIC OXIDATIVE
PYRUVATE
OXIDATION
CYCLE LATION
ATP
S-CoA 1 Acetyl CoA (from
oxidation of pyruvate)
C O
adds its two-carbon acetyl 2 Citrate is
CH3 group to oxaloacetate, converted to
producing citrate. its isomer,
Acetyl CoA
isocitrate, by
8 The substrate removal of
is oxidized, CoA-SH one water
reducing NAD+ to molecule and
NADH and addition of
regenerating NADH O C COO– another.
oxaloacetate. + H+ CH2 1 COO– H2O
–
COO CH2 COO–
NAD +
8 Oxaloacetate HO C COO– CH2
2
–
CH2 HC COO–
COO
–
COO HO CH
HO CH
Malate Citrate COO–
CH2 3 Isocitrate
Isocitrate is oxidized,
COO–
7 Addition of NAD + reducing
a water NAD+ to
CITRIC NADH NADH. Then
molecule 3
ACID + H+ the resulting
rearranges 7 CYCLE
bonds in the H2O compound
CO2 loses a CO2
substrate. COO–
COO– molecule.
CH
Fumarate CoA-SH
c-Ketoglutarate
CH2
HC
CH2
COO–
4 C O
6 CoA-SH COO–
COO– COO–
CH2 CH2 4 Another CO2

FADH 2 5 CO2
CH2 CH2 NAD + is lost, and the
FAD resulting
COO– C O compound is
6 Two
Succinate S-CoA NADH oxidized,
hydrogens are Pi
transferred to + H+ reducing NAD+
GTP GDP Succinyl to NADH.
FAD, forming CoA
FADH2 and The remain-
ing molecule is
oxidizing ADP
then attached
succinate.
to coenzyme A
ATP by an unstable
5 CoA is displaced by a bond.
phosphate group, which is
transferred to GDP, forming GTP,
a molecule with functions
similar to ATP. GTP can also be
Mastering Biology BioFlix® Animation: The Citric Acid Cycle used, as shown, to generate ATP.

CONCEPT CHECK 9.3 . Figure 9.12 Free-energy change during electron transport.
The overall energy drop (∆G) for electrons traveling from NADH to
1. VISUAL SKILLS In the citric acid cycle shown in Figure 9.11, oxygen is 53 kcal/mol, but this “fall” is broken up into a series of smaller
what molecules capture energy from the redox reactions? steps by the electron transport chain. (An oxygen atom is represented
How is ATP produced? here as 1⁄2 O2 to show that O2 is reduced, not individual oxygen atoms.)
2. What processes in your cells produce the CO2 that you To view these proteins in their cellular context, see Figure 6.32b.
exhale?
3. VISUAL SKILLS The conversions shown in Figure 9.9 and
Mastering Biology
step 4 of Figure 9.11 are each catalyzed by a large multien-
Figure Walkthrough
zyme complex. What similarities are there in the reactions
that occur in these two cases? GLYCOLYSIS
PYRUVATE CITRIC
ACID
OXIDATIVE
PHOSPHORY-
OXIDATION
CYCLE LATION
For suggested answers, see Appendix A.
CONCEPT 9.4 ATP
During oxidative phosphorylation, NADH NADH has the lowest affinity for electrons.
chemiosmosis couples electron 50

2 e–
transport to ATP synthesis NAD+
FADH2
Our main objective in this chapter is to learn how cells harvest Complexes I-IV each
2 e– FAD consist of multiple
the energy of glucose and other nutrients in food to make
40 FMN I proteins with electron
ATP. But the metabolic components of respiration we have II carriers.
Fe•S Fe•S
examined so far, glycolysis and the citric acid cycle, produce
Free energy (G) relative to O2 (kcal/mol)

only 4 ATP molecules per glucose molecule, all by substrate- Q
III
level phosphorylation: 2 net ATP from glycolysis and 2 ATP Cyt b
from the citric acid cycle. At this point, molecules of NADH 30 Fe•S
(and FADH2) account for most of the energy extracted from Cyt c1 IV
each glucose molecule. These electron escorts link glycolysis Cyt c
and the citric acid cycle to the machinery of oxidative phos- Cyt a
phorylation, which uses energy released by the electron trans- Electron transport chain
Cyt a3
Electrons (from NADH or FADH2)
port chain to power ATP synthesis. In this section, you will 20
move from an electron carrier with a
learn first how the electron transport chain works and then lower affinity for electrons to an electron
how electron flow down the chain is coupled to ATP synthesis. carrier down the chain with a greater affinity
for electrons, releasing free energy.
2 e–
The Pathway of Electron Transport 10
The last electron carrier (Cyt a3)
The electron transport chain is a collection of molecules embed- passes its electrons to an O in O2,
ded in the inner membrane of the mitochondrion in eukaryotic which is very electronegative.
cells. (In prokaryotes, these molecules reside in the plasma
membrane.) The folding of the inner membrane to form cris- 2 H+ + 1 2 O2
0
O2 has the highest affinity for electrons.
tae increases its surface area, providing space for thousands of
copies of each component of the electron transport chain in a
mitochondrion. Structure fits function: The infolded membrane VISUAL SKILLS Compare the position of the electrons in
with its concentration of electron carrier molecules is well-suited NADH (see Figure 9.3) at the top of the chain with that in H2O,
H2O
for the series of sequential redox reactions that take place along at the bottom. Describe why the electrons in H2O have less
potential energy, using the term electronegativity.
the electron transport chain. Most components of the chain are
proteins, which exist in multiprotein complexes numbered I
through IV. Tightly bound to these proteins are prosthetic groups,
nonprotein components such as cofactors and coenzymes of the chain becomes reduced when it accepts electrons from
essential for the catalytic functions of certain enzymes. its “uphill” neighbor, which has a lower affinity for electrons.
Figure 9.12 shows the sequence of electron carriers in the It then returns to its oxidized form as it passes electrons to its
electron transport chain and the drop in free energy as elec- “downhill” neighbor, which has a higher affinity for electrons.
trons travel down the chain. During this electron transport, Now let’s take a closer look at the electrons as they drop in
electron carriers alternate between reduced and oxidized states energy level, passing through the components of the electron
as they accept and then donate electrons. Each component transport chain in Figure 9.12. We’ll first look at the passage of

electrons through complex I in some detail as an illustration of complex called ATP synthase, the enzyme that makes ATP
the general principles involved in electron transport. Electrons from ADP and inorganic phosphate (Figure 9.13). ATP syn-
acquired from glucose by NAD + during glycolysis and the citric thase works like an ion pump running in reverse. Ion pumps
acid cycle are transferred from NADH to the first molecule of usually use ATP as an energy source to transport ions against
the electron transport chain in complex I. This molecule is a their gradients. Enzymes can catalyze a reaction in either direc-
flavoprotein, so named because it has a prosthetic group called tion, depending on the ΔG for the reaction, which is affected
flavin mononucleotide (FMN). In the next redox reaction, the by the local concentrations of reactants and products (see
flavoprotein returns to its oxidized form as it passes electrons Concepts 8.2 and 8.3). Under the conditions of cellular respira-
to an iron-sulfur protein (Fe # S in complex I), one of a family tion, rather than hydrolyzing ATP to pump protons against
of proteins with both iron and sulfur tightly bound. The iron- their concentration gradient, ATP synthase uses the energy
sulfur protein then passes the electrons to a compound called of an existing ion gradient to power ATP synthesis. The power
ubiquinone (Q in Figure 9.12). This electron carrier is a small source for ATP synthase is a difference in the concentration
hydrophobic molecule, the only member of the electron trans- of H + (a pH difference) on opposite sides of the inner mito-
port chain that is not a protein. Ubiquinone is individually chondrial membrane. This process, in which energy stored
mobile within the membrane rather than residing in a particu- in the form of a hydrogen ion gradient across a membrane
lar complex. (Another name for ubiquinone is coenzyme Q, or is used to drive cellular work such as the synthesis of ATP, is
CoQ; you may have seen it sold as a nutritional supplement.)
Most of the remaining electron carriers between ubiquinone
. Figure 9.13 ATP synthase, a molecular mill. Multiple
and oxygen are proteins called cytochromes. Their prosthetic
ATP synthases reside in eukaryotic mitochondrial and
group, called a heme group, has an iron atom that accepts and chloroplast membranes and in prokaryotic plasma membranes.
donates electrons. (The heme group in a cytochrome is similar (See Figure 6.32b and c.)
to the heme group in hemoglobin, the protein of red blood
Inner
cells, except that the iron in hemoglobin carries oxygen, not Intermembrane space mitochondrial
electrons.) The electron transport chain has several types of Mitochondrial matrix membrane
cytochromes, each named “cyt” with a letter and number to
distinguish it as a different protein with a slightly different
electron-carrying heme group. The last cytochrome of the 1 H+ ions flowing
INTERMEMBRANE SPACE
chain, cyt a3, passes its electrons to oxygen (in O2), which is down their gradient
very electronegative. Each O also picks up a pair of hydrogen enter a channel in
a stator, which is
ions (protons) from the aqueous solution, neutralizing the anchored in the
-2 charge of the added electrons and forming water. membrane.
Another source of electrons for the electron transport 2 H+ ions enter binding
chain is FADH2, the other reduced product of the citric acid H+ ions Stator sites within a rotor,
changing the shape of
cycle. Notice in Figure 9.12 that FADH2 adds its electrons Rotor each subunit so that
from within complex II, at a lower energy level than NADH the rotor spins within
does. Consequently, although NADH and FADH2 each donate the membrane.
an equivalent number of electrons (2) for oxygen reduction, 3 Each H+ ion makes one
the electron transport chain provides about one-third less complete turn before
leaving the rotor and
energy for ATP synthesis when the electron donor is FADH2 passing through a second
rather than NADH. We’ll see why in the next section. channel in the stator
into the mitochondrial
The electron transport chain makes no ATP directly. Internal matrix.
Instead, it eases the fall of electrons from food to oxygen, rod
4 Spinning of the
breaking a large free-energy drop into a series of smaller steps rotor causes an internal
that release energy in manageable amounts, step by step. How Catalytic rod to spin as well. This
does the mitochondrion (or the plasma membrane in prokary- knob rod extends like a stalk
into the knob below it,
otes) couple this electron transport and energy release to ATP which is held stationary
synthesis? The answer is a mechanism called chemiosmosis. ADP by part of the stator.
+ 5 Turning of the rod
Pi ATP activates catalytic sites
Chemiosmosis: in the knob that
produce ATP from ADP
The Energy-Coupling Mechanism MITOCHONDRIAL MATRIX
and P i .
Populating the inner membrane of the mitochondrion or the Mastering Biology BioFlix® Animation: ATP Synthase
prokaryotic plasma membrane are many copies of a protein Animation: Rotating ATP Synthase

called chemiosmosis (from the Greek osmos, push). The word How does the inner mitochondrial membrane (or the pro-
osmosis was previously used in discussing water transport, but karyotic plasma membrane) generate and maintain the H +
here it refers to the flow of H + across a membrane. gradient that drives ATP synthesis by the ATP synthase protein
From studying the structure of ATP synthase, scientists complex? Establishing the H + gradient is a major function of the
have learned how the flow of H + through this enzyme powers electron transport chain, which is shown in its mitochondrial
ATP generation. ATP synthase is a multisubunit complex with location in Figure 9.14. The chain is an energy converter that
four main parts, each made up of multiple polypeptides (see uses the exergonic flow of electrons from NADH and FADH2 to
Figure 9.13). Protons move one by one into binding sites on the pump H + across the membrane, from the mitochondrial matrix
rotor, causing it to spin in a way that catalyzes ATP production into the intermembrane space. The H + has a tendency to move
from ADP and ~ P i. The flow of protons thus behaves somewhat back across the membrane, diffusing down its gradient. And the
like a rushing stream that turns a waterwheel. ATP synthase is ATP synthases are the only sites that provide a route through
the smallest molecular rotary motor known in nature. the membrane for H +. As we described previously, the passage
. Figure 9.14 Chemiosmosis couples chain, forming water. Most of the electron than occurs with NADH. Chemical energy
the electron transport chain to ATP carriers of the chain are grouped into four originally harvested from food is transformed
synthesis. 1 NADH and FADH2 shuttle complexes (I–IV). Two mobile carriers, into a proton-motive force, a gradient
high-energy electrons extracted from food ubiquinone (Q) and cytochrome c (Cyt c), of H+ across the membrane. 2 During
during glycolysis and the citric acid cycle into move rapidly, ferrying electrons between the chemiosmosis, the protons flow back down
an electron transport chain built into the large complexes. As the complexes shuttle their gradient via ATP synthase, which is built
inner mitochondrial membrane. (See Figure electrons, they pump protons from the into the membrane nearby. The ATP synthase
6.32b.) The gold arrows trace the transport mitochondrial matrix into the intermembrane harnesses the proton-motive force to
of electrons, which are finally passed to a space. FADH2 deposits its electrons via phosphorylate ADP, forming ATP. Together,
terminal acceptor (O2, in the case of aerobic complex II and so results in fewer protons electron transport and chemiosmosis make
respiration) at the “downhill” end of the being pumped into the intermembrane space up oxidative phosphorylation.
Intermembrane space Inner

Mitochondrial matrix mitochondrial
membrane
CITRIC OXIDATIVE
PYRUVATE
OXIDATION
CYCLE LATION
ATP
H+
H+ H+ H+
H+ H+ ATP
H+ H+ synthase
H+
H+ H+ H+ H+
Protein complex Cyt c
Intermembrane H+
space of electron
carriers
IV
Q
I III
Inner II
2 H+ + 1 2 O2 H2O
mitochondrial FADH2 FAD
membrane
NADH NAD+
ADP + P i ATP
(carrying electrons
from food)
H+
Mitochondrial 1 Electron transport chain 2 Chemiosmosis

matrix Electron transport and pumping of protons (H+), ATP synthesis powered by the flow
which create an H+ gradient across the membrane of H+ back across the membrane
Oxidative phosphorylation
WHAT IF? If complex IV were nonfunctional, could chemiosmosis Mastering Biology Animation: Electron Transport
produce any ATP, and if so, how would the rate of synthesis differ? BioFlix® Animation: Electron Transport

of H + through ATP synthase uses the exergonic flow of H + to chemical energy) drives both electron flow down an electron
drive the phosphorylation of ADP. Thus, the energy stored in an transport chain and the resulting H + gradient formation.
H + gradient across a membrane couples the redox reactions of Prokaryotes, as already mentioned, generate H + gradients across
the electron transport chain to ATP synthesis. their plasma membranes. They then tap the proton-motive force
At this point, you may be wondering how the electron not only to make ATP inside the cell but also to rotate their fla-
transport chain pumps hydrogen ions into the intermembrane gella and to pump nutrients and waste products across the mem-
space. Researchers have found that certain members of the brane. Because of its central importance to energy conversions
electron transport chain accept and release protons (H +) along in prokaryotes and eukaryotes, chemiosmosis has helped unify
with electrons. (The aqueous solutions inside and surround- the study of bioenergetics. Peter Mitchell was awarded the Nobel
ing the cell are a ready source of H +.) At certain steps along the Prize in 1978 for originally proposing the chemiosmotic model.
chain, electron transfers cause H + to be taken up and released
into the surrounding solution. In eukaryotic cells, the elec-
tron carriers are spatially arranged in the inner mitochondrial
An Accounting of ATP Production
membrane in such a way that H + is accepted from the mito- by Cellular Respiration
chondrial matrix and deposited in the intermembrane space In the last few sections, we have looked rather closely at the
(see Figure 9.14). The H + gradient that results is referred to as a key processes of cellular respiration. Now let’s take a step back
proton-motive force, emphasizing the capacity of the gradi- and remind ourselves of its overall function: harvesting the
ent to perform work. The force drives H + back across the mem- energy of glucose for ATP synthesis.
brane through the H + channels provided by ATP synthases. During respiration, most energy flows in this sequence: glu-
In general terms, chemiosmosis is an energy-coupling mecha- cose S NADH S electron transport chain S proton-motive
nism that uses energy stored in the form of an H + gradient across a force S ATP. We can do some bookkeeping to calculate the
membrane to drive cellular work. In mitochondria, the energy for ATP profit when cellular respiration oxidizes a molecule of
gradient formation comes from exergonic redox reactions along glucose to six molecules of carbon dioxide. The three main
the electron transport chain, and ATP synthesis is the work per- departments of this metabolic enterprise are glycolysis,
formed. But chemiosmosis also occurs elsewhere and in other pyruvate oxidation and the citric acid cycle, and the electron
variations. Chloroplasts use chemiosmosis to generate ATP transport chain, which drives oxidative phosphorylation.
during photosynthesis; in these organelles, light (rather than Figure 9.15 gives a detailed accounting of the ATP yield for
. Figure 9.15 ATP yield per molecule of glucose at each stage of cellular respiration.
CYTOSOL Electron shuttles MITOCHONDRION

span membrane 2 NADH
or
2 FADH2
2 NADH 2 NADH 6 NADH 2 FADH2
GLYCOLYSIS PYRUVATE OXIDATION OXIDATIVE

CITRIC PHOSPHORYLATION
ACID
Glucose 2 Pyruvate 2 Acetyl CoA CYCLE (Electron transport
and chemiosmosis)
+ 2 ATP + 2 ATP + about 26 or 28 ATP

by substrate-level by substrate-level by oxidative phosphorylation, depending
phosphorylation phosphorylation on which shuttle transports electrons
from NADH in cytosol
Maximum per glucose: About

30 or 32 ATP
VISUAL SKILLS After reading the discussion in the text, explain exactly Mastering Biology Animation: ATP Yield from
how the total of 26 or 28 ATP from oxidative phosphorylation was Cellular Respiration
calculated (see the yellow bar).

each glucose molecule that is oxidized. The tally adds the 4 We can now roughly estimate the efficiency of respiration—
ATP produced directly by substrate-level phosphorylation dur- that is, the percentage of chemical energy in glucose that has
ing glycolysis and the citric acid cycle to the many more mol- been transferred to ATP. Recall that the complete oxidation of
ecules of ATP generated by oxidative phosphorylation. Each a mole of glucose releases 686 kcal of energy under standard
NADH that transfers a pair of electrons from glucose to the conditions (∆G = - 686 kcal/mol). Phosphorylation of ADP
electron transport chain contributes enough to the proton- to form ATP stores at least 7.3 kcal per mole of ATP. Therefore,
motive force to generate a maximum of about 3 ATP. the efficiency of respiration is 7.3 kcal per mole of ATP times
Why are the numbers in Figure 9.15 inexact? There are three 32 moles of ATP per mole of glucose divided by 686 kcal per
reasons we cannot state an exact number of ATP molecules gen- mole of glucose, which equals 0.34. Thus, about 34% of the
erated by the breakdown of one molecule of glucose. First, phos- potential chemical energy in glucose has been transferred to
phorylation and the redox reactions are not directly coupled to ATP; the actual percentage is bound to vary as ∆G varies under
each other, so the ratio of the number of NADH molecules to the different cellular conditions. Cellular respiration is remark-
number of ATP molecules is not a whole number. We know that ably efficient in its energy conversion. By comparison, even
1 NADH results in 10 H + being transported out across the inner the most efficient automobile converts only about 25% of the
mitochondrial membrane, but the exact number of H + that must energy stored in gasoline to energy that moves the car.
reenter the mitochondrial matrix via ATP synthase to generate The rest of the energy stored in glucose is lost as heat. We
1 ATP has long been debated. Based on experimental data, how- humans use some of this heat to maintain our relatively high
ever, most biochemists now agree that the most accurate number body temperature (37°C), and we dissipate the rest through
is 4 H +. Therefore, a single molecule of NADH generates enough sweating and other cooling mechanisms.
proton-motive force for the synthesis of 2.5 ATP. The citric acid Surprisingly, perhaps, it may be beneficial under certain
cycle also supplies electrons to the electron transport chain via conditions to reduce the efficiency of cellular respiration.
FADH2, but since its electrons enter later in the chain, each mol- A remarkable adaptation is shown by hibernating mam-
ecule of this electron carrier is responsible for transport of only mals, which overwinter in a state of inactivity and lowered
enough H + for the synthesis of 1.5 ATP. These numbers also take metabolism. Although their internal body temperature is
into account the slight energetic cost of moving the ATP formed lower than normal, it still must be kept significantly higher
in the mitochondrion out into the cytosol, where it will be used. than the external air temperature. One type of tissue, called
Second, the ATP yield varies slightly depending on the type brown fat, is made up of cells packed full of mitochondria.
of shuttle used to transport electrons from the cytosol into The inner mitochondrial membrane contains a channel
the mitochondrion. The mitochondrial inner membrane is protein called the uncoupling protein that allows protons
not permeable to NADH, so NADH in the cytosol is segregated to flow back down their concentration gradient without
from the machinery of oxidative phosphorylation. The 2 elec- generating ATP. Activation of these proteins in hibernating
trons of NADH captured in glycolysis must be conveyed into mammals results in ongoing oxidation of stored fuel (fats),
the mitochondrion by one of several electron shuttle systems. generating heat without any ATP production. In the absence
Depending on the kind of shuttle in a particular cell type, the of such an adaptation, the buildup of ATP would eventu-
electrons are passed either to NAD + or to FAD in the mitochon- ally cause cellular respiration to be shut down by regulatory
drial matrix (see Figures 9.14 and 9.15). If the electrons are mechanisms that will be discussed later. Brown fat is also
passed to FAD, as in brain cells, only about 1.5 ATP can result used for heat generation in humans. In the Scientific Skills
from each NADH that was originally generated in the cytosol. Exercise, you can work with data in a related but different
If the electrons are passed to mitochondrial NAD +, as in liver case where a decrease in metabolic efficiency in cells is used
cells and heart cells, the yield is about 2.5 ATP per NADH. to generate heat.
A third variable that reduces the yield of ATP is the use of
Mastering Biology BioFlix® Animation: Cellular Respiration
the proton-motive force generated by the redox reactions
of respiration to drive other kinds of work. For example, the
proton-motive force powers the mitochondrion’s uptake of CONCEPT CHECK 9.4
pyruvate from the cytosol (see Figure 9.9). However, if all
1. WHAT IF? What effect would an absence of O2 have on the
the proton-motive force generated by the electron transport process shown in Figure 9.14?
chain were used to drive ATP synthesis, one glucose molecule 2. WHAT IF? In the absence of O2, as in question 1, what
could generate a maximum of 28 ATP produced by oxida- do you think would happen if you decreased the pH of
tive phosphorylation plus 4 ATP (net) from substrate-level the intermembrane space of the mitochondrion? Explain
your answer.
phosphorylation to give a total yield of about 32 ATP (or only
3. MAKE CONNECTIONS Membranes must be fluid to
about 30 ATP if the less efficient shuttle were functioning). function properly (see Concept 7.1). How does the operation
Mastering Biology Animation: Electron Transport Chain: of the electron transport chain support that assertion?
Factors Affecting ATP Yield For suggested answers, see Appendix A.

Scientific Skills Exercise
Making a Bar Graph and INTERPRET THE DATA
Evaluating a Hypothesis 1. To visualize any differ-

ences in O2 consump-
Does Thyroid Hormone Level Affect O2 Consumption tion between cell types,
in Cells? Some animals, such as mammals and birds, maintain it will be useful to
a relatively constant body temperature, above that of their graph the data in a bar
environment, by using heat produced as a by-product of me- graph. First, set up the
tabolism. When the core temperature of these animals drops axes. (a) What is the
below an internal set point, their cells are triggered to reduce independent variable
the efficiency of ATP production by the electron transport (intentionally varied by
chains in mitochondria. At lower efficiency, extra fuel must be the researchers), which goes on the x-axis? List the catego-
consumed to produce the same number of ATPs, generating ries along the x-axis; because they are discrete rather than
additional heat. This response is moderated by the endocrine continuous, you can list them in any order. (b) What is the
system, and researchers hypothesized that it might be trig- dependent variable (measured by the researchers), which
gered by thyroid hormone. In this exercise, you will use a bar goes on the y-axis? (c) What units (abbreviated) should go
graph to visualize data from an experiment that compared on the y-axis? Label the y-axis, including the units specified
the metabolic rates (by measuring O2 consumption) in mito- in the data table. Determine the range of values of the data
chondria of cells from animals with different levels of thyroid that will need to go on the y-axis. What is the largest value?
hormone. Draw evenly spaced tick marks and label them, starting with
0 at the bottom.
How the Experiment Was Done Liver cells were isolated from 2. Graph the data for each sample. Match each x-value with its
sibling rats that had low, normal, or elevated thyroid hormone y-value and place a mark on the graph at that coordinate, then
levels. The oxygen consumption rate due to activity of the mito- draw a bar from the x-axis up to the correct height for each
chondrial electron transport chains of each type of cell was mea- sample. Why is a bar graph more appropriate than a scatter plot
sured under controlled conditions. or line graph? (For additional information about graphs, see the
Scientific Skills Review in Appendix D.)
Data from the Experiment
3. Examine your graph and look for a pattern in the data.
Oxygen Consumption Rate (a) Which cell type had the highest rate of O2 consump-
Thyroid Hormone Level [nmol O2/(min # mg cells)] tion, and which had the lowest? (b) Does this support the
Low 4.3 researchers’ hypothesis? Explain. (c) Based on what you know
about mitochondrial electron transport and heat production,
Normal 4.8
predict which rats had the highest, and which had the lowest,
Elevated 8.7 body temperature.
Data from M. E. Harper and M. D. Brand, The quantitative contributions of mito-
chondrial proton leak and ATP turnover reactions to the changed respiration rates Instructors: A version of this Scientific Skills Exercise can be
of hepatocytes from rats of different thyroid status, Journal of Biological Chemistry assigned in Mastering Biology.
268:14850–14860 (1993).
CONCEPT 9.5 two is that an electron transport chain is used in anaerobic

respiration but not in fermentation. (The electron transport
Fermentation and anaerobic chain is also called the respiratory chain because of its role in
respiration enable cells to produce both types of cellular respiration.)
We have already mentioned anaerobic respiration, which
ATP without the use of oxygen takes place in certain prokaryotic organisms that live in
Because most of the ATP generated by cellular respiration is environments without O2. These organisms have an electron
due to the work of oxidative phosphorylation, our estimate transport chain but do not use O2 as a final electron acceptor
of ATP yield from aerobic respiration depends on an adequate at the end of the chain. O2 performs this function very well
supply of O2 to the cell. Without the electronegative oxygen because it consists of two extremely electronegative atoms,
atoms in O2 to pull electrons down the transport chain, oxi- but other substances can also serve as final electron acceptors.
dative phosphorylation eventually ceases. However, there are Some “sulfate-reducing” marine bacteria, for instance, use
two general mechanisms by which certain cells can oxidize the sulfate ion (SO42- ) at the end of their respiratory chain.
organic fuel and generate ATP without the use of O2: anaerobic Operation of the chain builds up a proton-motive force used
respiration and fermentation. The distinction between these to produce ATP, but H2S (hydrogen sulfide) is made as a

by-product rather than water. The rotten-egg odor you may . Figure 9.16 Fermentation. In the absence of oxygen, many cells
have smelled while walking through a salt marsh or a mudflat use fermentation to produce ATP by substrate-level phosphorylation.
NAD + is regenerated for use in glycolysis when pyruvate, the end
signals the presence of sulfate-reducing bacteria.
product of glycolysis, serves as an electron acceptor for oxidizing
Fermentation is a way of harvesting chemical energy with- NADH. Two of the common end products formed from fermentation
out using either O2 or any electron transport chain—in other are (a) ethanol and (b) lactate, the ionized form of lactic acid.
words, without cellular respiration. How can food be oxidized
without cellular respiration? Remember, oxidation simply
2 ADP + 2 P i 2 ATP O–
refers to the loss of electrons to an electron acceptor, so it does
not need to involve O2. Glycolysis oxidizes glucose to two mol- C O
ecules of pyruvate. The oxidizing agent of glycolysis is NAD +, O
C
and neither O2 nor any electron transfer chain is involved. Glucose GLYCOLYSIS
CH3
Overall, glycolysis is exergonic, and some of the energy made
available is used to produce 2 ATP (net) by substrate-level 2 Pyruvate
phosphorylation. If O2 is present, then additional ATP is made
2 NAD+ 2 NADH 2 CO2
by oxidative phosphorylation when NADH passes electrons + 2 H+
removed from glucose to the electron transport chain. But gly- H H
colysis generates 2 ATP whether oxygen is present or not—that
H C OH C O
is, whether conditions are aerobic or anaerobic. NAD+ REGENERATION
CH3 CH3
As an alternative to respiratory oxidation of organic nutri-
ents, fermentation is an extension of glycolysis that allows con- 2 Ethanol 2 Acetaldehyde
tinuous generation of ATP by the substrate-level phosphoryla-
tion of glycolysis. For this to occur, there must be a sufficient (a) Alcohol fermentation
supply of NAD + to accept electrons during the oxidation step
of glycolysis. Without some mechanism to recycle NAD + from 2 ADP + 2 P i 2 ATP
NADH, glycolysis would soon deplete the cell’s pool of NAD +
by reducing it all to NADH and would shut itself down for
lack of an oxidizing agent. Under aerobic conditions, NAD + is
Glucose GLYCOLYSIS
recycled from NADH by the transfer of electrons to the electron O–
transport chain. An anaerobic alternative is to transfer electrons C O
from NADH to pyruvate, the end product of glycolysis.
2 NAD+ 2 NADH C O
O– + 2 H+ CH3
Types of Fermentation C O
2 Pyruvate
Fermentation consists of glycolysis plus reactions that regenerate H C OH
NAD+ REGENERATION
NAD + by transferring electrons from NADH to pyruvate or deriv- CH3
atives of pyruvate. The NAD + can then be reused to oxidize sugar
2 Lactate
by glycolysis, which nets two molecules of ATP by substrate-level
phosphorylation. There are many types of fermentation, differ- (b) Lactic acid fermentation
ing in the end products formed from pyruvate. Two types are
Mastering Biology Animation: Fermentation
alcohol fermentation and lactic acid fermentation, and both are
harnessed by humans for food and industrial production. During lactic acid fermentation (Figure 9.16b), pyruvate
In alcohol fermentation (Figure 9.16a), pyruvate is is reduced directly by NADH to form lactate as an end product,
converted to ethanol (ethyl alcohol) in two steps. The first regenerating NAD + with no release
step releases CO2 from the pyruvate, which is converted to of CO2. (Lactate is the ionized . Cacao beans and fruits
the two-carbon compound acetaldehyde. In the second step, form of lactic acid.) Lactic acid
acetaldehyde is reduced by NADH to ethanol. This regener- fermentation by certain fungi and
ates the supply of NAD + needed for the continuation of gly- bacteria is used in the dairy indus-
colysis. Many bacteria carry out alcohol fermentation under try to make cheese and yogurt. A
anaerobic conditions. Yeast (a fungus), in addition to aerobic complex series of fermentation
respiration, also carries out alcohol fermentation. For thou- and aerobic respiration pathways
sands of years, humans have used yeast in brewing, winemak- carried out by yeasts and bacteria
ing, and baking. The CO2 bubbles generated by baker’s yeast on cacao beans is responsible for
during alcohol fermentation allow bread to rise. the production of chocolate.

What about lactate production in humans? Previously, process is shuttled by NADH and FADH2 in the form of electrons
we thought that human muscle cells only produced lactate to the electron transport chain. There, the electrons move step-
when O2 was in short supply, such as during intense exercise. wise down a series of redox reactions to a final electron acceptor.
Research done over the last few decades, though, indicates (In aerobic respiration, the final electron acceptor is O2; in anaer-
that the lactate story, in mammals at least, is more compli- obic respiration, the final acceptor is another molecule with a
cated. There are two types of skeletal muscle fibers. One (red high affinity for electrons, although less so than O2.) Stepwise
muscle) preferentially oxidizes glucose completely to CO2; the electron transport drives oxidative phosphorylation, yielding
other (white muscle) produces significant amounts of lactate ATP. Thus, cellular respiration harvests much more energy from
from the pyruvate made during glycolysis, even under aero- each sugar molecule than fermentation can. In fact, aerobic res-
bic conditions, offering fast but energetically inefficient ATP piration yields up to 32 molecules of ATP per glucose molecule—
production. The lactate product is then mostly oxidized by up to 16 times as much as does fermentation.
red muscle cells in the vicinity, with the remainder exported Some organisms, called obligate anaerobes, carry out
to liver or kidney cells for glucose formation. Because this lac- only fermentation or anaerobic respiration. In fact, these
tate production is not anaerobic, but the result of glycolysis organisms cannot survive in the presence of oxygen, some
in these cells, exercise physiologists prefer not to use the term forms of which can actually be toxic if protective systems
fermentation. are not present in the cell. A few cell types, such as cells of
During strenuous exercise, when carbohydrate catabolism the vertebrate brain, can carry out only aerobic oxidation of
outpaces the supply of O2 from the blood to the muscle, lac- pyruvate, and need O2 to survive. Other organisms, including
tate can’t be oxidized to pyruvate. The lactate that accumu- yeasts and many bacteria, can make enough ATP to survive
lates was once thought to cause muscle fatigue during intense using either fermentation or respiration. Such species are
exercise and pain a day or so later. However, research suggests called facultative anaerobes. In yeast cells, for example,
that, contrary to popular opinion, lactate production actually pyruvate is a fork in the metabolic road that leads to two
improves performance during exercise! Furthermore, within alternative catabolic routes (Figure 9.17). Under aerobic con-
an hour, excess lactate is shuttled to other tissues for oxida- ditions, pyruvate can be converted to acetyl CoA, and oxida-
tion or to the liver and kidneys for production of glucose or tion continues in the citric acid cycle via aerobic respiration.
its storage molecule, glycogen. (Nextday muscle soreness is Under anaerobic conditions, lactic acid fermentation occurs.
more likely caused by trauma to cells in small muscle fibers, Pyruvate is diverted from the citric acid cycle, serving instead
which leads to inflammation and pain.)
. Figure 9.17 Pyruvate as a key juncture in catabolism.
Glycolysis is common to fermentation and cellular respiration.
Comparing Fermentation with The end product of glycolysis, pyruvate, represents a fork in the
Anaerobic and Aerobic Respiration catabolic pathways of glucose oxidation. In a facultative anaerobe,
capable of both aerobic cellular respiration and fermentation,
Fermentation, anaerobic respiration, and aerobic respiration
pyruvate is committed to one of those two pathways, usually
are three alternative cellular pathways for producing ATP by depending on whether or not oxygen is present.
harvesting the chemical energy of food. All three use glycoly-
Glucose
sis to oxidize glucose and other organic fuels to pyruvate,
with a net production of 2 ATP by substrate-level phosphory-
Glycolysis
lation. And in all three pathways, NAD + is the oxidizing agent CYTOSOL
that accepts electrons from food during glycolysis.
Pyruvate
A key difference is the contrasting mechanisms for oxi-
dizing NADH back to NAD + , which is required to sustain No O2 present: O2 present:
Fermentation Aerobic cellular
glycolysis. In fermentation, the final electron acceptor is an respiration
organic molecule such as pyruvate (lactic acid fermentation)
or acetaldehyde (alcohol fermentation). In cellular respira-
tion, by contrast, electrons carried by NADH are transferred MITOCHONDRION
to an electron transport chain, which regenerates the NAD + Ethanol, Acetyl CoA
required for glycolysis. lactate, or
Another major difference is the amount of ATP produced. other products
CITRIC
Fermentation yields two molecules of ATP, produced by ACID
substrate-level phosphorylation. In the absence of an electron CYCLE
transport chain, the energy stored in pyruvate is unavailable.
In cellular respiration, however, pyruvate is completely oxidized
in the mitochondrion. Most of the chemical energy from this

as an electron acceptor to recycle NAD + . To make the same . Figure 9.18 The catabolism of various molecules from
amount of ATP, a facultative anaerobe has to consume sugar food. Carbohydrates, fats, and proteins can all be used as fuel for
cellular respiration. Monomers of these molecules enter glycolysis
at a much faster rate when fermenting than when respiring.
or the citric acid cycle at various points. Glycolysis and the citric acid
cycle are catabolic funnels through which electrons from all kinds of
The Evolutionary Significance of Glycolysis organic molecules flow on their exergonic fall to oxygen.
EVOLUTION The role of glycolysis in both fermentation

Proteins Carbohydrates Fats
and respiration has an evolutionary basis. Ancient prokary-
otes are thought to have used glycolysis to make ATP long
before oxygen was present in Earth’s atmosphere. The old- Amino Sugars Glycerol Fatty
acids acids
est known fossils of bacteria date back 3.5 billion years, but
appreciable quantities of oxygen probably did not begin
GLYCOLYSIS
to accumulate in the atmosphere until about 2.7 billion
years ago. Cyanobacteria produced this O2 as a by-product Glucose
of photosynthesis. Therefore, early prokaryotes may have
generated ATP exclusively from glycolysis. The fact that Glyceraldehyde 3- P
glycolysis is today the most widespread metabolic pathway
among Earth’s organisms suggests that it evolved very early NH3 Pyruvate
in the history of life. The cytosolic location of glycolysis
also implies great antiquity; the pathway does not require
any of the membrane-enclosed organelles of the eukaryotic Acetyl CoA
cell, which evolved approximately 1 billion years after the
first prokaryotic cell. Glycolysis is a metabolic heirloom
from early cells that continues to function in fermentation
CITRIC
and as the first stage in the breakdown of organic molecules ACID
by respiration. CYCLE
CONCEPT CHECK 9.5
1. Consider the NADH formed during glycolysis. What is the

final acceptor for its electrons during fermentation? During
OXIDATIVE PHOSPHORYLATION
aerobic respiration? During anaerobic respiration?
2. WHAT IF? A glucose-fed yeast cell is moved from an aerobic
environment to an anaerobic one. How would its rate of
glucose consumption change if ATP were to be generated at
animals. We obtain most of our calories in the form of fats,
the same rate? proteins, and carbohydrates such as sucrose and other disac-
For suggested answers, see Appendix A. charides, and starch, a polysaccharide. All these organic
molecules in food can be used by cellular respiration to
make ATP (Figure 9.18).
Glycolysis can accept a wide range of carbohydrates for
CONCEPT 9.6
catabolism. In the digestive tract, starch is hydrolyzed to glu-
Glycolysis and the citric acid cose, which is broken down in cells by glycolysis and the cit-
ric acid cycle. Glycogen, the polysaccharide that humans and
cycle connect to many other many other animals store in their liver and muscle cells, can
metabolic pathways be hydrolyzed to glucose between meals as fuel for respira-
tion. Digestion of disaccharides, including sucrose, provides
So far, we have looked at the oxidative breakdown of glucose glucose and other monosaccharides as fuel for respiration.
in isolation from the cell’s overall metabolic economy. In this Proteins can also be used for fuel, but first they must be
section, you will learn that glycolysis and the citric acid cycle digested to their constituent amino acids. Many of the amino
are major intersections of the cell’s catabolic (breakdown) acids are used by the organism to build new proteins. Amino
and anabolic (biosynthetic) pathways. acids present in excess are converted by enzymes to inter-
mediates of glycolysis and the citric acid cycle. Before amino
The Versatility of Catabolism acids can feed into glycolysis or the citric acid cycle, their
Throughout this chapter, glucose has been used as an amino groups must be removed, a process called deamination.
example of a fuel for cellular respiration. But free glucose The nitrogenous waste is excreted from the animal in the
molecules are not common in the diets of humans and other form of ammonia (NH3), urea, or other waste products.

Catabolism can also harvest energy stored in fats obtained amino acid, for example, the anabolic pathway that synthesizes
either from food or from fat cells in the body. After fats are that amino acid from an intermediate of the citric acid cycle is
digested to glycerol and fatty acids, the glycerol is converted switched off. The most common mechanism for this control is
to glyceraldehyde 3-phosphate, an intermediate of glycoly- feedback inhibition: The end product of the anabolic pathway
sis. Most of the energy of a fat is stored in the fatty acids. A inhibits the enzyme that catalyzes an early step of the pathway
metabolic sequence called beta oxidation breaks the fatty (see Figure 8.21). This prevents the needless diversion of key
acids down to two-carbon fragments, which enter the citric metabolic intermediates from uses that are more urgent.
acid cycle as acetyl CoA. NADH and FADH2 are also generated The cell also controls its catabolism. If the cell is work-
during beta oxidation; they can enter the electron transport ing hard and its ATP concentration begins to drop, cellular
chain, leading to further ATP production. Fats make excel- respiration speeds up. When there is plenty of ATP to meet
lent fuels, in large part due to their chemical structure and demand, respiration slows down, sparing valuable organic
the high energy level of their electrons (present in many molecules for other functions. Again, control is based mainly
C ¬ H bonds, equally shared between C and H) compared to on regulating the activity of enzymes at strategic points in the
those of carbohydrates. A gram of fat oxidized by respiration catabolic pathway. As shown in Figure 9.19, one important
produces more than twice as much ATP as a gram of carbohy- switch is phosphofructokinase, the enzyme that catalyzes
drate. Unfortunately, this also means that a person trying to step 3 of glycolysis (see Figure 9.8). That is the first step that
lose weight must work hard to use up fat stored in the body
because so many calories are stockpiled in each gram of fat. . Figure 9.19 The control of cellular respiration. Allosteric
enzymes at certain points in the respiratory pathway respond to
inhibitors and activators that help set the pace of glycolysis and the
Biosynthesis (Anabolic Pathways) citric acid cycle. Phosphofructokinase, which catalyzes an early step
in glycolysis (see Figure 9.8, step 3 and Figure 6.32b), is one such
Cells need substance as well as energy. Not all the organic mol- enzyme. It is stimulated by AMP (derived from ADP) but is inhibited
ecules of food are destined to be oxidized as fuel to make ATP. In by ATP and by citrate. This feedback regulation adjusts the rate of
addition to calories, food must also provide the carbon skeletons respiration as the cell’s catabolic and anabolic demands change.
that cells require to make their own molecules. Some organic Glucose
monomers obtained from digestion can be used directly. For
example, as previously mentioned, amino acids from the hydro- AMP
GLYCOLYSIS
lysis of proteins in food can be incorporated into the organism’s Fructose 6-phosphate Stimulates
own proteins. Often, however, the body needs specific molecules +
that are not present as such in food. Compounds formed as inter- Phosphofructokinase
–
mediates of glycolysis and the citric acid cycle can be diverted –
into anabolic pathways as precursors from which the cell can Fructose 1,6-bisphosphate
Inhibits Inhibits
synthesize the molecules it requires. For example, humans can
make about half of the 20 amino acids in proteins by modifying
compounds siphoned away from the citric acid cycle; the rest are
“essential amino acids” that must be obtained in the diet. Also,
glucose can be made from pyruvate, and fatty acids can be syn-
thesized from acetyl CoA. Of course, these anabolic, or biosyn-
thetic, pathways do not generate ATP, but instead consume it. Pyruvate
In addition, glycolysis and the citric acid cycle function as
metabolic interchanges that enable our cells to convert some
ATP Citrate
kinds of molecules to others as we need them. For example, Acetyl CoA
an intermediate compound generated during glycolysis,
dihydroxyacetone phosphate (see Figure 9.8, step 5), can
be converted to one of the major precursors of fats. If we eat
more food than we need, we store fat even if our diet is fat- CITRIC
free. Metabolism is remarkably versatile and adaptable. ACID
CYCLE
Regulation of Cellular Respiration

via Feedback Mechanisms
Basic principles of supply and demand regulate the metabolic
economy. The cell does not waste energy making more of a par- Oxidative
phosphorylation
ticular substance than it needs. If there is a surplus of a certain

commits the substrate irreversibly to the glycolytic pathway. key steps of glycolysis and the citric acid cycle. Cells are thrifty,
By controlling the rate of this step, the cell can speed up or expedient, and responsive in their metabolism.
slow down the entire catabolic process. Phosphofructokinase Review the first page of this chapter to put cellular respi-
can thus be considered the pacemaker of cellular respiration. ration into the broader context of energy flow and chemi-
Phosphofructokinase is an allosteric enzyme with receptor cal cycling in ecosystems. The energy that keeps us alive is
sites for specific inhibitors and activators. It is inhibited by ATP released, not produced, by cellular respiration. We are tapping
and stimulated by AMP (adenosine monophosphate), which energy that was stored in food by photosynthesis, which cap-
the cell derives from ADP. As ATP accumulates, inhibition tures light and converts it to chemical energy, a process you
of the enzyme slows down glycolysis. The enzyme becomes will learn about next, in Chapter 10.
active again as cellular work converts ATP to ADP (and AMP)
faster than ATP is being regenerated. Phosphofructokinase is
CONCEPT CHECK 9.6
also sensitive to citrate, the first product of the citric acid cycle.
1. MAKE CONNECTIONS Compare the structures of a
If citrate accumulates in mitochondria, some of it passes into
carbohydrate and a fat (see Figures 5.3 and 5.9). What
the cytosol and inhibits phosphofructokinase. This mecha- features make fat a much better fuel?
nism helps synchronize the rates of glycolysis and the citric 2. Under what circumstances might your body synthesize
acid cycle. As citrate accumulates, glycolysis slows down, and fat molecules?
the supply of pyruvate and thus acetyl groups to the citric 3. VISUAL SKILLS What will happen in a muscle cell that
acid cycle decreases. If citrate consumption increases, either has used up its supply of O2 and ATP? (Review Figures 9.17
and 9.19.)
because of a demand for more ATP or because anabolic path-
4. VISUAL SKILLS During intense exercise, can a muscle cell
ways are draining off intermediates of the citric acid cycle, gly- use fat as a concentrated source of chemical energy? Explain.
colysis accelerates and meets the demand. Metabolic balance (Review Figures 9.17 and 9.18.)
is augmented by the control of enzymes that catalyze other For suggested answers, see Appendix A.
9 Chapter Review Go to Mastering Biology for Assignments, the eText,

the Study Area, and Dynamic Study Modules.
first to NAD ∙, reducing it to NADH, and are then passed from

SUMMARY OF KEY CONCEPTS NADH to an electron transport chain, which conducts the
electrons to O2 in energy-releasing steps. The energy that is re-
To review key terms, go to the Vocabulary Self-Quiz in the leased is used to make ATP.
Mastering Biology eText or Study Area, or go to goo.gl/zkjz9t. • Aerobic respiration occurs in three stages: (1) glycolysis, (2) py-
ruvate oxidation and the citric acid cycle, and (3) oxidative
CONCEPT 9.1 phosphorylation (electron transport and chemiosmosis).
Catabolic pathways yield energy by oxidizing organic ? Describe the difference between the two processes in cellular
fuels (pp. 165–169) respiration that produce ATP: oxidative phosphorylation and
substrate-level phosphorylation.
• Cells break down glucose and other organic fuels to yield chemical
energy in the form of ATP. Fermentation is a process that results
in the partial degradation of glucose without the use of oxygen (O2). CONCEPT 9.2
The process of cellular respiration is a more complete breakdown
of glucose. In aerobic respiration, O2 is used as a reactant; in Glycolysis harvests chemical energy by oxidizing
anaerobic respiration, other substances are used in place of O2. glucose to pyruvate (pp. 170–171)
• The cell taps the energy stored in food molecules through redox
reactions, in which one substance partially or totally shifts • Glycolysis (“splitting of sugar”) is a series of reactions that breaks
electrons to another. Oxidation is the total or partial loss of down glucose into two pyruvate molecules, which may go on to
electrons, while reduction is the total or partial addition of elec- enter the citric acid cycle, and nets 2 ATP and 2 NADH per glucose
trons. During aerobic respiration, glucose (C6H12O6) is oxidized to molecule.
CO2, and O2 is reduced to H2O: Inputs Outputs
becomes oxidized GLYCOLYSIS

C6H12O6 1 6 O2 6 CO2 1 6 H2O 1 Energy Glucose 2 Pyruvate + 2 ATP + 2 NADH
becomes reduced
• Electrons lose potential energy during their transfer from glucose ? Which reactions in glycolysis are the source of energy for the
or other organic compounds to O2. Electrons are usually passed formation of ATP and NADH?

CONCEPT 9.3 CONCEPT 9.5
After pyruvate is oxidized, the citric acid cycle Fermentation and anaerobic respiration enable cells
completes the energy-yielding oxidation of organic to produce ATP without the use of oxygen (pp. 179–182)
molecules (pp. 171–174) • Glycolysis nets 2 ATP by substrate-level phosphorylation, whether O2
• In eukaryotic cells, pyruvate enters the mitochondrion and is is present or not. Under anaerobic conditions, anaerobic respiration
oxidized to acetyl CoA, which is further oxidized in the citric or fermentation can take place. In anaerobic respiration, an electron
acid cycle. transport chain is present with a final electron acceptor other than
oxygen. In fermentation, the electrons from NADH are passed to
Inputs Outputs pyruvate or a derivative of pyruvate, regenerating the NAD + required
to oxidize more glucose. Two common types of fermentation are
alcohol fermentation and lactic acid fermentation.
2 Pyruvate 2 Acetyl CoA ATP
2 8 NADH • Fermentation, anaerobic respiration, and aerobic respiration
CITRIC all use glycolysis to oxidize glucose, but they differ in their final
2 Oxaloacetate ACID
CYCLE 6 CO2 2 FADH 2 electron acceptor and whether an electron transport chain is used
(respiration) or not (fermentation). Respiration yields more ATP;
aerobic respiration, with O2 as the final electron acceptor, yields
about 16 times as much ATP as does fermentation.
• Glycolysis occurs in nearly all organisms and is thought to
? What molecular products indicate the complete oxidation of glucose have evolved in ancient prokaryotes before there was O2 in the
during cellular respiration? atmosphere.
? Which process yields more ATP, fermentation or anaerobic

CONCEPT 9.4 respiration? Explain.
During oxidative phosphorylation,
chemiosmosis couples electron transport
CONCEPT 9.6
to ATP synthesis (pp. 174–179)
Glycolysis and the citric acid cycle connect to many
• NADH and FADH2 transfer electrons to the electron transport
chain. Electrons move down the chain, losing energy in several other metabolic pathways (pp. 182–184)
energy-releasing steps. Finally, electrons are passed to O2, reduc- • Catabolic pathways funnel electrons from many kinds of organic
ing it to H2O. molecules into cellular respiration. Many carbohydrates can enter
glycolysis, most often after conversion to glucose. Amino acids
of proteins must be deaminated before being oxidized. The fatty
INTERMEMBRANE
SPACE
H+ H+ acids of fats undergo beta oxidation to two-carbon fragments
H+ H+
H+ H+ and then enter the citric acid cycle as acetyl CoA. Anabolic path-
H+ H+
H+ H+ ways can use small molecules from food directly or build other
Protein complex H+ Cyt c substances using intermediates of glycolysis or the citric acid cycle.
of electron
carriers • Cellular respiration is controlled by allosteric enzymes at key
points in glycolysis and the citric acid cycle.
IV
Q
III ? Describe how the catabolic pathways of glycolysis and the citric acid
I
cycle intersect with anabolic pathways in the metabolism of a cell.
II
2 H+ + 1 2 O2 H2O
FADH2 FAD
NADH NAD+
MITOCHONDRIAL MATRIX
(carrying electrons from food) TEST YOUR UNDERSTANDING
• Along the electron transport INTER- For more multiple-choice questions, go to the Practice Test in the
chain, electron transfer causes MEMBRANE H+
Mastering Biology eText or Study Area, or go to goo.gl/GruWRg.
SPACE H+
protein complexes to move H +
from the mitochondrial matrix Levels 1-2: Remembering/Understanding
(in eukaryotes) to the intermem-
brane space, storing energy as a 1. The immediate energy source that drives ATP synthesis by ATP
proton-motive force (H + gradi- synthase during oxidative phosphorylation is the
ent). As H + diffuses back into the MITO- (A) oxidation of glucose and other organic compounds.
matrix through ATP synthase, CHONDRIAL (B) flow of electrons down the electron transport chain.
ATP
MATRIX
its passage drives the phosphory- synthase (C) H + concentration gradient across the membrane holding
lation of ADP to form ATP, called ATP synthase.
chemiosmosis. (D) transfer of phosphate to ADP.
• About 34% of the energy stored ADP + P i H+ ATP 2. Which metabolic pathway is common to both fermentation
in a glucose molecule is trans-
and cellular respiration of a glucose molecule?
ferred to ATP during cellular res-
piration, producing a maximum of about 32 ATP. (A) the citric acid cycle
(B) the electron transport chain
? Briefly explain the mechanism by which ATP synthase produces ATP. (C) glycolysis
List three locations in which ATP synthases are found. (D) reduction of pyruvate to lactate

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9.1 Catabolic pathways yield energy by

9.2 Glycolysis harvests chemical energy by

9.3 After pyruvate is oxidized, the citric acid

9.4 During oxidative phosphorylation,

9.5 Fermentation and anaerobic

CHAPTER 9 Cellular Respiration and Fermentation 165

becomes oxidized becomes reduced

166 UNIT TWO The Cell

CHAPTER 9 Cellular Respiration and Fermentation 167

produced by respiration represents frag-

heat and light ATP Some of the steps of glycolysis and

2 e– which dehydrogenases transfer electrons

12 O from substrates to NAD + or the related

168 UNIT TWO The Cell

Mastering Biology Animation: Overview

CHAPTER 9 Cellular Respiration and Fermentation 169

Glycolysis harvests chemical energy Mastering Biology

WHAT IF? What would happen if you removed the dihydroxyacetone

Hexokinase transfers Glucose 6- Phosphofructokinase Aldolase cleaves C O

170 UNIT TWO The Cell

the citric acid cycle completes

Glycolysis releases less than a quarter of the chemical energy in 10 nm

GLYCOLYSIS: Energy Payoff Phase

CHAPTER 9 Cellular Respiration and Fermentation 171

172 UNIT TWO The Cell

CH2 CH2 4 Another CO2

CHAPTER 9 Cellular Respiration and Fermentation 173

CONCEPT 9.4 ATP

chemiosmosis couples electron 50

Free energy (G) relative to O2 (kcal/mol)

174 UNIT TWO The Cell

CHAPTER 9 Cellular Respiration and Fermentation 175

Intermembrane space Inner

Mitochondrial 1 Electron transport chain 2 Chemiosmosis

176 UNIT TWO The Cell

CYTOSOL Electron shuttles MITOCHONDRION

2 NADH 2 NADH 6 NADH 2 FADH2

GLYCOLYSIS PYRUVATE OXIDATION OXIDATIVE

+ 2 ATP + 2 ATP + about 26 or 28 ATP

Maximum per glucose: About

CHAPTER 9 Cellular Respiration and Fermentation 177

178 UNIT TWO The Cell

Evaluating a Hypothesis 1. To visualize any differ-

CONCEPT 9.5 two is that an electron transport chain is used in anaerobic

CHAPTER 9 Cellular Respiration and Fermentation 179

180 UNIT TWO The Cell

CHAPTER 9 Cellular Respiration and Fermentation 181

EVOLUTION The role of glycolysis in both fermentation

CONCEPT CHECK 9.5

1. Consider the NADH formed during glycolysis. What is the

182 UNIT TWO The Cell

Regulation of Cellular Respiration

CHAPTER 9 Cellular Respiration and Fermentation 183

9 Chapter Review Go to Mastering Biology for Assignments, the eText,

first to NAD ∙, reducing it to NADH, and are then passed from

becomes oxidized GLYCOLYSIS

184 UNIT TWO The Cell

? Which process yields more ATP, fermentation or anaerobic

CHAPTER 9 Cellular Respiration and Fermentation 185