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Respiratory System:
• Primary function is to obtain oxygen for use by body's cells & eliminate carbon
dioxide that cells produce
• Includes respiratory airways leading into (& out of) lungs plus the lungs
themselves
• Pathway of air: nasal cavities (or oral cavity) > pharynx > trachea > primary
bronchi (right & left) > secondary bronchi > tertiary bronchi > bronchioles >
alveoli (site of gas exchange)
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The exchange of gases (O2 & CO2) between the alveoli & the blood occurs by simple
diffusion: O2 diffusing from the alveoli into the blood & CO 2 from the blood into the
alveoli. Diffusion requires a concentration gradient. So, the concentration (or pressure) of
O2 in the alveoli must be kept at a higher level than in the blood & the concentration (or
pressure) of CO2 in the alveoli must be kept at a lower lever than in the blood. We do this,
of course, by breathing - continuously bringing fresh air (with lots of O2 & little CO2)
into the lungs & the alveoli.
Breathing is an active process - requiring the contraction of skeletal muscles. The primary
muscles of respiration include the external intercostal muscles (located between the ribs)
and the diaphragm (a sheet of muscle located between the thoracic & abdominal cavities).
The external intercostals plus the diaphragm contract to bring about inspiration:
• Contraction of external intercostal muscles > elevation of ribs & sternum >
increased front- to-back dimension of thoracic cavity > lowers air pressure in
lungs > air moves into lungs
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To exhale:
As the external intercostals & diaphragm contract, the lungs expand. The
expansion of the lungs causes the pressure in the lungs (and alveoli) to
become slightly negative relative to atmospheric pressure. As a result, air
moves from an area of higher pressure (the air) to an area of lower pressure
(our lungs & alveoli). During expiration, the respiration muscles relax &
lung volume descreases. This causes pressure in the lungs (and alveoli) to
become slight positive relative to atmospheric pressure. As a result, air
leaves the lungs.
The walls of alveoli are coated with a thin film of water & this creates a
potential problem. Water molecules, including those on the alveolar walls,
are more attracted to each other than to air, and this attraction creates a force
called surface tension. This surface tension increases as water molecules
come closer together, which is what happens when we exhale & our alveoli
become smaller (like air leaving a balloon). Potentially, surface tension
could cause alveoli to collapse and, in addition, would make it more difficult
to 're-expand' the alveoli (when you inhaled). Both of these would represent serious
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problems: if alveoli collapsed they'd contain no air & no oxygen to diffuse into the blood
&, if 're-expansion' was more difficult, inhalation would be very, very difficult if not
impossible. Fortunately, our alveoli do not collapse & inhalation is relatively easy
because the lungs produce a substance called surfactant that reduces surface tension.
Exchange of gases:
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• External respiration:
o exchange of O2 & CO2 between external environment & the cells of the
body
o efficient because alveoli and capillaries have very thin walls & are very
abundant (your lungs have about 300 million alveoli with a total surface
area of about 75 square meters)
• Internal respiration - intracellular use of O2 to make ATP
• occurs by simple diffusion along partial pressure gradients
• the partial pressure exerted by each gas in a mixture equals the total pressure
times the fractional composition of the gas in the mixture. So, given that total
atmospheric pressure (at sea level) is about 760 mm Hg and, further, that air is
about 21% oxygen, then the partial pressure of oxygen in the air is 0.21 times 760
mm Hg or 160 mm Hg.
• Alveoli
o PO2 = 100 mm Hg
o PCO2 = 40 mm Hg
• Alveolar capillaries
o Entering the alveolar capillaries
PO2 = 40 mm Hg (relatively low because this blood has just
returned from the systemic circulation & has lost much of its
oxygen)
PCO2 = 45 mm Hg (relatively high because the blood returning from the systemic
circulation has picked up carbon dioxide).
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While in the alveolar capillaries, the diffusion of gasses occurs: oxygen diffuses from the
alveoli into the blood & carbon dioxide from the blood into the alveoli.
Blood leaving the alveolar capillaries returns to the left atrium & is pumped by the left
ventricle into the systemic circulation. This blood travels through arteries & arterioles and
into the systemic, or body, capillaries. As blood travels through arteries & arterioles, no
gas exchange occurs.
Because of the differences in partial pressures of oxygen & carbon dioxide in the
systemic capillaries & the body cells, oxygen diffuses from the blood & into the cells,
while carbon dioxide diffuses from the cells into the blood.
Blood leaving the systemic capillaries returns to the heart (right atrium) via venules &
veins (and no gas exchange occurs while blood is in venules & veins). This blood is then
pumped to the lungs (and the alveolar capillaries) by the right ventricle.
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How are oxygen & carbon dioxide transported in the blood?
Because almost all oxygen in the blood is transported by hemoglobin, the relationship
between the concentration (partial pressure) of oxygen and hemoglobin saturation (the %
of hemoglobin molecules carrying oxygen) is an important one.
Hemoglobin saturation:
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The relationship between oxygen levels and hemoglobin saturation is indicated by the
oxygen-hemoglobin dissociation (saturation) curve (in the graph above). You can see
that at high partial pressures of O2 (above about 40 mm Hg), hemoglobin saturation
remains rather high (typically about 75 - 80%). This rather flat section of the oxygen-
hemoglobin dissociation curve is called the 'plateau.'
Recall that 40 mm Hg is the typical partial pressure of oxygen in the cells of the body.
Examination of the oxygen-hemoglobin dissociation curve reveals that, under resting
conditions, only about 20 - 25% of hemoglobin molecules give up oxygen in the systemic
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capillaries. This is significant (in other words, the 'plateau' is significant) because it
means that you have a substantial reserve of oxygen. In other words, if you become more
active, & your cells need more oxygen, the blood (hemoglobin molecules) has lots of
oxygen to provide
When you do become more active, partial pressures of oxygen in your (active) cells may
drop well below 40 mm Hg. A look at the oxygen-hemoglobin dissociation curve reveals
that as oxygen levels decline, hemoglobin saturation also declines - and declines
precipitously. This means that the blood (hemoglobin) 'unloads' lots of oxygen to active
cells - cells that, of course, need more oxygen.
The oxygen-hemoglobin dissociation curve 'shifts' under certain conditions. These factors
can cause such a shift:
• lower pH
• increased temperature
• more 2,3-diphosphoglycerate
• increased levels of CO2
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These factors change when tissues become more active. For example, when a skeletal
muscle starts contracting, the cells in that muscle use more oxygen, make more ATP, &
produce more waste products (CO2). Making more ATP means releasing more heat; so the
temperature in active tissues increases. More CO2 translates into a lower pH. That is so
because this reaction occurs when CO2 is released:
& more hydrogen ions = a lower (more acidic) pH. So, in active tissues, there are higher
levels of CO2, a lower pH, and higher temperatures. In addition, at lower PO2 levels, red
blood cells increase production of a substance called 2,3-diphosphoglycerate. These
changing conditions (more CO2, lower pH, higher temperature, & more 2,3-
diphosphoglycerate) in active tissues cause an alteration in the structure of hemoglobin,
which, in turn, causes hemoglobin to give up its oxygen. In other words, in active tissues,
more hemoglobin molecules give up their oxygen. Another way of saying this is that the
oxygen-hemoglobin dissociation curve 'shifts to the right' (as shown with the light blue
curve in the graph below). This means that at a given partial pressure of oxygen, the
percent saturation for hemoglobin with be lower. For example, in the graph below,
extrapolate up to the 'normal' curve (green curve) from a PO2 of 40, then over, & the
hemoglobin saturation is about 75%. Then, extrapolate up to the 'right-shifted' (light blue)
curve from a PO2 of 40, then over, & the hemoglobin saturation is about 60%. So, a 'shift
to the right' in the oxygen-hemoglobin dissociation curve (shown above) means that more
oxygen is being released by hemoglobin - just what's needed by the cells in an active
tissue!
Carbon dioxide - transported from the body cells back to the lungs as:
o formed when CO2 (released by cells making ATP) combines with H2O
(due to the enzyme in red blood cells called carbonic anhydrase) as shown
in the diagram below
2 - carbaminohemoglobin - 30%
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Control of Respiration
Your respiratory rate changes. When active, for example, your respiratory rate goes up;
when less active, or sleeping, the rate goes down. Also, even though the respiratory
muscles are voluntary, you can't consciously control them when you're sleeping. So, how
is respiratory rate altered & how is respiration controlled when you're not consciously
thinking about respiration?
Apneustic center (located in the pons) - stimulate I neurons (to promote inspiration)
Pneumotaxic center (also located in the pons) - inhibits apneustic center & inhibits
inspiration
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Heavy exercise ==> greatly increases respiratory rate
Mechanism?
The primary function of the respiratory system is to supply the blood with oxygen in
order for the blood to deliver oxygen to all parts of the body. The respiratory system does
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this through breathing. When we breathe, we inhale oxygen and exhale carbon dioxide.
This exchange of gases is the respiratory system's means of getting oxygen to the blood.
Respiration is achieved through the mouth, nose, trachea, lungs, and diaphragm. Oxygen
enters the respiratory system through the mouth and the nose. The oxygen then passes
through the larynx (where speech sounds are produced) and the trachea which is a tube
that enters the chest cavity. In the chest cavity, the trachea splits into two smaller tubes
called the bronchi. Each bronchus then divides again forming the bronchial tubes. The
bronchial tubes lead directly into the lungs where they divide into many smaller tubes
which connect to tiny sacs called alveoli. The average adult's lungs contain about 600
million of these spongy, air-filled sacs that are surrounded by capillaries. The inhaled
oxygen passes into the alveoli and then diffuses through the capillaries into the arterial
blood. Meanwhile, the waste-rich blood from the veins releases its carbon dioxide into
the alveoli. The carbon dioxide follows the same path out of the lungs when you exhale.
The diaphragm's job is to help pump the carbon dioxide out of the lungs and pull the
oxygen into the lungs. The diaphragm is a sheet of muscles that lies across the bottom of
the chest cavity. As the diaphragm contracts and relaxes, breathing takes place. When the
diaphragm contracts, oxygen is pulled into the lungs. When the diaphragm relaxes,
carbon dioxide is pumped out of the lungs.
Cellular Respiration
Cellular respiration is the process of oxidizing food molecules, like glucose, to carbon
dioxide and water The equation for the oxidation of glucose is:
. The energy released is trapped in the form of ATP for use by all the energy-consuming
activities of the cell. ATP is known as the universal currency because when the
phosphoanhydride bonds in ATP are hydrolysed in an exergonic reaction, the energy yield
is 30kJ per mole under standard conditions. Waste products (CO2 + H2O) are released
through exhaled air, sweat and urine.
Mitochondria
Mitochondria are membrane-enclosed organelles distributed through the cytosol of most
eukaryotic cells. Their number within the cell ranges from a few hundred to, in very
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active cells, thousands. Their main function is the conversion of the potential energy of
food molecules into ATP. Mitochondria have:
The Matrix
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o a 2-carbon fragment of acetate bound to coenzyme A forming acetyl-CoA
Summary:
• ubiquinone
• cytochrome c
• the stepwise transfer of electrons from NADH (and FADH2) to oxygen molecules
to form (with the aid of protons) water molecules (H2O);
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• harnessing the energy released by this transfer to the pumping of protons (H+)
from the matrix to the intermembrane space.
• Approximately 20 protons are pumped into the intermembrane space as the 4
electrons needed to reduce oxygen to water pass through the respiratory chain.
• The gradient of protons formed across the inner membrane by this process of
active transport forms a miniature battery.
• The protons can flow back down this gradient, reentering the matrix, only through
another complex of integral proteins in the inner membrane, the ATP synthase
complex .
Chemiosmosis in mitochondria
The energy released as electrons pass down the gradient from NADH to oxygen is
harnessed by three enzyme complexes of the respiratory chain (I, III, and IV) to pump
protons (H+) against their concentration gradient from the matrix of the mitochondrion
into the intermembrane space (an example of active transport).
As their concentration increases there (which is the same as saying that the pH
decreases), a strong diffusion gradient is set up. The only exit for these protons is through
the ATP synthase complex. As in chloroplasts, the energy released as these protons flow
down their gradient is harnessed to the synthesis of ATP. The process is called
chemiosmosis and is an example of facilitated diffusion.
One-half of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John
E. Walker for their discovery of how ATP synthase works.
It is tempting to try to view the synthesis of ATP as a simple matter of stoichiometry (the
fixed ratios of reactants to products in a chemical reaction). But (with 3 exceptions) it is
not.
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Most of the ATP is generated by the proton gradient that develops across the inner
mitochondrial membrane. The number of protons pumped out as electrons drop from
NADH through the respiratory chain to oxygen is theoretically large enough to generate,
as they return through ATP synthase, 3 ATPs per electron pair (but only 2 ATPs for each
pair donated by FADH2).
Add to this the 4 ATPs that are generated by the 3 exceptions and one arrives at 38.
But the energy stored in the proton gradient is also used for the active transport of several
molecules and ions through the inner mitochondrial membrane into the matrix.
So the actual yield of ATP as mitochondria respire varies with conditions. It probably
seldom exceeds 30.
• one step in the citric acid cycle yielding 2 ATPs for each glucose molecule. This
step is the conversion of alpha-ketoglutaric acid to succinic acid.
• at two steps in glycolysis yielding 2 ATPs for each glucose molecule.
The human mitochondrion contains 5–10 identical, circular molecules of DNA. Each
consists of 16,569 base pairs carrying the information for 37 genes which encode:
The rRNA and tRNA molecules are used in the machinery that synthesizes the 13
polypeptides.
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• 7 subunits that make up the mitochondrial NADH dehydrogenase
• 3 subunits of cytochrome c oxidase
• 2 subunits of ATP synthase
• cytochrome b
Each of these protein complexes also requires subunits that are encoded by nuclear genes,
synthesized in the cytosol, and imported from the cytosol into the mitochondrion. Nuclear
genes also encode ~900 other proteins that must be imported into the mitochondrion.
[More]
• cytochrome b
• 12S rRNA
• ATP synthase
• subunits of NADH dehydrogenase
• several tRNA genes
Although many different organs may be affected, disorders of the brain and muscles are
the most common. Perhaps this reflects the great demand for energy of both these organs.
Some of these disorders are inherited in the germline. In every case, the mutant gene is
received from the mother because none of the mitochondria in sperm survives in the
fertilized egg. Other disorders are somatic; that is, the mutation occurs in the somatic
tissues of the individual.
A number of humans who suffer from easily-fatigued muscles turn out to have a
mutations in their cytochrome b gene. Curiously, only the mitochondria in their muscles
have the mutation; the mtDNA of their other tissues is normal. Presumably, very early in
their embryonic development, a mutation occurred in a cytochrome b gene in the
mitochondrion of a cell destined to produce their muscles.
The severity of mitochondrial diseases varies greatly. The reason for this is probably the
extensive mixing of mutant DNA and normal DNA in the mitochondria as they fuse with
one another. A mixture of both is called heteroplasmy. The higher the ratio of mutant to
normal, the greater the severity of the disease. In fact by chance alone, cells can on
occasion end up with all their mitochondria carrying all-mutant genomes — a condition
called homoplasmy (a phenomenon resembling genetic drift).
Many of the features of the mitochondrial genetic system resemble those found in
bacteria. This has strengthened the theory that mitochondria are the evolutionary
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descendants of a bacterium that established an endosymbiotic relationship with the
ancestors of eukaryotic cells early in the history of life on earth. However, many of the
genes needed for mitochondrial function have since moved to the nuclear genome.
The recent sequencing of the complete genome of Rickettsia prowazekii has revealed a
number of genes closely related to those found in mitochondria. Perhaps rickettsias are
the closest living descendants of the endosymbionts that became the mitochondria of
eukaryotes.
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Aerobic respiration
Theoretically, 36 ATP molecules can be made per glucose during cellular respiration,
however, such conditions are generally not realized due to such losses as the cost of
moving pyruvate into mitochondria. Aerobic metabolism is more efficient than anaerobic
metabolism. They share the initial pathway of glycolysis but aerobic metabolism
continues with the Krebs cycle and oxidative phosphorylation. The post glycolytic
reactions take place in the mitochondria in eukaryotic cells, and at the cell membrane in
prokaryotic cells.
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Overview of the cellular respiration processes.
Glycolysis
Glycolysis is a metabolic pathway that is found in the cytoplasm of cells in all living
organisms and does not require oxygen. The process converts one molecule of glucose
into two molecules of pyruvate, and makes energy in the form of two net molecules of
ATP. Four molecules of ATP per glucose are actually produced but two are consumed for
the preparatory phase. The initial phosphorylation of glucose is required to destabilize the
molecule for cleavage into two triose sugars. During the pay-off phase of glycolysis four
phosphate groups are transferred to ADP by substrate-level phosphorylation to make four
ATP and two NADH are produced when the triose sugars are oxidized. Glycolysis takes
place in the cytoplasm of the cell. The overall reaction can be expressed this way:
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Graphic summary of the glycolysis process.
Produces acetyl-CoA from pyruvate inside the mitochondrial matrix. This oxidation
reaction also releases carbon dioxide as a product. In the process one molecule of NADH
is formed per pyruvate oxidized.
When oxygen is present, acetyl-CoA enters the citric acid cycle inside the mitochondrial
matrix, and gets oxidised to CO2 while at the same time reducing NAD to NADH.
NADH can be used by the electron transport chain to create further ATP as part of
oxidative phosphorylation. To fully oxidise the equivalent of one glucose molecule two
acetyl-CoA must be metabolised by the Krebs cycle. Two waste products, H2O and CO2
are created during this cycle.
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Summary of the Krebs' (or citric acid) cycle.
Oxidative phosphorylation
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Electron transport system.
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Theoretical yields
The yields in the table below are for one glucose and molecule being fully oxidised to
carbon dioxide. It is assumed that all the reduced coenzymes are oxidised by the electron
transport chain and used for oxidative phosphorylation.
coenzyme ATP
Step Source of ATP
yield yield
Glycolysis
Phosphorylation of glucose and fructose 6-phosphate
preparatory -2
uses two ATP from the cytoplasm.
phase
4 Substrate-level phosphorylation
Oxidative phosphorylation. Only 2 ATP per NADH
Glycolysis pay-
since the coenzyme must feed into the electron
off phase 2 NADH 4
transport chain from the cytoplasm rather than the
mitochondrial matrix.
Oxidative
2 NADH 6 Oxidative phosphorylation
carboxylation
2 Substrate-level phosphorylation
Krebs cycle 6 NADH 18 Oxidative phosphorylation
2 FADH2 4 Oxidative phosphorylation
From the complete oxidation of one glucose
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Total yield molecule to carbon dioxide and oxidation of all the
ATP
reduced coenzymes.
Although there is a theoretical yield of 36 ATP molecules per glucose during cellular
respiration, such conditions are generally not realized due to losses such as the cost of
moving pyruvate (from glycolysis), phosphate and ADP (substrates for ATP syhthesis)
into the mitochondria. All are actively transported using carriers that utilise the stored
energy in the proton electrochemical gradient.
• The pyruvate carrier is a symporter and the driving force for moving pyruvate
into the mitochondria is the movement of protons from the intermembrane space
to the matrix.
• The phosphate carrier is an antiporter and the driving force for moving
phosphate ions into the mitochondria is the movement of hydroxyls ions from the
matrix to the intermembrane space.
• The adenine nucleotide carrier is an antiporter and exchanges ADP and ATP
across the inner membrane. The driving force is due to the ATP (-4) having a more
negative charge than the ADP (-3) and thus it dissipates some of the electrical
component of the proton electrochemical gradient.
The outcome of these transport processes using the proton electrochemical gradient is
that more than 3 H+ are needed to make 1 ATP. Obviously this reduces the theoretical
efficiency of the whole process. Other factors may also dissipate the proton gradient
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creating an apparently leaky mitochondria. An uncoupling protein known as thermogenin
is expressed in some cell types and is a channel that can transport protons. When this
protein is active in the inner membrane it short circuits the coupling between the electron
transport chain and ATP synthesis. The potential energy from the proton gradient is not
used to make ATP but generates heat. This is particularly important in a babies brown fat,
for thermogenesis, and hibernating animals.
Anaerobic respiration
2 ATP are produced during anaerobic respiration per glucose, compared to the 36 ATP per
glucose produced by aerobic respiration.
Under anaerobic conditions, the absence of oxygen, pyruvic acid can be routed
by the organism into one of three pathways: lactic acid fermentation, alcohol
fermentation, or cellular (anaerobic) respiration. Humans cannot ferment
alcohol in their own bodies, we lack the genetic information to do so. These
biochemical pathways, with their myriad reactions catalyzed by reaction-
specific enzymes all under genetic control, are extremely complex. We will
only skim the surface at this time and in this course.
Alcohol fermentation is the formation of alcohol from sugar. Yeast, when under
anaerobic conditions, convert glucose to pyruvic acid via the glycolysis
pathways, then go one step farther, converting pyruvic acid into ethanol, a C-2
compound.
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Fermentation of ethanol
Many organisms will also ferment pyruvic acid into, other chemicals, such as
lactic acid. Humans ferment lactic acid in muscles where oxygen becomes
depleted, resulting in localized anaerobic conditions. This lactic acid causes the
muscle stiffness couch-potatoes feel after beginning exercise programs. The
stiffness goes away after a few days since the cessation of strenuous activity
allows aerobic conditions to return to the muscle, and the lactic acid can be
converted into ATP via the normal aerobic respiration pathways.
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