Download Cellular Energy and Mitochondrial ATP Production: A

Cellular Energy and Mitochondrial ATP Production: A Primer
By
Mark J. Donohue
“Metabolism is a basic characteristic of all living organisms – indeed it is the metabolic
reactions, particularly those that transfer energy, which keep the organism alive. It is
only the truly dead parts of organisms, such as the hair and nails of mammals, the shells
of mollusks and the lignified fibers of plants, which do not metabolize – and it is because
they do not metabolize that they are dead” (Roberts 2000)
Energy is the foundation of all life. In humans energy originates within the human cell. It is there that
numerous bio-chemical reactions take place to generate cellular energy in a process called metabolism.
1) me·tab·o·lism - the sum of the chemical reactions that take place within each cell of a living
organism and that provide energy for vital processes and for synthesizing new organic
material. Encyclopedia Britannica – Link
2) me·tab·o·lism - the sum total of the chemical processes that occur in living organisms,
resulting in growth, production of energy, elimination of waste material, etc.
The Free Dictionary - Link
Human metabolism/cellular energy is the limiting factor in determining the quality of health an
individual will experience. Optimal metabolism results in the 100 trillion human cells to function at peak
performance. A person whose metabolism is functioning in such a manner will have an abundance of
energy and a sharp mind to enjoy life and handle its many challenges with few worries of becoming ill.
However, a person whose metabolism is functioning at a sub-optimal level will have just the opposite
experience. Such a person, from the moment they wake in the morning till the moment they hit the
pillow at night, will be in a dulled mental state with difficulty thinking and concentrating while sluggishly
dragging through the day. Colds and flues are a common occurrence, while the consumption of energy
boosters (i.e. caffeine) is a daily ritual/habit if not an addiction.
If the production of cellular energy continues to decline in such a person, more and more of the body’s
cells will continue to function poorly. Soon various bio-chemical pathways, organs and even complete
body systems will begin to fail. This will result in chronic medical conditions, eventually leading to early
aging and death.
Because of this direct connection between the level of cellular energy and personal health it is
paramount to have a basic understanding of human metabolism. As mentioned, the production of
cellular energy originates within each cell in the human body. So it is there we will use as our starting
point to explain… in a simplified manner… the very complicated subject of human metabolism.
The Human Cell
The word cell comes from the Latin cellula, meaning "a small room".
The cell is the functional basic unit of life. It is the smallest unit of life that is classified as a living thing,
and is often called the building block of life. Some organisms, such as most bacteria, are unicellular
(consist of a single cell). Other organisms, such as humans, are multi-cellular. Humans have about 100
trillion or 1014 cells; a typical cell size is 10 µm (micron or micrometer = one-millionth of a meter).
 Cell Size Scale, The University of Utah, (Totally Cool)
Link (use scroll button on site to activate)
A cell is made up of a thin outer membrane called the cell or plasma membrane, which regulates what
passes in and out of the cell. The area within the cell membrane is referred to as the cytoplasm and
contains a watery gel called cytosol along with the minute cell parts or organs (except nucleus) called
organelles.
Figure: Human Cell
There are two primary types of cells found in nature:
1. Eukaryotic cells – found in multi-cellular organisms such as fungi, plants, and animals (humans).
2. Prokaryotic cells - are primitive independent cells such as bacteria.
The major difference between prokaryotes and eukaryotes is that eukaryotic cells contain membranebound organelles in which specific metabolic activities take place. The defining organelles that set
eukaryotic cells apart from prokaryotic cells are the nucleus and mitochondria. The nucleus is the
control center of the cell housing its nuclear deoxyribonucleic acid (nDNA), which contains the
information needed to keep a cell operating and working properly.
 Parts of a Cell, Khan Academy Videos,
Link (21:00)
 Tour of the Cell, Bozeman Science Videos,
Link (14:17)
Mitochondria
Regardless as to whether it is a fungus, plant, animal or human cell… the source of cellular energy in all
eukaryotic cells is the same. Meaning, the source of cellular energy for all eukaryotic biochemical
reactions, comes from one of the cell’s organelles called the mitochondria.
Mitochondria are known as the cell’s “power house” where cellular
energy is produced in the form of a molecule called – adenosine
triphosphate (ATP). And depending on the tissue, mitochondria can
number anywhere from a couple of dozen (neuron) to several
thousand (heart) per cell.
Another interesting fact – mitochondria have their own set of DNA –
mitochondria DNA (mtDNA), which is inherited from the mother.
Mitochondria are made from a combination of nDNA & mtDNA
Figure: Mitochondria
 Learn Biology: Cells – Mitochondria, Mahalo Learn Anything
Link (1:35)
Bottom line: human metabolism/cellular energy and the quality of persons health revolves around the
microscopic cellular organelles – mitochondria – and their ability to efficiently produce ATP. “It’s all
about ATP”… and there are several ways in which the body can produce ATP.
ATP Production: Cellular Respiration
Carbohydrates, lipids (fats), and proteins are the major constituents or nutrients of foods and serve as
fuel for the human body. More specifically, it is the end products of digestion – which breaks down
these macro nutrients into smaller nutrients – that are the true fuel sources for the body’s 100 trillion
cells.
The major absorbed end products of food digestion are glucose (from carbohydrates); short, medium
and long-chain fatty acids (from lipids); and amino acids (from protein). All three classes of these
nutrients can serve as fuel sources for the mitochondria to produce cellular energy in the form of ATP.
Adenosine Triphosphate (ATP)
ATP is a high energy nucleotide and is
considered the cell’s “energy currency”
which provides the needed energy for the
cell’s many metabolic bio-chemical
functions. ATP is a molecule which is
made up of three phosphate groups and
an adenosine group (ribose and adenine).
When the “high-energy” bond between
the second and third phosphate are
broken a substantial amount of energy is
liberated.
Figure – Adenosine Triphosphate (ATP)
 ATP: Adenosine Triphosphate, Khan Academy Videos
Link (13:35)
 Cellular Respiration, Part 1: ATP, Professor Fink’s Biology Videos,
Link (8:12)
 ATP: Adenosine Triphosphate, Bozeman Science Videos
Link (9:46)
Cellular Respiration
The major metabolic bio-chemical pathway which is responsible for the production of ATP/cellular
energy is called cellular respiration. The sole purpose of cellular respiration is to break down glucose,
fatty acids and small amounts of amino acids into ATP. Cellular respiration takes place via a long stepby-step process of enzymatic reactions. These enzymatic reactions can be divided into two main
categories:
1. Anaerobic Respiration – are the enzymatic reactions that DO NOT require oxygen. This includes the
metabolic pathway of glycolysis and fermentation which occurs in the cytoplasm of the human cell.
2. Aerobic Respiration – are the enzymatic reactions that DO require oxygen. This includes the
metabolic pathways of pyruvate oxidation, Krebs cycle and oxidative phosphorylation (electron
transport chain & chemiosmosis) which all occur in the mitochondria.
 Introduction to Cellular Respiration, Khan Academy Videos
Link (14:19)
 Cellular Respiration, Part 2: ATP & Oxygen, Professor Fink’s Biology Videos
Link (9:27)
 Overview of Glucose Metabolism, Prentice Hall (hit play on site)
Link (3:55)
Figure: Cellular Respiration
Anaerobic Respiration
Glycolysis
The first stage of cellular respiration is known as glycolysis. This stage is unique to glucose metabolism
which takes place in the cytoplasm of the cell and does not require oxygen. Through a series of biochemical enzymatic reactions the process of glycolysis breaks down glucose to pyruvate/pyruvic acid.
Glycolysis also generates 2 molecules of ATP and 2 molecules of NADH. NADH is the reduced form
(gained hydrogen atoms) of nicotinamide adenine dinucleotide (NAD).
NAD is a co-enzyme which is derived from the vitamin – niacin (B3). Once reduced NADH acts as an
electron carrier and will be transferred to the mitochondria and utilized in the electron transport chain
to assist in producing additional molecules of ATP.
 Diagram of Glycolysis, Wikimedia Commons, Best one on the Web
Link
 Glycolysis, Khan Academy Videos
Link (13:30)
 Cellular Respiration, Part 3: Glycolysis, Professor Fink’s Biology Videos
Link (10:50)
Fermentation
In the continual absence of oxygen (after
glycolysis has been completed) the process
continues to follow the anaerobic pathway and a
process called fermentation.
There are several types of fermentation, but the
two most common types are lactic acid/lactate
fermentation and alcohol fermentation.
In fermentation the pyruvate/pyruvic acid
molecules, which are toxic to the cell and cannot
enter the mitochondria due to the lack of oxygen,
are converted by enzymes into waste products.
Also fermentation does not produce any
additional energy/ATP.
Lactic acid fermentation takes place in some fungi and some bacteria like Lactobacillus acidophilus
(yogurt). In humans, lactic acid fermentation takes place in the muscles during times of strenuous
exercise or great exertion. Under these conditions the oxygen supplied by the lungs and blood system
cannot get to the cells fast enough to keep up with the muscles’ demands.
At this point the muscle cells will switch over to lactic acid fermentation, by converting pyruvate into
lactic acid via the enzyme lactic acid dehydrogenase (LDH). The build-up of lactic acid can cause
cramping and a burning sensation in the over worked muscles as well as sore muscles the following day
until the lactic acid is washed out of the system.
The glycolysis-fermentation pathway is
important to muscle cells, by producing
“some” ATP, during times when oxygen
is in short supply. However, this process
cannot be applied to the nerve
cells/neurons in the nervous system.
This is because of one major difference
between nerve cells and muscle cells
which is - nerve cells cannot switch to
lactic acid fermentation if oxygen is low.
The nervous system is totally
dependent, from minute-to-minute and
second-to-second, on the oxygen
delivered by the blood. Therefore, the
lack of proper oxygen levels in the brain
will result in impaired brain functioning.
Yeasts, however, have different enzymes, and convert pyruvate into acetaldehyde and then into ethyl
alcohol, a process utilized in brewing. This process may also be utilized by the intestinal bacteria Candida albicans.
 Cellular Respiration, Part 4: Glycolysis & Fermentation, Professor Fink’s Biology Videos
Link (8:57)
 Anaerobic Respiration, Bozeman Science Videos
Link (8:00)
 Fermentation, Biologybyme - YouTube
Link (7:55)
Aerobic Respiration
Pyruvate Oxidation/Transition Reaction
After the completion of glycolysis and the production of pyruvate - if oxygen is present, pyruvate enters
the mitochondria and forms acetyl-coA during the second stage called - pyruvate oxidation or transition
reaction. In this stage an acetyl group is produced by cleaving off a carbon atom from pyruvate. The
acetyl group is then bonded with coenzyme A (CoA) thereby forming acetyl-CoA. CoA is synthesized in
the body from pantethine and cysteine.
Though glycolysis is the primary source of acetyl-coA formation,
acetyl-coA is also associated with the metabolism of fatty acids
ketones and amino acids. Since acetyl-coA is common to all four
pathways, it is sometimes called the “crossroads compound”.
Also produced in this pathway are 2 molecules of NADH.
 Cellular Respiration, Part 5: Transition Reaction,
Professor Fink’s Biology Videos
Link (9:18)
Figure: Pyruvate Oxidation
Krebs/Citric Acid Cycle/TCA Cycle
Once formed, acetyl-coA will enter into the Krebs/citric acid cycle/TCA cycle which is a “circular” series
of enzymatic reactions which take place in the matrix/inner compartment of the mitochondria. The
result of the Krebs cycle is an additional 2 molecules of ATP and 6 molecules of NADH.
Also produced in the Krebs cycle are 2 molecules of another electron carrier called FADH2. FADH2 is the
reduced form (gained hydrogen atoms) of flavin adenine dinucleotide (FAD). FAD is a co-enzyme which
is derived from the vitamin – riboflavin (B2) and once reduced it will also be used in the electron
transport chain to assist in producing additional ATP.
 Diagram of Krebs Cycle/Citric Acid Cycle, Wikimedia Commons
Link
 Krebs/Citric Acid Cycle, Khan Academy Videos
Link (17:47)
 Cellular Respiration, Part 6: Krebs/Citric Acid Cycle, Professor Fink’s Biology Videos
Link (8:54)
Oxidative Phosphorylation: The Electron Transport Chain & Chemiosmosis
The electron transport chain is a series of five protein complexes (I, II, III, IV, V) within the cristae/inner
mitochondrial membrane. And by means of a very complicated series of events the electron carriers NADH and FADH2 - produced during the earlier stages of glycolysis, pyruvate oxidation, Krebs cycle - are
now used to create a high gradient of hydrogen atoms in the outer mitochondrial compartment.
This high gradient forces the hydrogen atoms to cross back through the cristae into the matrix. This
process of transferring hydrogen atoms across the cristae is called chemiosmosis and occurs via a special
membrane protein called ATP Synthase (complex V). ATP synthase is the machinery or protein molecule
that is responsible for actually producing ATP from adenosine diphosphate (ADP) and phosphate.
This entire process, that takes place through the electron transport chain, and chemiosmosis generates
an additional 34 molecules of ATP and is referred to as oxidative phosphorylation.
 Electron Transport Chain, Virtual Cell Animation, Detailed Animation
Link (3:49)
 ATP Synthase Gradient, Virtual Cell Animation, Detailed Animation
Link (3:47)
 Electron Transport System and ATP Synthesis, YouTube, Detailed Animation
Link (2:00)
 Cellular Respiration 5 - Oxidative Phosphorylation, Handwritten Tutorials
Link (4:39)
 Electron Transport Chain, Khan Academy Videos
Link (17:16)
 Oxidative Phosphorylation and Chemiosmosis, Khan Academy Videos
Link (4:59)
ATP Tally: Glucose
We started out stating that ATP was the “energy currency” of the cell which was produced by means of
a process called cellular respiration. Through this process it was noted that ATP was formed at various
stages along with the high energy carriers – NADH and FADH2
NADH and FADH2, are major contributors to the production of ATP via the creation of a hydrogen
gradient in the electron transport chain. During this process each NADH (indirectly) yields 3 ATP while
each FADH2 (indirectly) yields 2 ATP. Therefore the total amount of ATP produced per one molecule of
glucose is:
Glycolysis
o Directly produced
o 2 NADH x 3 ATP
2 ATP
6 ATP
Pyruvate Oxidation
o 2 NADH x 3 ATP
6 ATP
Kreb Cycle
o Directly produced
o 6 NADH x 3 ATP
o 2 FADH2 x 2 ATP
2 ATP
18 ATP
4 ATP
Total ATP Production
38 ATP
Bottom line: via the process of glucose cellular respiration, one molecule of glucose produces a total of
38 molecules of high-energy ATP (adenosine triphosphate). This high-energy ATP is now ready to be
used by the cell for its metabolic bio-chemical functions.
ATP Production: Beta Oxidation
Man does not live by glucose alone. Though brain cells use glucose almost exclusively, other tissues such
as muscle, especially cardiac tissue (muscle) prefer fatty acids as their source of energy. Normally, 60%
to 90% of the energy required for contraction of the heart is derived from the oxidation of fatty acids.
Also, if for some reason adequate amounts of glucose are not available such as - during times of stress,
long periods between meals, and fasting - the body cells can catabolize (break down) stored fats/lipids
and even proteins for energy.
Lipid/Fatty Acid Catabolism
Lipolysis
Lipids provide highly efficient energy storage, storing much more energy for their weight than
carbohydrates like glucose. Lipids are primarily stored in adipose tissue (body fat) as triglycerides which
are composed of a glycerol backbone with three fatty acids attached.
Triglycerides form fatty droplets that exclude water and take up
minimal space. Fatty acids are also more highly reduced than
carbohydrates, so they provide more energy during oxidation.
The efficiency of energy storage of lipids is probably an
important reason why animals (humans) store most of their
energy as fats and only a small amount of energy as
carbohydrates.
When needed as an energy source the fat reserves are mobilized via a process called lipolysis. Lipolysis
largely occurs in adipose tissue where glycerol is cleaved off of the fatty acids. Once completed the fatty
acids and glycerol are then released from the adipose tissue into the blood and transported to the
energy requiring tissue.
In the cell glycerol – a sugar alcohol - is further converted into one of the intermediate products of
glycolysis – glyceraldehyde phosphate – and then to pyruvate. Glycerol makes up only 5% of the lipid
metabolism. The remaining 95% of lipid metabolism takes place when the fatty acids enter the
mitochondria’s Krebs cycle.
Carnitine Palmitoyltransferase System (CPT)
Before fatty acids can enter the mitochondria they need to be “activated”. The activation of fatty acids
takes place in the cell’s cytosol where the enzyme acyl-CoA synthetase (ACS) - located on the “outer
surface” of the outer mitochondria membrane - links the sulfhydryl group of Coenzyme A (CoA) to a
fatty acid. ATP drives the formation of this linkage to form a new compound called Acyl-CoA .
Once activated the short chain fatty acid acyl-CoA’s (<6 carbon atoms long) and medium chain fatty acid
acyl-CoA’s (6-12 carbon atoms long) can freely diffuse into the mitochondria to be oxidized via a process
called beta-oxidation. However, the long chain fatty acid acyl-CoA’s (>12 carbon atoms long) are unable
to diffuse into the mitochondria and therefore must be transported in.
The transport of long chain fatty acids into mitochondria is accomplished by the carnitine
palmitoyltransferase system (CPT system - CPTI & CPTII), sometimes referred to as the carnitine
shuttle. The CPTI enzyme, which is bound to the “inner surface” of the outer mitochondrial membrane,
exchanges coenzyme A for carnitine on the long chain fatty acid acyl CoA molecule. The bonding of
carnitine forms a fatty acid-carnitine conjugate called acyl-carnitine.
Acyl-carnitine is then shuttled across the inner mitochondrial membrane by a transporter
protein/enzyme called the carnitine-acylcarnitine translocase (CACT). Once acyl-carnitine has been
transported into the matrix of the mitochondria CPTII exchanges carnitine for CoA, thereby, once again
producing a long chain fatty acid acyl-CoA. Now in the mitochondria matrix, the long chain fatty acid
acyl- CoA can be oxidized via a beta-oxidation. The removed carnitine is transported back through the
CACT to be re-used.
Beta Oxidation
Beta-oxidation is the process whereby
all activated fatty acid (short, medium &
long chain) acyl-CoA’s are oxidized, via a
repeating four-step enzymatic cycle. In
each four-step cycle, a fatty acid is
progressively shortened by having two
of its carbon atoms cleaved off. The
remaining fatty acid chain re-enters the
beta oxidation pathway resulting in
another pair of carbon atoms cleaved
off. This process is repeated until all the
carbon atoms in the original fatty acid
acyl-CoA are gone.
The cleaved pairs of carbon atoms are
used to produce acetyl groups which are
then linked with coenzyme A molecules
to produce molecules of acetyl-CoA. As
we learned earlier acetyl-CoA is the
entry point into the Krebs cycle where
ATP, NADH and FADH2 are produced.
Figure: Beta Oxidation
Also, during each four-step enzymatic cycle, the electron carriers NAD+ and FAD are reduced to produce
(1) NADH and (1) FADH2 which are transported to the electron transport chain to assist in producing ATP.
 Metabolism – Beta Oxidation, Nutrition Science Animations
Link (2:00)
 Cellular Respiration 4 - Beta Oxidation, Handwritten Tutorials
Link (9:10)
 Fatty Acid Degredation, Armando Hasudungan
Link (7 :45)
ATP Tally: Fatty Acids
The number of ATP produced from the breakdown of fatty acids depends on which fatty acid is utilized.
However, the following example of palmitate/palmitic acid, a common saturated fat found in plants
and animals, will give a good example of why fatty acids are a highly concentrated source of energy.
Palmitate is a 16 carbon atom and will therefore cycle through the beta oxidation pathway 7 times.
Thereby forming 7 NADH’s, 7 FADH2’s and 7 acetyl-CoA’s. Plus the last two remaining carbon atoms will
also be converted to acetyl CoA. Making the total number of acetyl-CoA produced to be 8.
Beta Oxidation (7 cycles)
o 1 NADH x 3 ATP x 7 cycles =
o 1 FADH2 x 2 ATP x 7 cycles =
21 ATP
14 ATP
Krebs Cycle (from 8 acety-CoA)
o Directly produced – 1 ATP x 8 cycles =
o 3 NADH x 3 ATP x 8 cycles =
o 1 FADH2 x 2 ATP x 8 cycles =
8 ATP
72 ATP
16 ATP
Total ATP Production
131 ATP
Bottom line: one molecule of palmintate/palmitic acid - 16 carbon long chain fatty acid – will produce
131 molecules of high energy ATP. While glucose – 6 carbon atom – will produce 38 ATP. Also keep in
mind that these calculations apply to one single specific fatty acid (palmintate). A triglyceride is made
up of 3 fatty acids plus a glycerol back bone.
Examples
The two figures below are excellent examples of glycolysis, beta oxidation and cellular respiration during
times when oxygen is available (aerobic) and when oxygen is not available (anaerobic). These examples
take place in the heart tissue which contains the highest concentration of mitochondria in the body.
Figure 1 (Aerobic Heart) - Energy metabolism in normal aerobic heart: the schematic shows some of the major
metabolic pathways which contribute to myocardial energy production. Fatty acids are transported into
mitochondria as acyl-CoA which undergoes β-oxidation to release acetyl–CoA. Acetyl–CoA then enters tricarboxylic
acid cycle (TCA) to produce ATP, CO2 and H2O. Glucose on the other hand undergoes glycolysis to produce
pyruvate. Pyruvate is then oxidized via TCA cycle in the mitochondria
Figure 2 (Ischemic – Low Blood Flow - Anaerobic Heart) - Energy metabolism in ischemic myocardium: due to lack
of oxygen supply, mitochondrial oxidation of fatty acids and glucose is restricted. However, anaerobic glycolysis
persists to meet the energy demand. When pyruvate is not oxidized in mitochondria, the hydrogen ion generated
as a result of hydrolysis of glycolytic ATP accumulates in cytosol. Accumulation of proton (H+) then leads to Na+
influx via Na+/H+ exchanger which then leads to Ca2+ accumulation via the Na+/Ca2+ exchanger.
ATP Production: Ketogenisis
Ketogenesis & Ketosis
Ketosis is simply the accumulation of ketones/ketone bodies in the body. This is a controversial subject
with the debate centered on whether or not ketosis is potentially dangerous or even beneficial for some
people.
On one side of the issue it is claimed that ketones are formed due to the result of a restricted or low
intake of carbohydrates. This occurs during times of starvation, fasting, severe dieting or when glucose is
not fully utilized as in diabetes. Due to such a restricted carbohydrate intake, the body converts to the
oxidation of more fats for energy.
This shift occurs mainly because the entry of acetyl-coA into the Krebs cycle depends on the availability
of oxaloacetic acid (1st step in Krebs cycle), which becomes deficient in a low carbohydrate diet. This
scenario of low oxaloacetic acid levels will in turn cause fatty acid oxidation to be incomplete thereby
causing an excess of acetyl-coA to accumulate in the cells. The excess acetyl-coA is transported to the
liver where it is converted to ketones via a process called ketogenesis.
Since most ketones are acidic, in certain people ketosis can
lead to metabolic acidosis or ketoacidosis which is an
increase in blood and tissue acidity which can be dangerous.
The body eliminates most ketones (i.e. acetone) by excreting
them through the urine as well as the breath. Ketones
excreted through the breath give a person’s breath a sweet,
fruity smell that has been likened to the smell of nail varnish.
 Ketosis, YouTube
Link (1:21)
 How to lose weight through Ketosis, eHow Health
Link (1:38)
 Primitive Nutrition 59: Ketosis, YouTube
Link (5:22)
However, on the other side of the issue it is claimed that ketones, especially beta-hydroxybutyrate and
acetoacetate (beta-ketobutyrate) are of physiological significance. And that the synthesis of these
ketones takes place under certain conditions where the production of acetyl-CoA, either from betaoxidation or pyruvate oxidation is more rapid than it can be utilized for other metabolic processes. The
primary conditions that regulate ketogenesis are any conditions that increase mobilization of fatty acids.
“As analytical techniques have gained in precision and sensitivity, ketone bodies have
proved to be normal components of blood, not products that appear only when the
metabolism of carbohydrate is disordered.” (VanItallie 2003)
The physiological significance of these ketone bodies takes the form of ATP production. For example it is
known that there is limited transport of fatty acids across the blood-brain barrier, which explains why
fatty acids are not a significant fuel source for the brain. Ketone bodies, however, can cross the bloodbrain barrier and can therefore be an alternative source of energy for the brain.
“Unlike glucose, the uptake of ketone bodies occurs via the family of monocarboxylate
transporters (MCTs), which are not insulin mediated. MCT proteins enable ketones to
pass readily through the blood-brain barrier. Many types of peripheral cells, including
brain cells, not only use glucose, but also use ketones to produce acetyl-CoA.” (VanItallie
2003)
Figure: Ketones and Cellular Respiration
ATP is produced by ketones when the ketone bodies – beta-hydroxybutyrate (BHB) and acetoacetate
(AcAc) enter the mitochondria and are acted upon by several enzymes. Ketolysis – the splitting up of
ketones – takes place first when 3-oxoacid-CoA transferace (OCT) adds coenzymeA to AcAc, which is
then split into two molecules of acetyl-CoA by acetoacetyl-CoA thiolase (ACT). The acetyl-CoA
molecules then enter into the Krebs/TCA cycle.
“In the liver, much of the acetyl CoA generated from beta-oxidation of fatty acids is used
for synthesis of the ketone bodies acetoacetate and beta-hydroxybutyrate, which enter
the blood. In skeletal muscles and other tissues, these ketone bodies are converted back
to acetyl-CoA, which is oxidized in the TCA cycle to produce ATP.” (Mark’s 2003)
According to Dr. Michael Eades (author of several books about “Protein Power”), ketones are basically
water soluble fats which dissolve in blood. And are a source of energy for many tissues including the
muscles, brain and heart. Though ketones can’t totally replace all the sugar required by the brain, they
can replace a good chunk of it. Dr. Eades also claims that ketones are the preferred fuel for the heart,
making that organ operate at 28% greater efficiency. Dr. Eades assertions appear to be supported:
“Ketolysis: … Heart, kidney cortex, brain… uses ketone bodies for energy production…
Heart and kidney cortex prefers to use ketone bodies rather than glucose. (Rao 2007)
“Veech and associates also observed that the introduction of ketone bodies into the rat
heart produced a 16-fold rise in acetyl-CoA content and increases in TCA (Krebs) cycle
intermediates.” (VanItallie 2003)
ATP Production: Protein/Amino Acid Catabolism
The first step in protein catabolism is to digest protein molecules into individual amino acids. Once this
is done the removal of the amino group (NH2) is required and takes place in the liver via a process called
deamination. The removed amino group is converted to ammonia (NH3). Ammonia is highly toxic and is
further converted in the liver to urea and then excreted from the body via the kidneys.
Once the amino group is removed the remaining carbon skeleton – a keto acid - can enter the cellular
respiration cycle either as pyruvic acid (50%), acetyl CoA (25%) or enter directly into the Krebs/citric acid
cycle (25%) to generate ATP (different amino acids go through different pathways).
Catabolism of amino acids is not a practical source of quick energy and is typically only used in starvation
situations. Proteins are harder to break apart than carbohydrates or lipids, their catabolism generates
toxic waste products (ammonia), and they are the structural and functional parts of every cell, and thus
tend to only be used when no other energy source is available.
Figure: Protein usage in the body
ATP Production: ATP Turnover
Regardless of the source of ATP – glycolysis, beta-oxidation, Krebs cycle, oxidative phosphorylation –
ATP needs to be “turned over” so that it is re-used over and over. This is to supply the body with the
huge amounts of ATP it demands, of which cannot be produced in such volumes from scratch by normal
metabolic pathways. The turnover process takes place naturally by means of a protein called adenine
nucleotide translocator (ANT) or ATP-ADP translocase.
Adenine Nucleotide Translocator (ANT)/ATP-ADP Translocase
The production of ATP, via ATP synthase, occurs on the inside of the mitochondrial inner membrane – in
the matrix. But most of the cellular ATP usage is required outside the mitochondria - in the cytosol.
Therefore ATP needs to be transported from the mitochondria’s matrix to the cell’s cytosol.
This is accomplished through a special protein called adenine nucleotide translocator (ANT) or
sometimes referred to as the ATP-ADP translocase which is located on the inner membrane of the
mitochondria. ANT is the most abundant protein of the inner mitochondrial membrane and is the most
active enzyme in animal (human) cells.
Once transported into the cytosol, ATP
undergoes hydrolysis via the enzyme
ATPase. ATPase breaks the phosphate
bonds and thereby releasing energy to
be used for the cells many biochemical
functions. This process also results in the
formation of a new molecule adenosine di-phosphate (ADP) and a
phosphate molecule. ANT will now be
used to transport the ADP molecule back
into the matrix for reprocessing.
ANT simultaneously transports both ATP
and ADP. For each ATP molecule
transported out of the matrix, one
molecule of ADP is transported into the
matrix. Once in the matrix ADP and
phosphate are re-synthesized via ATP
synthase to produce a new molecule
of ATP… starting the cycle all over.
Figure: Adenosine Nucleotide Translocator/ATP-ADP Translocase
ATP Production: The ATP–CP System
We learned that the body can produce cellular energy/ATP by means of anaerobic metabolic pathways
(glycolysis & fermentation) and by means of aerobic metabolic pathways (cellular respiration, betaoxidation ketogenesis & protein catabolism). We also learned that the production of ATP through the
means just mentioned is not enough to keep up with the body’s high demands for ATP. Therefore, ATP
needs to be quickly and continually recycled to meet these demands.
However, in certain circumstances this too may not be enough which is why the body also has a reserve
tank called: The ATP-CP System. Unlike the normal metabolic pathways this pathway or system is
exclusive to muscle (includes cardiac), brain and eye cells only. The ATP-CP system is a non-lactic acid
producing, anaerobic (without oxygen) system whose primary use is for quick short-acting bursts of
energy.
The ATP–Creatine Phosphate (CP)/ATP–Phosphocreatine (PCr) System
When the body is at rest energy needs are fulfilled by aerobic catabolism because the low demand for
oxygen can easily be met by oxygen exchange in the lungs and by the oxygen carried to the muscle by
the cardiovascular system.
If physical activity is initiated, the energy requirements of contracting muscle are met by existing ATP.
However, stores of ATP in muscle are limited, providing enough energy for only a few seconds. If the
physical activity continues ATP levels diminish as it is converted to ADP.
Luckily, the body has a small reservoir of creatine phosphate(CP)/phosphocreatine (PCr) which can be
used to quickly regenerate ADP into ATP. Creatine phosphate is nothing more than a molecule of
creatine with a phosphate molecule bonded to it. This process is catalyzed by the enzyme creatine
kinase (CK), and the reaction is reversible. The enzyme can either add a phosphate to creatine to make
creatine phosphate, or remove one to make creatine, depending on the needs of the cell.
Creatine phosphate is found in muscle, brain and eye cells in the amount of 4 to 6 times greater than
that of ATP. Thus most energy is stored at these sites in creatine phosphate pools. Because only one
enzymatic reaction is involved in this energy transfer, ATP can be formed rapidly (within a fraction of a
second) by using creatine phosphate.
At rest, muscle fibers produce more ATP than is required by the body. This excess ATP is used to
synthesize creatine phosphate. The enzyme creatine kinase catalyzes muscles fibers to break down
excess ATP and transfer a phosphate group to creatine, forming creatine phosphate and ADP. During
contraction, muscle fibers transfer the phosphate group from creatine phosphate to ADP, forming ATP.
All though the ATP-CP system creates ATP almost instantly, it does have its limits. In that in can only
produce about 15 seconds worth of physical activity. Although this may seem like a very limited amount
of time, creatine phosphate provides the muscles with ATP before aerobic respiration can take over. The
ATP-CP system is active at the beginning of all forms of activities but is especially important in high
intensity exercises that require short bursts of energy.
 ATP – CP System for Exercise Physiology, Kinesiology College Channel
Link (5:59)
 Sports Nutrition: ATP – CP Energy System
Link (1:00)
The Methylation Connection
Methylation is one of the most common metabolic functions of the body, occurring in the order of a
billion times per second. It is the process by which a methyl group (CH3) is transferred from one
molecule (a methyl donor) to another (which becomes 'methylated'). In doing so this activates/controls
over 100 different biochemical reactions in the body, which are catalyzed by methlytransferase
enzymes, influencing such things as:
- Energy (co-q10, carnitine, creatine)
- Cell membrane growth & repair (myelin, phospholipids)
- Neurotransmitters (adrenaline, nor-adrenaline, dopamine, serotonin, histamine)
- Hormones (thyroid, adrenal, melatonin)
- Immunity (T-cells, autoimmunity, histamine, TH1/TH2 balance, viral DNA, NK cell function)
- DNA & RNA
- Detoxification (sulfur metabolism, glutathione, redox)
The main methyl donor in the body is called S-adenosylmethionine (SAMe). Levels of SAMe are
maintained by a basic cellular biochemical cycle, called the methylation cycle. Whereby SAMe is
synthesized from the amino acid methionine.
Indicated by the figure below (left circle – folate cycle, right circle – methylation cycle) the methylation
cycle is very complicated and a detailed description of it is beyond the scope of this report.
&
CoQ10,
Carnitine
However, what needs to be mentioned is that – the methylation cycle is intricately involved in the
production of several metabolic substrates: CoQ10, carnitine, creatine and adenosine (described
below).
Methylation & Coenzyme Q10 Synthesis
Coenzyme Q10 (CoQ10) is a vital component of the electron transport chain where it is responsible for
the transfer of electrons between complex I, II & III. Without out CoQ10 there would be no ATP
production.
CoQ10 is a non-essential nutrient which is naturally produced in the human body and is synthesized
from the amino acid tyrosine and precursor molecules. Two of the final steps in the biosynthesis of
CoQ10 involve methylation by SAMe.
Methylation & Carnitine Synthesis
Carnitine is responsible for the shuttling of long chain fatty acids across the mitochondrial membrane so
they may be used in the beta-oxidation system.
Carnitine is a non-essential nutrient which is naturally produced in the human body from - the synthesis
which begins with the methylation of the amino acid lysine by SAMe. After several more steps requiring
consecutive methylations and the interaction of several enzymes, vitamins and minerals – carnitine is
produced in the body.
Methylation & Creatine Synthesis
The ATP–creatine phosphate system is the body’s energy reserve tank. Supplying energy for quick short
acting burst of energy.
Creatine is a non-essential nutrient which is naturally produced in the human body from the amino acids
– glycine, aginine and methionine. The synthesis of creatine occurs primarily in the kidneys and liver.
Once synthesized, creatine is transported in the blood for use by muscle tissue, brain and the eyes.
Approximately 95% of the human body's total creatine is located in muscle tissue.
The synthesis of creatine, via methylation, is the single greatest drain of the body’s methyl reserves,
consuming over 70% of the body’s entire supply. Furthermore, given that the body’s methyl reserves
are limited in size, creatine synthesis alone could potentially create a state of methyl-deficiency.
Methylation Cycle & Adenosine
Adenosine is a molecule, made up of ribose and adenine, which form the back bone to the all-important
molecule this report has centered on – adenosine tri-phosphate (ATP), adenosine di-phoshpate, (ADP),
and adenosine mono-phosphate (AMP).
Adenosine can be synthesized in the body through a couple of pathways, but a key pathway is through
the methylation cycle. In the methylation cycle SAMe is enzymatically converted into an intermediate
molecule called S-adenosylhomocysteine (SAH). And via a series of enzymatic activities SAH can be
converted to adenosine or any one of its byproducts AMP ADP ATP.
Conclusion
Carbohydrates, fats and proteins can all be used to provide energy. The fate of any type of nutrient in a
cell is strictly regulated and depends on the cell’s momentary physiological and biochemical needs.
The major pathways for ATP production are:







Glycolysis
Beta Oxidation
Ketogenesis
Protein Catabolism
Krebs/Citric Acid/TCA Cycle
Oxidative Phosphorylation
Creatine Phosphate (muscles only)
Ketones
Electron Transport Chain
Creatine Phosphate
(muscle only)
ATP
Figure: Cellular Energy – Metabolism – ATP Production
References

Advanced Biology, by Michael Roberts, Nelson Thornes (2000)
Chapter 8: Biochemical Reactions and Enzymes (pg. 118)
http://books.google.com/

Advanced Nutrition and Human Metabolism, Sareen Gropper, Wadsworth Cengage Learning (2009)
http://books.google.com/

Biochemistry 5 edition, by JM Berg, JL Tymoczko, L Stryer, W.H. Freeman (2002)
Section 22.2 the Utilization of Fatty Acids as Fuel Requires Three Stages of Processing
http://www.ncbi.nlm.nih.gov/books/NBK22581/

Cell Respiration, Bellevue College
http://scidiv.bellevuecollege.edu/rkr/biology160/lectures/pdfs/Respiration160.pdf

Encyclopedia Britannica
http://www.britannica.com/

How Cells Release Energy (Chapter 7), Citrus College
http://209.68.138.57/lc/archive/biology/Pages/Chapter07-Rabitoy.aspx

Human Physiology, by Lauralee Sherwood, Wadsworth Cengage Learning (2008)
http://books.google.com/

Learn Genetics: Genetic Science Learning Center, The University of Utah
http://learn.genetics.utah.edu/

Mark’s Basic Medical Biochemistry, by Michael Lieberman, Lippincott Williams & Wilkins (2008)
http://books.google.com/

Medical Biochemistry by Miriam D. Rosenthal, Wiley & Sons Pub. (2009)
http://uwashington.worldcat.org/title/medical-biochemistry-human-metabolism-in-health-anddisease/oclc/435650506&referer=brief_results

Medical Biochemistry, N Malikarjuna Rao, New Age International (2007)
http://books.google.com/

National Human Genome Research Institute, National Institutes of Health
http://www.genome.gov/

Principles of Biochemistry and Biophysics, by B.S. Chauhan, Firewall Media (2008)
http://books.google.com/
th

The Blog of Michael Eades, M.D.
http://www.proteinpower.com/drmike/ketones-and-ketosis/metabolism-and-ketosis/

University of Illinois at Chicago
http://www.uic.edu/classes/bios/bios100/lectures/respiration.htm

VanItallie T.B., et al, Ketones: Metabolism’s Ugly Duckling, Nutrition Reviews, 61(10):327-341 (2003)
http://onlinelibrary.wiley.com/doi/10.1301/nr.2003.oct.327-341/pdf

Wikipedia
http://en.wikipedia.org/wiki/Portal:Health_and_fitness
Videos:

bozemanscience.com
http://www.bozemanscience.com/science-videos/

Brightstorm
http://www.brightstorm.com/

College Level Biochemistry Channel, YouTube
http://www.youtube.com/user/aaronsbiochemvideos?feature=watch

Igines’s Channel, YouTube
http://www.youtube.com/user/lgines#p/u/2/kI33YvaP1t0

Khan Academy
http://www.khanacademy.org/

PBS’s NOVA
http://www.pbs.org/wgbh/nova/

Primitive Nutrition, YouTube
http://www.youtube.com/user/PrimitiveNutrition/videos

Professor Fink
http://www.professorfink.com/

YouTube
http://www.youtube.com/

Virtual Cell Animation Collection
http://vcell.ndsu.nodak.edu/animations/home.htm