SU 2: Bioenergetics and IEM

Principles of bioenergetics: Slide 5

- What is bioenergetics and where in the cell does it take place?
- Bioenergetics= is the transformation of free energy in cells driven primarily by
mitochondria.
- Mitochondria are organelles found in the cell cytoplasm and we will look in
more detail later on their structure and variety of functions in the cell.
- Bioenergetic processes include metabolic pathways that produce energy,
store energy, and break down energy.
- This flow of energy through living systems is essential to most aspects of
cellular metabolism and of life.

Principles of bioenergetic: Slide 6

- The basal metabolic rate or BMR= is the sum of all metabolic reactions in the
body during total rest.
- The BMR varies from individual to individual depending on age, gender and
body mass.
- Heat production by mitochondria makes up most of the BMR and the amount
of oxygen the body consumes during aerobic cellular respiration (a process
that takes place in mitochondria) is directly related to the BMR, so BMR can
also be measured by oxygen consumption measure.
- Gibbs free energy (or delta G)= is the energy value we use to refer to the
energy change that occurs during a metabolic reaction.
- It is the amount of energy that a chemical reaction produces or requires to
take place (at a constant temperature and pressure).
- So let's say, for a given reaction, substance A is converted to substance B in
the forward reaction: If in a biological system (at equilibrium) there is a greater
concentration of B, the reaction is thermodynamically favorable, which means
that it will occur spontaneously and release energy.
- Then we say ΔG is negative (ΔG<0).
- But if the concentration of A at equilibrium is greater than B, the reaction is
thermodynamically unfavorable meaning that it is non-spontaneous and
requires energy to occur. Then we say that ΔG is positive (ΔG>0).
- All biological reactions are considered reversible and the free energy of the
reverse reaction is equal to the forward reaction, but its sign is different.
- So we use the sign of ΔG to indicate whether reactions will occur in the
forward direction, spontaneously or non-spontaneously.
- You can look at Table 9.2 for the standard free energy change of some
hydrolysis reactions of some common metabolic intermediates.
 - Hydrolysis reactions occur when an organic substance reacts with water and
chemical compounds are split to form two or more new substances and this
generally occurs in metabolism.

Principles of bioenergetic: Slide 7:

- Most biosynthetic reactions in the body are thermodynamically unfavorable
and require energy to take place. This means that energy produced from other
metabolic reactions cannot all be lost as heat, some must be stored in a
chemical form to drive other non-spontaneous reactions.
- Adenosine triphosphate or ATP= is the body's central energy storage form
used to drive most non-spontaneous reactions in the body.
- Almost half of the energy obtained from metabolic fuels is used to produce
ATP.
- The free energy is stored in the high-energy phosphoanhydride bond that
forms when ADP binds with inorganic phosphate to form ATP.
- This energy is then released again during the hydrolysis of ATP, when one
phosphate group is removed by breaking the phosphoanhydride bond to
form ADP again.
- In this example you can see that the biosynthesis of glucose-6-phosphate (the
first step in glucose metabolism) has a positive delta G value which means that
the reaction needs energy to take place. But when the reaction is coupled to
the hydrolysis of ATP, which releases energy, a net, thermodynamically
favorable reaction can occur.
- Our bodies need about 100 to 150 mol of ATP daily, but the total amount of
ATP in an adult body is about 0.10 mol which means that each ATP molecule
must be recycled about 1000 to 1500 times a day. Basically, the daily turnover
of ATP in the human body is equal to the body mass.

Sources of energy: Slide 8

- Cells need energy to function normally.
- What we eat and drink are our sources of energy or metabolic fuel. Each class
of fuel has a different energy content.
- The unit we use to describe this energy content is the kilocalorie (which is
equivalent to the nutritional calorie) - and thermodynamically it is defined as
=the amount of energy required to raise the temperature of 1 L of water by 1
degree Celsius .
- Kilojoule (kJ)= is the SI unit of calories and to get the energy content in kJ
you just multiply the calorie by 4.2.

Sources of energy: Slide 9

 - For our cells to use metabolic fuels to produce energy, the fuels must be
metabolized/broken down.
- We call this breakdown catabolism.
- There are two general steps in this catabolic process:
1. First, the fuel is metabolized through several steps to finally form carbon
dioxide (CO2) and reduced coenzymes (NADH and FADH2).
2. Afterwards, the reduced coenzymes are oxidized, and their free energy is
used to produce ATP.
- In this process, oxygen (O2) is consumed and water is produced. We call this
process aerobic respiration – the total oxidation of metabolic fuels that uses
the O2 we inhale to produce energy and also produces water and the CO2
we exhale as waste products.
- The coenzymes NAD and FAD play a very important role in energy
metabolism and respiration because they are necessary for many metabolic
reactions to take place.
- They exist as redox couples that can accept and donate electrons during
metabolic reactions (so they can be reduced and oxidized). It is also important
that the ratio between the oxidized and reduced forms of these redox pairs
remains balanced so that normal energy metabolism can take place. When
there is an imbalance in redox status, it can inhibit metabolic reactions.

Sources of energy Slide 10:

- Please read up for yourself on the major metabolic pathways involved in the
production of ATP from different metabolic fuels.
- Here we are going to focus on the breakdown of the main carbohydrate,
glucose.
- During aerobic respiration, glucose is first broken down to pyruvate in the cell
cytoplasm through the process of glycolysis.
- For every one glucose molecule, 2 molecules of NADH, 2 molecules of ATP
and 2 pyruvate molecules are formed.
- Pyruvate can then be further oxidized in the mitochondrion where it is
converted to acetyl-CoA. Acetyl-coA then enters the TCA cycle or the Krebs
cycle where it is broken down to CO2.
- This cycle produces NADH, FADH2 and (indirectly) ATP.
- For one glucose molecule, the TCA cycle produces 3 NADH, 2 FADH2 and 2
ATP molecules. The coenzymes NADH and FADH2 produced from glucose
catabolism then carry electrons to the OXPHOS system which uses these
coenzymes, along with the oxygen, to drive ATP synthesis.
- 34 ATP molecules are produced by the OXPHOS system from these
coenzymes.
- So you can see that the OXPHOS system is responsible for the largest amount
of cellular energy production.
 - The breakdown of fats, alcohol, other carbohydrates and proteins also feeds
the OXPHOS system because their metabolism also produces NADH or
FADH2, acetyl-CoA or other TCA cycle intermediates.

Glycolysis: Slide 11:

- The catabolism of glucose or glycolysis is a multi-step process that does not
occur in isolation.
- Many glycolytic intermediates branch to other pathways, so there are
interactions with fat, protein and nucleic acid metabolism as well as other
pathways of carbohydrate metabolism.
- Glycolysis consists of three main steps:
1. In the first step, ATP is used for biosynthetic reactions to take place,
2. in the second step two intermediates are formed, only one of which moves on
to the
3. third step where ATP is produced.
- During the splitting step, two glyceraldehyde molecules form and finally two
pyruvate molecules, so the net ATP production from glycolysis is 2 ATP
molecules per 1 glucose molecule.
- Pyruvate can be reduced to lactate in the cytoplasm (called anaerobic
glycolysis), but this is an inefficient way of extracting energy from glucose as
it only yields these 2 moles of ATP per 1 mole of glucose – third and final step
of glycolysis – net yield of 2 ATP and 2 NADH.
- As we have already mentioned, pyruvate can alternatively be further oxidized
in the mitochondria to CO2 and water (this is called aerobic glycolysis) and
this is the most efficient way to extract energy from glucose as it extracts 36-
37 moles of ATP per mole of glucose.

The OXPHOS system: Slide 12

- Now we are going to look at the OXPHOS system, which is found in the
mitochondria.
- Mitochondria are found in all cells (except red blood cells) and there are many
copies of mitochondria in a single cell.
- Mitochondria are often called the metabolic center of the cell because they
are central to so many aspects of metabolism and because they are
responsible for the majority of cellular ATP production through OXPHOS.
- Let's take a quick look at the structure of mitochondria.
- They have a double membrane (an outer and inner membrane) that creates
an intermembrane space and a central matrix.
- Some parts of the inner membrane run parallel to the outer membrane while
other parts form cristae that extend into the matrix.
 - The OXPHOS system is found in these inner membrane cristae.
- The outer membrane is relatively permeable to molecules while the inner
membrane is relatively impermeable and contains many transporters that
move molecules across the membrane.
- The mitochondrial matrix contains many anabolic and catabolic enzymes,
including enzymes involved in the TCA cycle and fatty acid beta oxidation.
The matrix also contains the mitochondrion's own DNA (mitochondrial DNA)
and the machinery necessary for mitochondrial DNA transcription, replication
and protein synthesis.

The OXPHOS system: Slide 13

- Now we are going to look at the components of the OXPHOS system.
- The OXPHOS system consists of 5 enzyme complexes, the first 4 form part of
the electron transport chain or the respiratory chain.
- This chain also includes two mobile electron carriers: the first one, coenzyme
Q10, occurs in a pool in the inner membrane and the second one is
cytochrome C.
- Electrons coming from NADH or FADH2 are transported through the electron
transport chain and as it moves through the chain, complexes 1, 3 and 4 pump
hydrogen ions/protons from the matrix across the inner membrane into the
intermembrane space.
- At the end of the chain, the electrons are transferred to oxygen and water is
formed. This electron transport that causes proton pumping forms an
electrochemical gradient across the inner mitochondrial membrane that
makes the protons want to move back to the matrix.
- There are two ways by which these protons can move back through the inner
membrane, the first is through complex 5 of the OXPHOS system, this causes
complex 5 to produce ATP from ADP and inorganic phosphate. The second
option is through uncoupling proteins.
- These proteins disrupt the link between electron transport and oxidative ATP
production and instead produce heat.

The OXPHOS system: Slide 14:

- For ATP to be produced it is important that respiration or electron transport
is coupled to the oxidative phosphorylation of ADP to form ATP. Let's now
look again at how a connected OXPHOS system functions in a little more
detail.
- There are 5 enzyme complexes. The first 4 form the respiratory chain or the
electron transport chain which creates an electrochemical potential across the
inner mitochondrial membrane.
 - The fifth complex is called ATP synthase, and it is responsible for the synthesis
of ATP.
- As we mentioned earlier, the breakdown of nutrients produces coenzymes
NADH and FADH2 that carry electrons.
- These electrons are donated to the coenzyme Q10 pool when NADH is
oxidized by CI or FADH2 is oxidized by CII.
- There are also other dehydrogenase enzymes that can oxidize FADH2 and
donate it to the Q10 pool.
- After Q10 receives electrons, and is thus reduced, it transfers the electrons to
CIII.
- CIII then transfers the electrons to cytochrome c which then transfers the
electrons to CIV. Finally, CIV transfers the electrons to oxygen (it's the final
electron acceptor) and water is formed.
- As electrons move through CI, CIII and CIV, the decrease in redox potential is
linked to the transfer of protons (H+) through these complexes. These three
complexes act as proton pumps.
- So protons are pumped out of the mitochondrial matrix into the
intermembrane space and this causes there to be an electrochemical gradient
across the inner mitochondrial membrane.
- It consists of a pH gradient (ΔpH) and a membrane potential (ΔΨ). This
gradient forms potential energy - a proton driving force (Δp in mV) that causes
protons to flow back into the matrix.
- As protons flow back through a channel in CV, a part of the protein turns
(almost like wind turning a turbine).
- The mechanical movement of this rotor provides the energy needed to add
an inorganic phosphate (Pi) group to ADP to form ATP.

The OXPHOS system: Slide 15

- Mitochondria actually act like capacitors that generate a proton motive force
to produce energy.
- It can be compared to electrical circuits. In this representation, the proton
driving force is represented by the voltage across the circuit.
- The proton current is represented by the electric current and ATP synthase is
represented by a light bulb.
- An uncoupling protein is represented by a low-resistance wire that creates a
short circuit. In coupled mitochondria, protons flow back to the matrix through
CV, while that energy is coupled to ADP and Pi, producing ATP.
- So the circuit is complete, current flows (respiration takes place), ATP is
synthesized and the proton motive force (Δp) decreases slightly due to
'internal resistance'.
 - In uncoupled mitochondria, protons flow back to the matrix through
uncoupling proteins, so proton flow is uncoupled from OXPHOS and the
energy generates heat instead of ATP.
- A low-resistance short circuit occurs, the maximum current flows (respiration
occurs), but energy is lost as heat, and the potential (Δp) drops close to zero

The OXPHOS system: Slide 16

- This proton-motive force that creates the respiratory chain plays a central role
in energy production and drives a wide variety of processes in the cell
including the production of heat, redox signals and the regulation of ion and
metabolite transport.

The OXPHOS system: Slide 17

- Mitochondria are central to many cellular processes: they produce most of the
energy (ATP) from the breakdown of nutrients (carbohydrates, fatty acids and
amino acids) through OXPHOS.
- Mitochondria produce most of our body heat, especially in brown fat, where
thermogenesis mainly takes place - here mitochondria are mostly
disconnected and the energy generated by the electron transport chain is
used to produce heat. Mitochondria produce reactive oxygen species or ROS
(free radicals).
- ROS are produced when electrons leak at respiratory chain complexes (mainly
CI and CIII) and oxygen is only partially reduced to superoxide.
- Superoxide is then converted to hydrogen peroxide (H2O2) by SOD
(superoxide dismutase), which in turn can be converted to water or a hydroxyl
radical.
- Normally, these free radicals or ROS are not a bad thing. ROS are important
signaling molecules that activate transcriptional cascades of stress resistance,
cell proliferation and differentiation pathways.
- But excessive ROS production is called oxidative stress and it can oxidize
proteins, lipids or mitochondrial DNA (mtDNA) which ultimately leads to
mitochondrial dysfunction.
- Mitochondria are also responsible for ion transport. The transport of metal
ions such as Ca2+, K+, Na+, Mg2+, Zn2+ and Fe2+/Fe3+ is important for
mitochondrial and cellular functions.
- Furthermore, mitochondria also have important anabolic and catabolic
functions that are central to the regulation of glucose, amino acid, lipid, sulfur
and metal metabolic woes. Mitochondria function as signaling organelles,
constantly communicating with the nucleus and other subcellular
 compartments to monitor and regulate the cell's energetic and metabolic
status through the modulation of various cell signaling mechanisms.
- Mitochondria also play an important role in the initiation of apoptosis or
programmed cell death. Apoptosis is a normal and important process of
development that maintains the balance between cells in the body.

The OXPHOS system: Slide 18

- To summarize, if the OXPHOS system is working healthily: sufficient ATP is
produced, there is a healthy redox balance and manageable amounts of ROS.
- Heat production and ion transport take place effectively.
- But if the OXPHOS system is deficient, there is insufficient ATP production,
which has widespread consequences in the body - as all cells require energy
to function.
- It can especially affect cells with a high energy demand such as the brain, liver,
heart and muscles.
- It can also result in redox imbalance which can lead to metabolite
accumulation as certain steps in metabolic pathways are blocked.
- This can lead to excessive ROS production which can further lead to oxidative
stress, the activation of cell signaling mechanism and oxidation of molecules.
- Furthermore, it can also lead to poorly regulated heat production and an
imbalance in ion transport, which will especially affect excitable cells such as
neurons and muscle cells.

Slide 19
The next few "deeper look" slides are important parts that you should work through
on your own to gain insight into: the effect of exercise on mitochondrial biogenesis
(that's the process where new mitochondria are produced) and our cells' capacity for
oxidative metabolism

Regulation of energy balance: Slide 23

- Next we will look at the regulation of energy balance in the body.
- An individual's nutritional status - the balance between the intake and
consumption of nutrients - affects his health and susceptibility to disease.
- Both malnutrition and overnutrition put an individual at risk.
- Our nutritional status is determined by many factors. Biological factors such
as: our genotype, digestion, absorption, metabolism and excretion of
nutrients, age and phase of life cycle.
- Psychological factors: such as desire to eat, appetite, and how tasty certain
foods are to us. Social factors: such as the availability of food and cultural
customs.
- As well as our level of physical activity and the presence of disease
Regulation of energy balance Slide 24
- Food intake is regulated by signals generated in the stomach, pancreas,
adipose tissue and brain.
- The hypothalamus of the brain is the main centre that regulates your appetite
because it converts these signals into eating behaviour.
- The brain does this by sending efferent signals through a complex network of
neuropeptides.
- The catabolic neuropeptide proopiomelanocortin (POMPC) forms
melanocyte-stimulating hormone (MSH) which stimulates reduced food
intake.
- The anabolic neuropeptide Y (NPY)/ or agouti-related peptide (AgRP)
stimulates the brainstem satiety centre.
- Corticotropin-releasing hormone (CRH) decreases food intake and increases
energy expenditure while thyrotropin-releasing hormone (TRH) increases
thermogenesis and food intake.
- High levels of ghrelin are secreted by empty or contracted stomachs and
stimulate appetite.
- When you overeat for pleasure, your reality adjusts from an empty and full
stomach to abnormal levels in the brain and this leads to an unhealthy increase
in food intake and body mass.
- High levels of insulin, secreted by the pancreas after carbohydrates are broken
down into glucose, reduce food intake and reduce glucose production by the
liver so that excess glucose can be stored in the liver as glycogen.
- Overweight and an inactive lifestyle are the major causes of type 2 diabetes,
during which cells become insulin resistant and no longer respond to insulin
as they should.
- Over time, the pancreas no longer makes enough insulin and as a result there
is also an insulin deficiency and the body cannot regulate blood glucose
levels.
- Leptin levels reflect our adipose tissue mass. How levels of leptin, which is
secreted by adipose tissue, tell the brain to stop eating and the body to
increase metabolism because there are enough energy stores.
- We can also become leptin resistant – this condition is associated with obesity,
type 2 diabetes, excessive carbohydrate intake, and high stress and cortisol
levels. With leptin resistance, the body has a weaker ability to control appetite,
despite having enough energy stores, which leads to false hunger, overeating
and obesity.
Regulation of energy balance Slide 25
- Adipocytes or fat cells play an important role in the regulation of energy
balance.
- It is important to realize that adipose tissue is an active organ - it is an
endocrine organ that monitors the energy status and produces and releases
cell signaling molecules or cytokines.
- We call these cytokines released by adipocytes adipokines and they influence
the body's metabolic and inflammatory status. The most important adipokines
are leptin and adiponectin. Both play an important role in adjusting the body's
metabolism to its energy needs because they act on the body's main energy
sensor enzyme, adenosine monophosphate or AMPK.
- Both adiponectin and leptin activate AMPK in the muscle and liver.
- Adiponectin stimulates energy-producing processes such as glucose
consumption in muscle and fatty acid oxidation in muscle and liver, while it
reduces energy-consuming processes such as glucose production in liver.
- Thus, adiponectin increases insulin sensitivity while its deficiency leads to
insulin resistance.
- Adiponectin also has anti-inflammatory properties because it down-regulates
the secretion of pro-inflammatory cytokines.
- Exercise increases adiponectin expression and its receptors in muscle, but its
levels decrease with obesity and type 2 diabetes. Leptin stimulates fatty acid
oxidation and reduces lipogenesis (fat synthesis) in liver and muscle.
- As we have already seen, leptin also tells the body that food intake must
decrease because there is enough fat stored and this is done by inactivating
AMPK in the brain

Regulation of energy balance Slide 26

- We have already mentioned that AMPK is the main sensor of cellular energy
levels.
- Its main stimulant is the increase in AMP, a product of ATP conversion.
- So when energy is used, the amount of ATP decreases and the amount of
AMP increases.
- An increased AMP/ATP ratio therefore indicates low cellular energy levels.
This activates AMPK and activated AMPK then phosphorylates rate-limiting
enzymes in energy-producing and energy-consuming pathways to activate or
inhibit them.
- The ultimate effect of AMPK activation is the inhibition of energy-consuming
pathways such as lipogenesis or cholesterol synthesis and the stimulation of
energy-generating pathways such as glycolysis and fatty acid oxidation
Regulation of energy balance Slide 27
- The body's total daily energy consumption or TDEE = is the total amount of
calories you burn in a day.
- And it is basically the sum of our basal metabolic rate, heat production and
physical activity. To calculate TDEE we look at the sum of the BMR, the thermic
effect of food (TEF), non-exercise activity thermogenesis (NEAT), and the
thermic effect of physical activity (TEA).
- As you already know BMR is the energy used during total rest to keep you
alive - this includes things like maintaining body temperature, transport of
molecules across membranes and growth processes.
- TEF= is the energy used to digest, absorb and use or store food you have
eaten in the body.
- NEAT =is the energy used to do physical activity that is not sport or exercise,
such as walking, typing, cleaning the house, cooking etc.
- TEA= is the amount of energy used during exercise or sport.
- Physical activity is the most important component of the TDEE that we can
control and that varies greatly between individuals.
- In table 22.1 you can see the difference in the amount of energy used to do
different types of physical activities, watching TV does not use much energy,
but climbing stairs or going for a bike ride uses a lot.
- The energy we need daily increases from birth to age 18, after which the
amount of energy we need starts to decrease.
- So for us to maintain a healthy energy balance, our energy intake and
consumption must be balanced.

Interplay between genetics and bioenergetics Slide 28

- In the next section we will look at the interplay between genetics and
bioenergetics.
- Energy metabolism and the subunits of the OXPHOS system are regulated by
two separate genomes.
- The mitochondrial genome which is found in the matrix of the mitochondria
and the nuclear genome which is found in the nucleus of the cell.
- Although mitochondrial DNA codes for a small number of OXPHOS subunits,
and these are then made in the mitochondrion, most OXPHOS subunits are
encoded by nuclear DNA (shown here in blue) and made in the cytoplasm and
then to the mitochondria transport
Interplay between genetics and bioenergetics Slide 29
- How are these two genomes - the nuclear and mitochondrial DNA - different.
- The nuclear DNA is much larger than the mitochondrial DNA, it consists of
about 3.2 billion base pairs and there are two alleles for each gene while the
mitochondrial genome consists of just over 16 thousand five hundred base
pairs.
- Nuclear DNA consists of 23 pairs of linear chromosomes while mitochondrial
DNA consists of many copies of circular chromosomes.

Interplay between genetics and bioenergetics Slide 30

- In the picture, these differences are clearly visible. We find nuclear DNA in the
nucleus of the cell, there is one set of nuclear DNA that consists of 23 pairs of
chromosomes.
- Each chromosome is a twisted piece of linear DNA. Mitochondrial DNA is
found in the matrix of mitochondria, the DNA forms a circle and there are
many copies of this circular DNA in each mitochondria

Interplay between genetics and bioenergetics Slide 31

- During conception, only nuclear DNA, and not mitochondrial DNA, is
transferred from a sperm cell to an egg cell, so nuclear DNA is inherited from
both parents, but our mitochondrial DNA only comes from our mother.
- Nuclear DNA codes for over 20 thousand genes, of which more than 2
thousand code for molecules involved in energy metabolism.
- Mitochondrial DNA codes for just 37 genes, of which 13 are structural proteins
involved in the OXPHOS system.
- DNA can be damaged or errors can occur during DNA transcription. Nuclear
DNA has thorough safeguards, repair and proofreading mechanisms that
ensure that damage and errors are corrected.
- But these mechanisms are not as abundant in the mitochondria and
consequently mitochondrial DNA has a much higher mutation rate than
nuclear DNA. DNA recombination and epigenetics occur in nuclear DNA, but
not in mitochondrial DNA.
- Mutations in nuclear DNA are mostly neutral and less frequently cause harmful
mutations where gene products are not produced at all or do not function at
all.
- Mitochondrial DNA mutations more often result in scalar or functional
mutations.
- When we look at populations around the world, we don't really see a big
difference in the nuclear DNA sequence between populations - but there are
differences in the frequency at which certain alleles occur.
 - In mitochondrial DNA we see large differences in DNA sequences between
populations.
- Groups of individuals who have the same mitochondrial DNA sequence
variations or haplotype are called a haplogroup and these haplogroups can
be linked to a specific geographical location and common ancestor in the
maternal line.
- Mitochondrial DNA can adapt vining to a changed energy environment
because sequence variation occurs relatively vining, while sequence variation
occurs quite slowly in nuclear DNA.

Interplay between genetics and bioenergetics: Slide 32

- Humans were originally adapted to specific energy environments, which have
now changed, but the human genome has remained relatively unchanged.
- A general increase in daily energy intake and energy density (kJ/g) of the
food we eat leads to overnutrition.
- Less exercise and physical activity also lowers the oxidative capacity of
skeletal muscles and reduces mitochondrial biogenesis - so it lowers the
production of mitochondria and OXPHOS components.
- Together, increased energy supply and decreased physical activity shifted our
metabolism away from oxidative phosphorylation and toward anaerobic
glycolysis.
- Consequently, the incidence of oxidative stress, DNA mutations, OXPHOS
and mitochondrial dysfunction increases. And it increases our susceptibility to
metabolic diseases.

Associations of human diseases with bioenergetics: Slide 33

- Our diet and lifestyle have a profound effect on our health and susceptibility
to disease. This shift away from oxidative metabolism led to the occurrence of
modern diseases - also called metabolic syndrome where bioenergetics are
involved.
- You will learn about this in the next study unit.
- The Global Nutrition Report recently reported that although some of the
world's population suffers from malnutrition and starvation, the majority of the
population suffers from overnutrition and obesity-related diseases.

Associations of human diseases with bioenergetics: Slide 34

- Some of the most common of these modern diseases involving bioenergetics
include type 2 diabetes, cardiovascular disease and cancers.
- All of these are linked to changes in lifestyle and energy status. mtDNA
mutations are also associated with several "common" diseases such as cancer,
 neurodegenerative diseases (such as Alzheimer's and Parkinson's) and
diabetes.
- In the African population, there has also been a dramatic increase in
cardiometabolic diseases (~70% of the population) and this has to do with
rapid urbanization and the associated change in lifestyle, diet and increased
stress.
- There is also likely to be a genetic predisposition to cardiometabolic diseases
in this population, which includes genes involved in energy metabolism. We
refer to such disease states as congenital metabolic defects

Associations of human diseases with bioenergetics: Slide 35

- Congenital metabolic defects are a large group of rare, genetic diseases in
which the body cannot properly convert food into energy.
- These diseases are caused by DNA mutations that affect proteins or enzymes
involved in the breakdown or breakdown of nutrients such as carbohydrates,
fatty acids or proteins.
- Inborn metabolic defects usually lead to blockages in metabolic pathways
and the toxic accumulation of metabolites above the point of blockage.
- Although the diseases are individually very rare, as a group they are quite
common.
- Here at the Centre for Human Metabolomics we have the Potchefstroom
laboratory for congenital metabolic diseases or PLIEM. They can test for more
than 700 different congenital metabolic defects.
- Here you can look at which defects have already been observed in the South
African population. For many of these defects, dietary adjustments are the
treatment and if the defect is diagnosed early enough, before there is organ
damage, most patients can live long and healthy lives - that is why it is so
important that new born babies are tested.
- Go and watch the video of the New born screening that is done here.
- Diseases where the mitochondria or OXPHOS system is dysfunctional, are one
of the most common types of congenital metabolic defects.
- These diseases are extremely complex because they can be caused by a large
variety of mutations in either mitochondrial or nuclear DNA and because the
clinical images span a wide spectrum.
- The same mutation can result in vastly different clinical pictures, while different
mutations can result in the same clinical picture.
- Mitochondrial diseases can affect several organ systems or just a few organs,
symptoms can appear in early childhood or only later in life, and the severity
of the disease can also vary from moderate to fatal.
- However, in most cases the prognosis is poor and patients die in early
childhood. Unfortunately, there is also currently no effective treatment for
mitochondrial diseases.