Mitochondrial biogenesis

Mitochondrial
Biogenesis
How mitochondria influence
our health
Dr. Fathi Neana, MD
Chief of Orthopaedics
Dr. Fakhry & Dr. A. Al-Garzaie Hospital
August,21 - 2018

‫و‬ِ‫ب‬‫ا‬َ‫ن‬‫أ‬‫ع‬َ ‫أ‬‫اْل‬َ‫و‬ ِ‫ل‬‫ي‬ ِ‫خ‬َّ‫ن‬‫ال‬ ِ‫ت‬‫ا‬َ‫ر‬َ‫م‬َ‫ث‬ ‫ن‬ِ‫م‬ُ‫ه‬‫أ‬‫ن‬ِ‫م‬ َ‫ون‬ُ‫ذ‬ ِ‫خ‬َّ‫ت‬َ‫ت‬َ‫ك‬َ‫س‬‫ا‬ً‫ر‬َ‫ل‬ َ‫ك‬ِ‫ل‬ََٰ‫ذ‬ ‫ي‬ِ‫ف‬ َّ‫ن‬ِ‫إ‬ ۗ ‫ا‬ً‫ن‬َ‫س‬َ‫ح‬ ‫ا‬ً‫ق‬‫أ‬‫ز‬ ِ‫ر‬َ‫و‬ً‫ة‬َ‫ي‬
َ‫ون‬ُ‫ل‬ِ‫ق‬‫أ‬‫ع‬َ‫ي‬ ٍ‫م‬ ‫أ‬‫و‬َ‫ق‬ِِّ‫ل‬(67)‫النحل‬ ‫سورة‬

New Lifestyle diseases
Non-communicable diseases (NCDs)
• Obesity
• Metabolic syndrome
• Coronary artery disease
• Diabetes type 2
• Hypertension
• Arteriosclerosis
• Stroke
• Cancer
• Depression - anxiety
• Arthritis
• Osteomalacia
• Osteoporosis
• Swimmer's ear – loss of hearing
• Ch. obstructive pulmonary disease
• Liver Cirrhosis
• Nephritis
• Etc, etc, etc…
Emerged as bigger killers than infectious or hereditary ones.
The leading cause of death in the world.
63% of all annual deaths.
> 38 million people are killed /year.
1- Cardiovascular diseases (17.5 million)
Complications of hypertension (9.4 million)
2- Cancers (8.2 million)
3- Respiratory diseases (4 million)
5- Diabetes (1.5 million)
These 4 diseases account for 80 % of all NCDs deaths (> 38 million)
4- USA’s 4th Leading Cause of Death – Pharma’s Drugs
Posted on June 25, 2012 by Child Health Safety
Causes:
• Stress-Depression
• Diet
• Sleep-awake
• Lack of Exercise
• Sun avoidance
• Wireless WiFi devices
• Leaky gut syndrome
• Other pollutants
Including Medicines

The Root cause and Culprit behind
Chronic Diseases, Cancer and Aging
1- A state of chronic low grade
inflammation
Dr. Richard K. Bernstein
Diabetes & Inflammation—the Vicious Cycle
(Hyperglycemia – Omega 6 - Obesity) - Leukotriene B(4) (LTB(4)
Lindsay Christensen
Lindsay Christensen is a health writer and researcher with her B.S. in
Biomedical Science and an Emphasis in Nutrition
(Pathogens, unhealthy diet, lack of exercise).
2- Mitochondrial dysfunction
(not the genetic make up)
Dr. Ron Rosedale
Breakthrough views on clinical metabolic biochemistry
1- Harmful Effects of too much Sugar
->> Insulin and leptin receptor resistance
->> Free radicals (ROS) 90% Mitochondria
2- Harmful Effects of too much Protein
->> Activation of the mTOR metabolic signaling pathway
3- Physical inactivity (lack of exercise)
4- Pollutants
5- Drugs causing mitochondrial toxicity
(Iatrogenic) Mitochondrial dysfunction
Energy (ATP - ADP)
Leukotriene B(4) (LTB(4)
acts as a signal to relay
information from cell to
cell over long distances.

Dr Josef mercola:
I never learned anything about the root cause of chronic disease
in med school
Surprisingly, my seven years of medical school and family
practice residency never addressed the root cause of common
chronic illness.
All I was taught was how to manage symptoms through the use
of pharmaceuticals and medical procedures.
Then, in 1995, my understanding of chronic disease took a
quantum leap. I was introduced to Dr. Ron Rosedale and his
breakthrough views on clinical metabolic biochemistry.
What I Learned in 1995 Forever Shaped My View on Cancer and
Chronic Disease
Cancer Is One of the Most Manageable Diseases “Once we realize
that cancer is a metabolic disease
The Root cause and Culprit behind Chronic Diseases, Cancer and Aging
Clinical metabolic biochemistry - breakthrough

1- Our body’s lifeline.
2- Mitochondria are tiny organelles in our cell,
thousands of them comprising 15 to 50% of the cell
volume. Red blood cells and skin cells have very little
to none, while germ cells have 100,000, but most cells
have one to 2,000 of them.
3- They're the primary source of energy for our body.
They supply over 90% of our body’s energy
4- Converting the food we eat and the air we breathe
into usable energy.
The Mitochondria
How Your Mitochondria Influence Your Health
January 24, 2016
5- It have enormous potential to influence our health, specifically cancer, and optimizing
mitochondrial metabolism may be at the core of effective cancer treatment
6- Important nutrients and co-factors for mitochondrial function include:
all B vitamins, magnesium, omega-3 fat, CoQ10, acetyl L- carnitine, D-ribose, and alpha-
lipoic acid. Exercise is also important for mitochondrial health and function

AIR
O2
FUEL
Carb-Protein-Fat
How the human life is maintained
WATER
﴾ٍِّ‫ي‬َ‫ح‬ ٍ‫ء‬‫أ‬‫ي‬َ‫ش‬ َّ‫ل‬ُ‫ك‬ ِ‫اء‬َ‫م‬‫أ‬‫ل‬‫ا‬ َ‫ن‬ِ‫م‬ ‫ا‬َ‫ن‬‫أ‬‫ل‬َ‫ع‬َ‫ج‬َ‫﴿و‬[‫اْلن‬ ‫سورة‬‫الية‬ ‫بياء‬:30]
And We have made from water every living thing.
ENERGY
Waste (ROS)
Free radicals
Control system
(Signaling pathway - Feed back) - Nervous – Hormonal – Enzymatic

Acetic acid acetyl group, derived from
acetic acid, is fundamental to the
biochemistry of virtually all forms of life.
When bound to coenzyme A it forms
acetyl-CoA
The citric acid cycle is a key metabolic pathway that unifies carbohydrate, fat, and protein metabolism. The reactions of
the cycle are carried out by 8 enzymes that completely oxidize acetate, in the form of acetyl-CoA
ِ‫ب‬‫ا‬َ‫ن‬‫أ‬‫ع‬َ ‫أ‬‫اْل‬َ‫و‬ ِ‫ل‬‫ي‬ ِ‫خ‬َّ‫ن‬‫ال‬ ِ‫ت‬‫ا‬َ‫ر‬َ‫م‬َ‫ث‬ ‫ن‬ِ‫م‬َ‫و‬ُ‫ه‬‫أ‬‫ن‬ِ‫م‬ َ‫ون‬ُ‫ذ‬ ِ‫خ‬َّ‫ت‬َ‫ت‬
‫ا‬ً‫َر‬‫ك‬َ‫س‬ََٰ‫ذ‬ ‫ي‬ِ‫ف‬ َّ‫ن‬ِ‫إ‬ ۗ ‫ا‬ً‫ن‬َ‫س‬َ‫ح‬ ‫ا‬ً‫ق‬‫أ‬‫ز‬ ِ‫ر‬َ‫و‬‫أ‬‫ع‬َ‫ي‬ ٍ‫م‬ ‫أ‬‫و‬َ‫ق‬ِِّ‫ل‬ ً‫ة‬َ‫ي‬ َ‫ل‬ َ‫ك‬ِ‫ل‬َ‫ون‬ُ‫ل‬ِ‫ق‬
(67)‫النحل‬ ‫سورة‬
‫وسلم‬ ‫عليه‬ ‫هللا‬ ‫صلى‬ ‫قال‬:(َ‫خ‬‫ال‬ ُ‫م‬‫دا‬ِ‫اإل‬ َ‫م‬‫أ‬‫ع‬ِ‫ن‬ُّ‫ل‬)
‫مسلم‬ ‫رواه‬(2051)
‫الكحو‬ ‫ل‬ ّ‫تحو‬ ‫توضح‬ ‫التالية‬ ‫الكيميائية‬ ‫المعادلة‬‫إلى‬ ‫ل‬
‫األكسجين‬ ‫غاز‬ ‫مع‬ ‫بالتفاعل‬ ّ‫ل‬‫خ‬:
CH3CH2OH + 2 O2 --- >
2 CH3COOH + 2 H2O
Alcohol + Oxygen ---->
Acetic Acid + Water
‫كحول‬+‫أوكسجين‬----->‫حمض‬‫الخل‬+‫ماء‬
Mitochondria
CoA
How the human life is maintained

To produce energy, mitochondria require oxygen from the air we
breathe and fat and glucose from the food we eat.
Breathing and eating — are coupled together in a process called
oxidative phosphorylation. That's what the mitochondria use to
generate energy in the form of ATP.
Mitochondria have a series of electron transport chains. The
electrons pass from the reduced form of the food to combine
with oxygen from the air and ultimately to form water.
How Mitochondria Produce Energy
This process drives protons across the mitochondrial membrane, which recharges ATP (adenosine
triphosphate) from ADP (adenosine diphosphate). ATP is the carrier of energy throughout your body.
That process also produces byproducts such as reactive oxygen species (ROS), which are damaging to
cells, and mitochondrial DNA, which are then transferred to nuclear DNA.
Our body also ages from the damaging aspects from the ROS that are generated.
How quickly our body ages largely depends on how well our mitochondria work, and how much damage

Cancer as a metabolic disease:
Cancer cells, however, are resistant to this suicide protocol, (apoptosis). and have a built-in defense
against it (explained by Dr. Warburg and subsequently by Thomas Seyfried)
"One of the mechanisms by which chemotherapeutic drugs work is they create reactive oxygen species
ROS. They create damage, and that's enough to push that cancer cell to die. (explained by Patrick)
Cancer cell — which is not using its mitochondria, (using sugar – fructose). not producing those
reactive oxygen species ROS any longer
All of a sudden forcing it to use its mitochondria (cut off sugar) we get a burst of reactive oxygen
species ROS that's what mitochondria do, and boom, death, because that cancer cell is already primed
for that death. It's ready to die.”
Mitochondria's Role in Cancer
When cancer cells are present, the reactive oxygen
species ROS produced as a byproduct of ATP production
normally send a signal that sets in motion a process of
cellular suicide, also known as apoptosis.
By killing off damaged cells, the body can eliminate and
replace them with healthy cells.

One of the universal characteristics of cancer cells is they have serious mitochondrial dysfunction with
radically decreased numbers of functional mitochondria.
"The mitochondria can still function in cancer cells. But [cancer cells] immediately become dependent
on glucose and they're not using their mitochondria even though they have mitochondria there. They
make this metabolic switch," Patrick says.
ketogenic diet, forces cancer cells to use its mitochondria (cut off sugar) with a burst of reactive
oxygen species ROS.
ketogenic diet which radically improves mitochondrial health, could help most cancers, especially if
used in conjunction with glucose fermentation poisons like 3-bromopyruvate.
In order for our organs to function properly, they require energy, and that
energy is produced by the mitochondria.
Since mitochondrial function is at the very heart of everything that occurs in
our body,
Optimizing mitochondrial function - and preventing mitochondrial dysfunction
by get ting all the right nutrients and precursors our mitochondria need - is
extremely important for health and disease prevention.
Mitochondria's Role in Cancer
Dr. Otto Warburg was a physician with a Ph.D. in chemistry and was close friends with Albert Einstein.
Most experts recognize Warburg as the greatest biochemist of the 20th century.
He received a Nobel Prize in 1931 for his discovery that cancer cells use glucose as a source of energy production. This is called
the "Warburg Effect" and, sadly, to this day it is essentially ignored by nearly every expert.

Mitochondrial Fuel
Which Fuel You Burn In Your Mitochondria for Energy Determines How Long Your Mitochondria Last
and That Determines How Long You Live!
Just As Gasoline Engines Run Best With Gasoline and
Not Diesel or Aviation Fuel, So Too,
Our Mitochondrial Cellular Engines Run Best With Fat
As Fuel, Instead of Sugar!
According to Dr. Ron Rosedale - “If I were to summarize in a single sentence what practice
would best promote health, it would be this”:
“Health and life span are determined by the proportion of fat versus
sugar people burn throughout their lifetime
The more fat that one burns as fuel, the healthier a person will be,
and the more likely he or she will live a long time;
The more sugar a person burns, the more disease ridden and the
shorter a life span a person is likely to have.”
(The above sentence is perhaps the most IMPORTANT statement you will ever read in regard
to health and longevity).
The mitochondria can only burn fat or sugar for
energy. Which fuel is burned in the mitochondria for
energy determines how long the mitochondria stay in
good shape.

Creating energy, by burning fuel in the mitochondria, is necessary, but it is destructive to our
bodies, just like burning gasoline or diesel is necessary, but destructive to the engine of the
automobile.
•Burning fat in the mitochondria produces more energy than does burning sugar.
•Fewer free radicals are released when burning fat than when burning sugar
•However, burning sugar is very fast compared to burning fat, and so, sugar burning is very
USEFUL DURING TIMES OF EMERGENCY.
You could almost say that our cells were designed to burn sugar only temporarily in times of
great exigency, when the damage from free radicals is not as important as dealing with the
emergency
If our bodies had been designed to primarily burn sugar as a fuel, then we would store sugar
cubes within our bodies, but we don’t, we store fat. We store only minor amounts of sugar
(in the form of glycogen) — enough to last for 30 to 60 minutes of emergency exertion.
Main Mitochondrial Fuel Concept
Fat is the Best Fuel

The Hypothalamus Sends Signals to the Body
Instructing Fat Burning or Sugar Burning.
In Many People the Hypothalamus is
Erroneously Sending the ‘Burn Sugar Signal’
The hypothalamus is a gland in the brain that dictates to
the entire body which fuel the cells of the body are to use:
fat or sugar.
The hypothalamus decides which mode to put the body in
based on the amount of leptin it can measure in the body.
A great number of people’s bodies are being “forced,
unnecessarily” to burn sugar instead of fat because that
tiny hypothalamus gland believes the body is starving,
and, therefore, sends a signal to the cells of the body that
sugar should be burned instead of fat (in order to conserve
fat).
This is unnecessarily causing the mitochondria
to “deteriorate faster”.
Why Does the Hypothalamus Unnecessarily Force a Sugar
Burning Mode in Our Bodies?
One of the most important functions of the
hypothalamus is to link the nervous system to
the endocrine system via the pituitary gland.
Thehypothalamus is located below the
thalamus and is part of the limbic system. In
the terminology of neuroanatomy, it forms the
ventral part of the diencephalon.

•Too much stored fat (Obesity).
Too much stored fat produces large amounts of circulating leptin which desensitizes the hypothalamus’s ability
to detect leptin (Leptin resistance). When leptin levels are not able to be detected, because the receptors in the
hypothalamus have been desensitized, the hypothalamus believes the body is starving and instructs sugar
burning in order to conserve and build up fat stores. This is ironic because essential the body’s pantries are full
of fat, but these pantries are inaccessible and so the cells are instructed to ignore fat and look for sugar to burn
for energy ( Craving).
There are only three reasons for the body
to be in sugar burning mode:
•Too much stress.
Stress creates the adrenal gland to relase
adrenaline. Adrenaline overrides the
hypothalamus signal and instructs sugar
burning.
•Too much blood sugar.
Blood sugar (over time) damages receptors in the
hypothalamus. When these receptors are damaged
then the hypothalamus cannot correctly sense
leptin... and believe there is no fat (i.e. starvation is
occurring).

Mitochondrial fission, fusion, and stress
Youle RJ1, van der Bliek AM.
Mitochondrial fission and fusion play critical roles in
maintaining functional mitochondria when cells
experience metabolic or environmental stresses.
Fusion helps mitigate stress by mixing the contents of
partially damaged mitochondria as a form of
complementation.
Fission is needed to create new mitochondria, but it
also contributes to quality control by enabling the
removal of damaged mitochondria and can
facilitate apoptosis during high levels of cellular
stress.
Disruptions in these processes affect normal development, and they have been
implicated in neurodegenerative diseases, such as Parkinson's

Abbreviations: ATP, adenosine triphosphate; DHPR, dihydropyridine receptor; MCU, mitochondrial calcium uniporter; MICU1, mitochondrial
calcium uptake 1; NCLX, mitochondrial sodium/calcium exchanger; mPTP, mitochondrial permeability transition pore; SR, sarcoplasmic
reticulum; RyR, ryanodine receptors; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; ROS, reactive oxygen
species.
Mitochondrial fission, fusion, and stress
Youle RJ1, van der Bliek AM.

What causes
Mitochondrial
dysfunction?

Dr. Ron Rosedale : Defective metabolic processes in mitochondria, not the genetic make up That
cause cancer and nearly all other chronic diseases, including accelerated aging
What causes Mitochondrial dysfunction?
The causes of Defective metabolic processes in mitochondria ?
1- The Harmful Effects of too much Sugar
A- Diet (HCLF)
Insulin and leptin receptor resistance
Free radicals (ROS) 90% Mitochondria
B- Stress.
Adrenaline – hypothalamus ->> sugar
C- Obesity
Leptin resistance - hypothalamus ->> sugar
2- The Harmful Effects of too much Protein
Activation of the mTOR metabolic signaling pathway
3- Lack of exercise and Physical activity

Sugar is a “dirty” fuel, excessive free radicals caused by
reactive oxygen species (ROS).
Wile fat burns much cleaner. So by replacing carbs with
healthy fats,’ mitochondria are less likely to suffer damage
90 % or more of the total ROS (Reactive oxygen species)
are produced within the mitochondria, causing devastating
damage.
It was thought excessive ROS could be addressed by taking
antioxidants, but we now know that this was a flawed
strategy and it is far better to prevent their production by
eating an optimal fuel mixture.
LCHF OR MMT 0R KD can help your cells’ mitochondria
reach the “Goldilocks” zone for producing ROS — not too
much and not too little, but just the “right” amounts for
healthy cellular and mitochondrial function.
Harmful Effects of too much Sugar
Chronic low grade inflammation - Mitochondrial dysfunction

Harmful Effects of too much Sugar
Chronic low grade inflammation - Mitochondrial dysfunction
1- State of chronic inflammation
2- Lipoprotein Oxidation & Glycation
3- Hyper insulinemia syndrome - Metabolic syndrome
-> Insulin resistance (type 2 DM)
-> increased triglycerides VLDL
->Cholesterol (small dense LDL type B particles)
4- HFCS (High-fructose corn syrup) is found in almost all types
of processed foods and drinks (Sugar: toxic, addicting, and deadly)
7- feeds” the cancer cells fructose is readily used by cancer
cells (not using mitochondria – no ROS to kill it)
8- Gaining weight (insulin and leptin signaling resistance)
9- Increases uric acid levels - risk for heart & kidney
10- Overloads and damages the liver much sugar or fructose
likened the effects of alcohol
11- Other diseases linked to metabolic syndrome include: Type
2 diabetes, Heart disease, Hypertension, Polycystic ovarian
syndrome, Lipid problems, Dementia and Alzheimer's disease

Harmful Effects
of too much
protein

Harmful Effects of too much Protein
Paleo diet
Activation of the The mammalian Target Of Rapamycin (mTOR) metabolic
signaling pathway by too much protein
The figure highlight and summarize the current
understanding of how mTOR nucleates distinct multi-
protein complexes, how intra- and extracellular
signals are processed by the mTOR complexes, and
how such signals affect cell metabolism, growth,
proliferation and survival.
mTOR function in skeletal muscle a focal point for overnutrition and exercise . A. Rivas,a Sarah J. Lessard,b Vernon G. Coffeya
aExercise Metabolism Group, School of Medical Sciences, RMIT University, Bundoora, Victoria 3083ailartsuA ,‫ز‬ The. Research Division, Joslin Diabetes
Center and Department of Medicine, Harvard Medical School, Boston, MA 02215ASU ,.‫ز‬ Corresponding author (email: vernon.coffey@rmit.edu.au) .
Published on the web 6 October 2009. . Received March 29,2009yaM detpeccA .26,2009.

Harmful Effects of too much Protein
Paleo diet
The mammalian target of rapamycin (mTOR) -
Discoveries that have been made over the last decade
phosphatidylinositol 3-kinase-related kinase family of protein
kinases. signaling pathway integrates both intracellular and
extracellular signals
The mTOR pathway serves as a central regulator of cell
metabolism, growth, proliferation and survival.
The mTOR pathway is activated during:
1- Tumor formation, angiogenesis, insulin resistance,
adipogenesis and T-lymphocyte activation etc
2- Deregulated in diseases as cancer and type 2 diabetes.
Nutrients and Exercise modify mTOR function
Growing therapeutic use of mTOR inhibitors (rapamycin and
rapalogues) in solid tumors, organ transplantation, coronary
restenosis and rheumatoid arthritis.
The figure highlight and summarize the current
understanding of how mTOR nucleates distinct
multi-protein complexes, how intra- and
extracellular signals are processed by the
mTOR complexes, and how such signals affect
cell metabolism, growth, proliferation and
survival.

Cancer is One of the Most Manageable Diseases
Once we realize that cancer is a metabolic disease
Dr Josef Mercola - 2016
We can take charge of those kinds of things , with Eating too many
sugars and carbs without fiber, along with too much protein, we ignite
a cascade of metabolic events that includes:
•Widespread inflammation and cellular damage, especially our
mitochondria, or cells’ power factories
•Faster aging and a greater risk of all cancers from the activation of
body’s most important signaling pathway mTOR from eating excess
protein
•An increase in insulin resistance that can progress to prediabetes or
Type 2 diabetes because cells have lost their ability to respond to
insulin effectively
•Overeating due to leptin resistance with loss of control over appetite
and knowing when you’re “full”
•An inability to lose weight because body is holding on to fat instead
of burning it for fuel

29
A diet low in saturated
fat 'will not prevent
heart disease or
prolong life'

30
The typical atherosclerotic plaque comprises of the lipid core and
the fibrous cap, and is the most commonly classified histologically
by the American Heart Association
Atherosclerotic plaque
Causes:
1- Endothelial damage & permeability
2- Small dense particles LDL type B
Caused by:
1- Chronic inflammation
2- Insulin – Leptin resistance
(Diet too high in sugars + Obesity)
Treat the cause is the logical
thinking:
1- Anti-inflammatory lifestyle
2- Control Insulin - Leptin resistance
Hyper insulinemia – Hyper leptinemia
(Diet too high in sugars & Obesity)

In Summary, Saturated Fats Are Healthy
Saturated fats:
•Increase your LDL levels, but they increase the
large fluffy particles that are not associated with
an increased risk of heart disease
•Increase your HDL levels. This more than
compensates for any increase in LDL
•Do NOT cause heart disease as made clear in all
the above-referenced studies
•Do not damage as easily as other fats because
they do not have any double bonds that can be
damaged through oxidation
•Serve to fuel mitochondria and produce far less
damaging free radicals than carbs
Could Eating the Right Fats Save 1 Million Lives per Year?
D. Mercola - March 06, 2016

In many epileptic patients, anticonvulsant drugs either fail adequately to control
seizures or they cause serious side effects.
An important adjunct to pharmacologic therapy is the ketogenic diet, which often
improves seizure control, even in patients who respond poorly to medications.
The mechanisms that explain the therapeutic effect are incompletely understood.
Evidence points to an effect on brain handling of amino acids, especially glutamic
acid, the major excitatory neurotransmitter of the central nervous system.
The diet may limit the availability of oxaloacetate to the aspartate aminotransferase
reaction, an important route of brain glutamate handling.
The ketogenic diet and brain metabolism of amino acids: relationship to
the anticonvulsant effect.
Yudkoff M1, Daikhin Y, Melø TM, Nissim I, Sonnewald U, Nissim I.
Annu Rev Nutr. 2007;27:415-30.
As a result, more glutamate becomes accessible to the glutamate decarboxylase reaction to yield gamma-
aminobutyric acid (GABA), the major inhibitory neurotransmitter and an important antiseizure agent.
In addition, the ketogenic diet appears to favor the synthesis of glutamine, an essential precursor to GABA.
This occurs both because ketone body carbon is metabolized to glutamine and because in ketosis there
is increased consumption of acetate, which astrocytes in the brain quickly convert to glutamine.
The ketogenic diet also may facilitate mechanisms by which the brain exports to blood compounds such as
glutamine and alanine, in the process favoring the removal of glutamate carbon and nitrogen.

Alterations in the metabolism of excitatory amino acids
and γ-aminobutyric acid (GABA) during the high-fat, low-
carbohydrate ketogenic diet. Metabolism of acetyl-CoA
generated from fats leads to high consumption of
oxaloacetate (see Fig. 1). L-Aspartate, a nonessential
amino acid, is formed by the transamination of
oxaloacetate with an amino group from glutamate.
Reduced availability of oxaloacetate along with robust
availability of αketoglutarate from high activity of the first
part of the Krebs cycle leads to low aspartate levels. It
has been hypothesized that more glutamate is thus
accessible to glutamic acid decarboxylase for production
of GABA [33]. Not all Krebs cycle intermediates are
shown in the schematic.
The brain, energy is everything. The brain needs a crapload of
energy to keep all those membrane potentials maintained - to
keep pushing sodium out of the cells and pulling potassium into
the cells.
In fact, the brain, which is only 2% of our body weight, uses 20%
of our oxygen and 10% of our glucose stores just to keep
running.
(Some cells in our brain are actually too small (or have tendrils
that are too small) to accommodate mitochondria (the power
plants). In those places, we must use glucose itself (via
glycolysis) to create ATP.)
When we change the main fuel of the brain from glucose to
ketones, we change amino acid handling. And that means
we change the ratios of glutamate and GABA.
The best responders to a ketogenic diet for epilepsy end up with
the highest amount of GABA in the central nervous system.
glutamine, an essential precursor for GABA.
If you recall, GABA is the major inhibitory neurotransmitter in the
mammalian nervous system. Turns out, GABA is made from
glutamate, which just happens to be the major excitatory
neurotransmitter. You need them both, but we seem to get into
trouble when have too much glutamate. Too much excitement in
the brain means neurotoxicity, the extreme manifestation of
which is seizures. But neurological diseases as varied
as depression, bipolar disorder, migraines, ALS, and dementia
have all been linked in some way to neurotoxicity.

1- low carb High fat Diet Regime (LCHF) –
Mitochondrial Metabolic Therapy (MMT) 2017 -
Ketogenic diet ((KD)
2- Mitochondrial Metabolic Therapy (MMT) 2017 is
Similar to a ketogenic diet (epilepsy 30-50%)
3-MMT is a high fat, moderate protein, low carb
eating plan
Unlike a ketogenic diet, it emphasizes on high-
quality, unprocessed whole foods
NB : Paleo diet consume far too much protein
Mitochondrial Biogenesis
Salvage 1- The Harmful Effects of too much Sugar

Intermittent fasting
Beside longevity and health issues, it also provide powerful cancer
prevention and treatment benefit. And the mechanism for that is related to
the effect fasting has on your mitochondria.
Reactive oxygen ROS. Some free radicals are actually good and your body
requires them to regulate cellular function, but problems develop when you
have excessive free radical production. There are two possible solutions to
this problem:
•Increase your antioxidants
•Reduce mitochondrial free radical production by calorie restriction .
This is one of the reasons why intermittent fasting works, as it limits the
window that you are eating and automatically reduces your calories.
It is particularly effective if you avoid eating several hours before going to
sleep as that is your most metabolically lowered state.
A review paper1 that provides much of the experimental work for the above explanation was published
in 2011, titled "Mitochondrial DNA Damage and Animal Longevity: Insights from Comparative Studies.”
Interventional strategy
where in individuals are
subjected to varying periods
of fasting.

Interventional strategy where in
individuals are subjected to varying
periods of fasting.
Other Ways Fasting Promotes Healthy Mitochondrial Function
Our body has to rely on lipids and stored fats for energy, which means our
cells are forced to use their mitochondria. mitochondria are the only
mechanisms by which our body can make energy from fat. So, fasting
helps activate our mitochondria.
This is the mechanism by which intermittent fasting and a ketogenic diet
may kill cancer cells, and why certain drugs that activate mitochondria can
kill cancer cells. It creates a burst of reactive oxygen species ROS, the
damage from which tips the scale and causes the cancer cells to die.
Our body also clears away damaged cells through a process called autophagy, which basically means
when a cell that's damaged, it can die. But if it doesn't die, sometimes it becomes what's called
senescent and this happens a lot with aging. What that means is that the cell is not dead but it's not
really alive either. It's not doing its function.
It's just kind of sitting around in your body secreting pro-inflammatory molecules, things that are
damaging other nearby cells thereby accelerating the aging process because inflammation drives
aging in so many different ways.
Autophagy clears away those cells that are just sitting there creating damage and not doing much else,
which is nice because that's also a very important biological mechanism for staying healthy."

Overcoming too much stress.
Reducing stress is the antidote to adrenaline causing sugar burning. To do so, one
must eliminate fear, anxiety, and/or sleep deprivation. Sleeping sufficiently,
meditation and eliminating causes of stress are the keys.
Reducing blood sugar.
The best way to reduce blood sugar is to drastically reduce one’s consumption of
foods that contain sugar and other carbohydrates. The absolute best way to prevent
sugar fluctuations is to eat 5 to 6 small meals per day (every 2 to 3 hours), of non
sugar/carbohydrate containing foods.
Overcoming Leptin Insensitivity.(Obesity)
Overcoming leptin insensitivity (i.e. repairing the hypothalamus) isn’t so easy. The
rather long explanation of why it isn’t so easily overcome is that the bodies of sugar
burning people (primarily fat people) have large pantries of stored fat which creates
large amounts of the messenger molecule leptin which will push the leptin levels
above 9.0 ng/ml and damage the receptors. After a while, the hypothalamus cannot
detect leptin at all and thinks that its level is zero, and therefore, instructs sugar
burning mode. In a sugar burning mode, it is difficult to entice the body to burn fat
stores and therefore very difficult to get rid of fat so that leptin levels will go down to
a “fat burning”range of between 4.0 and 9.0. For a fairly in-depth discussion about
doing this, please request our Becoming Leptin Sensitive Booklet.

Managing Your Mitochondria, By Mark Sisson October
20, 2011
The single most fundamental – and simple – way to improve
mitochondrial function is to turn away from relying on sugar-
burning and transform yourself into a fat-burning beast.
See, mitochondria burn fatty acids cleaner than they burn carbohydrates. Generating ATP
via fats/ketones produces fewer free radicals, because it’s more efficient, whereas generating ATP via carbs
produces more. As a result, glutathione can do its job and our ketone-burning mitochondria have to divert less
attention to cleaning up free radicals. This doesn’t just make mitochondrial ATP production from ketones more
efficient; it has the potential to render it downright anti-inflammatory, too. When we dip into a full-fledged
ketogenic diet, cut back on bad carbs, or intermittently fast, we are switching over to fat-burning. When we
switch over to fat-burning, our mitochondria do the same. Heck, that’s what we mean by “fat-burning.” There’s
even evidence that ketosis can spur mitochondrial biogenesis, albeit thus far only in rats.
In my new book I present my Primal prescription for becoming a fat-burning beast. In fact, one of the reasons I
wrote the 21-Day Total Body Transformation is because untold millions of people are languishing in sugar-
burning land and their mitochondria aren’t burning quite as cleanly as they could. The “transformative” aspect of
the 21-Day Total Body Transformation is the epigenetic switch from sugar-burning to fat-burning. And improving
mitochondrial function and (if that rat study pans out in humans) increasing mitochondrial biogenesis are at the
heart of this switch.

Salvage 2- The Harmful Effects of too much Protein
Mitochondrial Metabolic Therapy (MMT) 2017
is a high fat, moderate protein, low carb eating plan
Unlike a ketogenic diet, it emphasizes on high-quality,
unprocessed whole foods
Unlike Paleo diet consume far too much protein
The mammalian target of rapamycin (mTOR) pathway is Central
regulator of cell metabolism, growth, proliferation and survival.

Salvage 3- Lack of exercise and Physical activity
Exercise Helps Keep Our Mitochondria Young
Exercise
Promotes mitochondrial health, as it forces your mitochondria to work harder. one of the
side effects of mitochondria working harder is that they're making reactive oxygen
species ROS , which act as signaling molecules. One of the functions they signal is to
make more mitochondria. So, when you exercise, your body will respond by creating
more mitochondria to keep up with the heightened energy requirement.
Aging
Is inevitable. But your biological age can be quite different from your chronological age,
and your mitochondrial health have a lot to do with your biological aging.
As noted by Patrick, "youthfulness" is not so much about your chronological age, but rather how old you feel, and
how well your body works:
"I want to learn how to optimize my own cognitive performance and my athletic performance. I want to also
increase the youthful part of my life. I want to be 90. I want to be out there, surfing in San Diego just like I was
when I was 20. I would like to not degenerate as rapidly as some people do. I like to stave off that degeneration
and extend the youthful part of my life as long as I possibly can so I can enjoy life."

Role of Regular Physical Exercise
A- Burn of fat
(as MMT & Ketogenic diet)
B- Improve insulin sensitivity
(depleting glycogen & fat stores)
C- Peak rise of hormones
Human growth hormone(HGH-GH) – Endorphins ,
Dopamine, Norepinephrine, Serotonin) - exercise
intensity
D- Mitochondrial Biogenesis

Exercise is one of the most powerful signals for PGC 1-
alpha
A protein encoded by PPARGC1A gene (Peroxisome proliferator-
activated receptor gamma coactivator 1-alpha (PGC-1α) )
PGC 1-alpha, which is the primary signal for
Mitochondria to Reproduce and Multiply, a process
called Mitochondrial biogenesis
PPARGC1A
(PGC-1α( is a protein encoded by the PPARGC1A gene. known as human accelerated
region 20 (HAR20).
PGC-1α is a transcriptional co activator that regulates the genes involved in energy
metabolism. It is the master regulator of mitochondrial biogenesis.

PPARGC1A
PGC-1α activating host factors
1- Free Radicals
Reactive oxygen species (ROS) and reactive nitrogen species (RNS),
both formed intracellularly as by-products of metabolism but
upregulated during times of cellular stress.
2- Cold Exposure
adaptive thermogenesis
3- Endurance Exercise
PGC-1α determines lactate metabolism, preventing high lactate levels
in endurance athletes & making lactate as an energy source
plays a central role in the regulation of cellular energy metabolism. It stimulates 1- mitochondrial biogenesis 2- promotes the
remodeling of muscle tissue to a fiber-type that is metabolically more oxidative and less glycolytic in nature
It participates in the regulation of both carbohydrate & lipid metabolism.
It is involved in obesity, diabetes, & cardiomyopathy.

Exercise (Mitochondrial Biogenesis) for
Cutting Cancer Risk
The mammalian target of rapamycin (mTOR) -
Discoveries that have been made over the last decade
The mTOR pathway is Central regulator of cell
metabolism, growth, proliferation and survival.
Nutrients and Exercise modify mTOR function
1- Activated during tumor formation, angiogenesis, insulin resistance, adipogenesis and T-lymphocyte activation etc
2- Deregulated in diseases as cancer and type 2 diabetes.
3- Growing therapeutic use of mTOR inhibitors (rapamycin and rapalogues) in solid tumors, organ transplantation,
coronary restenosis and rheumatoid arthritis.

Exercise slashed the risk of cancer in
13 out of the 26 cancers
for example
Kidney cancer by (23 %)
Lung cancer by (26 %)
Liver cancer by (27 %)
Esophageal adenocarcinoma by (42 %)
Large Study 2016 Underscores Value of Exercise for Cutting Cancer Risk
Journal of the American Medical Association Internal Medicine 2016; 176(6): 816-
825=
The research involved a mega-pool of
1.44 million men and women from a dozen
large European and U.S.
prospective cohort studies (groups of
participants who’d been followed for
several years).
Participant age, body mass index, gender,
self-reported data on exercise, smoking
status and, if applicable, any cancer
diagnoses, were analyzed to determine
the effect exercise had on various
cancers.
A total of 186,932 primary cancers were
diagnosed during the follow-up period,
which had a median length of 11 years.
Regardless of the person’s weight or
smoking history, the data suggested
physical activity cut their risk of cancer.

Salvage 4- Feeding Your Mitochondria
The following nutrients; co-factors needed for mitochondrial enzymes to
function properly:
•CoQ10 or ubiquinol (the reduced form)
•L-Carnitine, which shuttles fatty acids to the mitochondria
•D-ribose, which is raw material for ATP molecule
•Magnesium
•Omega-3 fatty acids
•All B vitamins, including riboflavin, thiamine, and B6
•Alpha-lipoic acid (ALA)
Get as many micronutrients as you can from whole foods

Mitochondrial biogenesis

Recomendados

Recomendados

Más contenido relacionado

La actualidad más candente

La actualidad más candente (20)

Similar a Mitochondrial biogenesis

Similar a Mitochondrial biogenesis (20)

Más de fathi neana

Más de fathi neana (20)

Último

Último (20)

Mitochondrial biogenesis

Notas del editor