The Mitochondrial Factor Open Release

The Mitochondrial Factor:
Key to Wellness
Andrew S. Bonci, BA, DC
Private Practice
Mission, Kansas
www.drbonci.com
A Special Thank You
And All
of You!
Missouri State Chiropractic Association
Dr. Robert Riley
Dr. Ron Manfredi
Dr. Russell Matthias
Dr. Doran Nicholson
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Get the Notes

Obtenga las Notas
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Disclosures
I work for NO special interest or
lobbying groups nor do I receive
stipends, consulting fees, gratuities
or honoraria from any
pharmaceutical or nutritional
companies.
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Most Humble Dedication
When I sing to make you dance

I truly know why there is music in leaves,
and why waves send their chorus of voices
to the heart of the listening earth.
Rabindranath Tagore
1913 Nobel Laureate; Literature
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Most Humble Acknowledgment

Warburg and co-workers
showed in the 1920s that,
under aerobic conditions, tumor
tissues metabolize
approximately tenfold more
glucose to lactate in a given
time than normal tissues, a
phenomenon known as the
Warburg effect.
Otto Heinrich Warburg

(1883-1970)
Nat Rev Cancer. 2011 May;11(5):325-37.
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Objectives
Review the Microscopic Anatomy,

Bioenergetics and Epigenetic Roles of the
Mitochondria
Understand the Influence Mitochondria Play
on Health Maintenance and Disease
Prevention
Discuss Nonpharmacologic Approaches to
Support Ideal Mitochondrial Function such as
Diet, Supplementation and Exercise.
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The key to growth is the introduction of

higher dimensions of consciousness into our
awareness.
~Lao Tzu~
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Minding My Own Business
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And He Says ...

It is well documented that
tumorigenicity can be
suppressed when cytoplasm
from enucleated normal
cells is fused with nucleated
tumor cells to form cybrids.
Seyfried, Thomas (2012-05-17T16:00:00+00:00). Cancer as a

Metabolic Disease: On the Origin, Management, and Prevention of
Cancer (Kindle Locations 5097-5099). Wiley Publishing. Kindle
Edition.
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Cybrids contain a single

nucleus and mixtures of
cytoplasm from two different
cells.
Edition.
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The Secret of Cybrids
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Suppression of Malignant State

Israel and Schaeffer In Vitro Cell Dev Biol. 1987;23:62732. showed that
suppression of the malignant state could reach 100% in
cybrids containing normal cytoplasm and tumorigenic
nuclei.
Seyfried, Thomas. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer (Kindle Locations 51065107). Wiley Publishing. Kindle Edition.
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Nuclei Ain't Nothin'

Israel and Schaeffer In Vitro Cell Dev Biol. 1988;24:48790. also showed that
nuclear/cytoplasmic hybrids derived by fusion of
cytoplasts from malignant cells (nucleus absent) with
karyoplasts from normal cells (nucleus present) produced
tumors in 97% of the animals injected.
Seyfried, Thomas. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer (Kindle Locations 51085109). Wiley Publishing. Kindle Edition.
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Whiskey Tango Foxtrot?

It is also well documented
that nuclei from cancer cells
can be reprogrammed to
form normal tissues when
transplanted into normal
cytoplasm despite the
continued presence of the
tumor-associated genomic
defects in the cells of the
derived tissues.
Edition.
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It's About the OxPhos

Normal mitochondria ...
suppress tumorigenesis
because their OxPhos is
sufficient for maintaining
energy homeostasis.
Seyfried, Thomas. Cancer as a Metabolic Disease: On the Origin,

Management, and Prevention of Cancer (Kindle Locations 52015202). Wiley Publishing. Kindle Edition.
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The Differentiated State

Respiration is required for
the emergence and
maintenance of
differentiation, while loss of
respiration leads to
glycolysis, dedifferentiation,
and unbridled proliferation.

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Hello! Is anyone listening?

Replacement of damaged
mitochondria with normal
mitochondria, which will
produce sufficient energy
through respiration, restores
the differentiated state.

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One More Time Hello?

In rephrasing, normal
mitochondrial function
maintains the differentiated
state thereby suppressing
carcinogenesis, whereas
dysfunctional mitochondria
can enhance
dedifferentiation thereby
facilitating carcinogenesis.
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Complexity is a strategy
used by professional elites
to maintain control.
Ian Roberts
The Energy Glut: The Politics of Fatness
in an Overheating World, 2010. p.90
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OxPhos = Mature State

Thus, establishment of the mitochondrial system and
engagement of oxidative metabolism are prerequisites
for the differentiation of stem cells into a functional
[cardiac] phenotype.
Nat Clin Pract Cardiovasc Med. 2007 February; 4(Suppl 1): S60S67.
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Gylcolysis = Immature State

Energy metabolism shifts from glycolysis to OxPhos
with differentiation, or from OxPhos to glycolysis
with reprogramming to pluripotency.
Cell Stem Cell. 2012 Nov 2;11(5):589-95.
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The Warburg Effect

The Warburg effect underlies the simultaneous increase
in glycolytic rate with a reduced mitochondrial respiratory
rate; a kind of mitochondrial dysfunction that is found in
tumor metabolic reprogramming pathways.
Antioxid Redox Signal. 2012 May 15;16(10):1150-80.
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Crabtree Effect
Cancer cells have also been shown to be different from
normal cells by reversibly down-regulating their oxygen
consumption in response to increases in glucose: the
Crabtree effect. PLoS One. 2013; 8(2): e56884.
Increasing concentrations of glucose accelerates
glycolysis (the breakdown of glucose) which results in the
production of appreciable amounts of ATP through
substrate-level phosphorylation. This reduces the need of
oxidative phosphorylation done by the TCA cycle via the
electron transport chain and therefore decreases oxygen
consumption. http://en.wikipedia.org/wiki/Crabtree_effect
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Joshua Lederberg, PhD

The impediment to real
discourse in academic
communities is the
tendency to proclaim what
we know more than what
we seek.
Joshua Lederberg, PhD

Nobel Prize Laureate Physiology and Medicine
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The Gray Scale of Disease

If it is true that a
completely dysfunctional
mitochondrial set results in
cancer, then is it possible
that a partially or
incompletely dysfunctional
mitochondrial set could
result in any of the wide
spectrum of diseases we
see associated with
genome instability or
bad genes?
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Getting Reacquainted
The word mitochondrion comes from

the Greek , mitos, i.e. "thread",
and , chondrion, i.e. "granule".
https://en.wikipedia.org/wiki/Mitochondrion
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Endosymbiotic Theory
The mitochondria are the product of a symbiosis
between two micro-organisms that occurred
about two billion years ago.
The nature of the original partner organisms is
actively debated, but the progenitor of the
mitochondrion is thought to have been an alphaproteobacterium that harboured a complete
OxPhos system.
Philos Trans R Soc Lond B Biol Sci. 2013 July 19; 368(1622): 20120267.
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Of Mitochondria and Chloroplasts

The endosymbiotic theory of mitochondrial
origin was substantiated with microbiological
evidence by Lynn Margulis in 1967. J Theor Biol. 1967
Mar;14(3):255-74.
Andreas Schimper (1883) that chloroplasts

closely resembled free-living cyanobacteria.
http://en.wikipedia.org/wiki/Endosymbiotic_theory
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Benefits of Symbiosis
A single bacterial cell can generate only enough energy
to sustain about 10,000 genes.
When the host cell acquired multiple oxidative bacteria,
the bacterial energy could be pooled to provide the
required energy for adding more genes to the host cells
DNA to create more complex anatomical structures.
Philos Trans R Soc Lond B Biol Sci. 2013 July 19; 368(1622): 20120267.
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Genome Expansion
By enabling oxidative phosphorylation across a wide
area of internal membranes, mitochondrial genes
enabled a roughly 200,000-fold rise in genome size
compared with bacteria.
Nature. 2010 Oct 21;467(7318):929-34.

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Costs of Gene Expression

Whereas the energetic cost of possessing genes is
trivial (2%), the cost of expressing them as protein (75%)
is not and consumes most of the cells energy budget.
Mitochondria increased the number of proteins that a
cell can evolve, inherit and express by four to six orders
of magnitude, but this requires mitochondrial DNA.
Nature. 2010 Oct 21;467(7318):929-34.

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The Price of Complexity
Growth and replication of the nucleus is limited by

mitochondrial energy production and thus calorie
availability. Mitochondrion. 10(1): 12-31.
Without mitochondria, [ cells ] cannot pay the energetic
price of complexity. Nature. 2010 Oct 21;467(7318):929-34.
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Mitochondria are of
Female Origin
The female oocyte (egg

cell) will pass on more than
100,000 mitochondria to
the next generation; sperm
cells typically possess less
than 100 mitochondria.
Evans, Joseph (2013-02-28). The Secret Life of Mitochondria
(Kindle Locations 136-138). Smashwords, Inc.. Kindle Edition.
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Whats the Significance for Us?

Well, it means to find what is the source of your own life,
and what is the relationship of your body, your physical
form, to this energy that animates it. The body without the
energy isnt alive, is it? So you distinguish in your own life
that which is of the body and that which is of energy and
consciousness.
Campbell, Joseph; Bill Moyers (2011-05-18). The Power of Myth (p. 211). Knopf Doubleday Publishing Group. Kindle Edition.
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The Giver of Forms

Its the female as the giver of forms. She is the one who
gave life to the forms and she knows where they came
from. It is from that which is beyond male and female. It
is from that which is beyond being and nonbeing. It both
is and is not. It neither is nor is not. It is beyond all
categories of thought and the mind.
Campbell, Joseph; Bill Moyers (2011-05-18). The Power of Myth (p. 226). Knopf Doubleday Publishing Group. Kindle Edition.
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A Cellular Yin and Yang
Mitochondria is the female energy and giver of forms.

Nucleus is the male energy or action and creativity.
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A Cellular Adam and Eve
Eve giver of forms

Adam consciousness ...
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A Cellular Shiva and Shakti
Shakti mitochondrial giver of forms

Shiva nuclear creative consciousness
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Power and Wisdom

is a Female Principle in
Religion, Myth and Culture.
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"I awoke, only to see the rest of

the world was still asleep."
Leonardo Davinci
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15 Pounds of Mitochondria
Adults possess approximately 10 million billion

mitochondria, which corresponds to approximately 10%
of our body weight!
Evans, Joseph (2013-02-28). The Secret Life of Mitochondria (Kindle Locations 138-139). Smashwords, Inc.. Kindle Edition.
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Mitochondrial Bioenergetics
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Mitochondrial Microanatomy
There are five distinct parts to a mitochondrion.
1. outer mitochondrial membrane
2. intermembrane space (the space between the outer
and inner membranes)
3. the inner mitochondrial membrane
4. the cristae space (formed by infoldings of the inner
membrane)
5. the matrix (space within the inner membrane)
Alberts, Bruce; Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter (1994). Molecular Biology of the Cell. New
York: Garland Publishing Inc. ISBN 0-8153-3218-1.
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Mitochondrial Outer Membrane
The outer mitochondrial membrane contains enzyme

systems for glycolysis, cardiolipin and phospholipid
synthesis.
Carolyn D. Berdanier. Mitochondria in Health and Disease CRC Press, 2005.
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Glycolysis
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Glycolysis Trivia
Glycolysis produces its energy 100 times faster than
aerobic respiration.
Glycolysis is the preferred energy source of rapidly
growing cell populations.
The early zygote becomes increasingly dependent on
glycolytic energy production as development progresses
to the blastocyst stage.
Int. J. Dev. Biol. 56: 799-808 (2012)
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Mitochondrial Matrix
The mitochondrial matrix contains enzyme
systems for the Krebs cycle and ketone
metabolism.
The matrix also anchors the mitochondrial DNA
(mtDNA).
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Citric Acid Cycle
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Mitochondrial Inner Membrane

The inner mitochondrial membrane
contains enzyme systems for partial fatty
acid oxidation and the electron transport
chain.
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NAD+/NADH
The mitochondrial
NADH is oxidized by
the electron transport
chain, which pumps
protons across a
membrane and
generates ATP
through oxidative
phosphorylation.
Biochem Soc Trans. 2003 Dec;31(Pt 6):1095105.
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FAD/FADH2
The primary biochemical role
of FADH2 in eukaryotes is to
carry high-energy electrons
used for oxidative
phosphorylation.
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Coenzyme Q10
CoQ10 functions as an electron carrier from enzyme
complex I and enzyme complex II to complex III in
this process a process which also involves
menaquinones or Vitamin K2.
Science 336, 1306 (2012)
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Cytochrome C
Cytochrome c carries an
electron in the ETC and
is also an intermediate in
apoptosis, a controlled
form of cell death used to
kill cells in the process of
development or in
response to infection or
DNA damage.
Cell. 1996 Jul 12;86(1):147-57.
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Cardiolipin: Mitochondrial-Specific Lipid

Cardiolipin is a complex, mitochondrial-specific
phospholipid that regulates numerous enzyme activities,
especially those related to OxPhos and coupled
respiration.
Seyfried, Thomas (2012-05-17T16:00:00+00:00). Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of
Cancer (Kindle Locations 2125-2129). Wiley Publishing. Kindle Edition.
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Cardiolipin:
ETC Caulking
Cardiolipin (CL) which represents 20% of membrane
phospholipids is necessary for maintaining coupled
mitochondria, and defects in CL can produce protein
independent uncoupling.
Hence, alterations in the content or composition of CL will
alter cellular respiration.
Seyfried, Thomas (2012-05-17T16:00:00+00:00). Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of
Cancer (Kindle Locations 2125-2129). Wiley Publishing. Kindle Edition.
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Mitochondrial Distribution
Mitochondria are distributed throughout the
cytoplasm in a nonrandom manner by
cytoskeleton motors.
Cells that are rapidly dividing have mitochondria
close to the nucleus and to ribosomes because
de novo protein synthesis is highly dependent on
the energy provided by ATP.
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Mitochondrial Genome
The mitochondrial genome contains 37 genes that
encode 13 proteins, 22 transfer RNAs, and 2 ribosomal
RNAs.
The 13 mitochondrial gene-encoded proteins all instruct
cells to produce protein subunits of the enzyme
complexes of the oxidative phosphorylation system,
which enables mitochondria to act as the powerhouses of
our cells.
Nature Education 1(1):217; 2008.
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mtDNA Mutations
Most pathogenic mitochondrial DNA (mtDNA) mutations

induce defects in mitochondrial oxidative phosphorylation
(OxPhos).
Epigenetics. 2012 Apr;7(4):326-34.
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ROS mtDNA Dysfunction

The mitochondrial free radical theory
postulates that aging is caused by the toxicity
of ROS, initiating a vicious cycle whereby
damage to mtDNA and other mitochondrial
constituents leads to respiratory chain
dysfunction, which in turn leads to increased
generation of ROS further facilitating mtDNA
damage and thus creating a self-amplifying
deterioration.
J Intern Med. 2013 June; 273(6): 529543.
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Reactive Oxygen Species

In general, harmful effects of reactive oxygen species on
the cell are most often:
damage of nDNA and mtDNA

oxidations of polyunsaturated fatty acids in lipids (lipid
peroxidation)
oxidations of amino acids in proteins
oxidatively inactivate specific enzymes by oxidation of
co-factors
http://en.wikipedia.org/wiki/Reactive_oxygen_species
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Antioxidant Defenses
Antioxidant defenses are also up-regulated in conjunction
with OxPhos to offset the effects of increased
mitochondrial ROS production. Mitochondrion. 10(1): 12-31.
Endogenous, genetically encoded antioxidant systems
linked to the Antioxidant Response Elements (AREs) will
be discussed in future slides.
Exogenous antioxidants will be given passing attention in
favor of the more powerful and evolutionary significant
endogenous antioxidants.
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Drug-induced
Mitochondrial Toxicity
Drugs that injure mitochondria usually do so by inhibiting
respiratory complexes of the electron chain; inhibiting or
uncoupling oxidative phosphorylation; inducing
mitochondrial oxidative stress; or inhibiting DNA
replication, transcription or translation.
It is important to test for mitochondrial toxicity early in
drug development as impairment of mitochondrial
function can induce various pathological conditions that
are life threatening or can increase the progression of
existing mitochondrial diseases.
Expert Opin Drug Metab Toxicol. 2005 Dec;1(4):655-69.
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NSAID Induced
Mitochondrial Toxicity
[Mitochondrial toxicity] involves specific biochemical
damage of mitochondria and uncoupling the oxidative
phosphorylation reaction.
Electron microscopic studies show vacuolisation and
ballooning of mitochondria within an hour of
indomethacin administration which is highly characteristic
of uncoupling of oxidative phosphorylation.
The consequence of uncoupling is diminished cellular
ATP, which alters the intercellular junction, increases
intestinal permeability, and releases calcium into cytosol
which in turn causes secondary biochemical damage.
Gut. 2001 February; 48(2): 163167.
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Mitochondrial Dysfunction
Injury to the mitochondrial electron transport chain (ETC)
or mutations of mtDNA leading to mitochondrial
dysfunction have recently been suggested as an
important factor in the pathogenesis of mitochondrial
cancer
a range
of other
diseases, aging,
and a range
of other human
disorders.
human disorders.

Biochim Biophys Acta. 2010
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Muscles
Common Symptoms:
Hypotonia, weakness, cramping,
muscle pain, ptosis, and
ophthalmoplegia.
Despite the subjective
weakness, many patients have
minimal objective findings,
possibly because fatigability is
difficult to quantify in a
physicians office.
Cleve Clin J Med. 2001 Jul;68(7):625-6, 629-42.
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Fibromyalgia?
The etiology is unknown; however, recent studies
suggest that mitochondrial dysfunction is involved in the
pathophysiology of fibromyalgia.
Mitochondrial DNA content (mtDNA/gDNA ratio) was
reduced in fibromyalgia patients versus healthy controls
(p<0.001).
Expression levels of peroxisome proliferator-activated
receptor gamma-coactivator 1-alpha was significantly
lower in fibromyalgia patients (p<0.001) compared with
healthy controls.
Antioxid Redox Signal. 2013 Nov 20;19(15):1855-60.
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Brain
Common Symptoms: Developmental delay, mental
retardation, autism, dementia, seizures, neuropsychiatric
disturbances, atypical cerebral palsy, atypical migraines,
stroke and stroke-like events.
Migraine, dementia, seizures, and strokelike episodes
can occur at any stage of the disease, but like myopathy,
brain involvement is not required for the diagnosis.
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Nerves
Common Symptoms: Neuropathic pain and weakness
(which may be intermittent), acute and chronic
inflammatory demyelinating polyneuropathy, absent deep
tendon reflexes, neuropathic gastrointestinal problems
(gastroesophageal reflux, constipation, bowel
pseudoobstruction), fainting, absent or excessive
sweating, and aberrant temperature regulation.
Nerve cells and Schwann cells are extremely active
metabolically: nerve cells require a tremendous amount
of energy to maintain the electrochemical gradient
necessary for nerve transmission.
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Kidneys
Common Symptoms: Proximal renal tubular dysfunction,
may result in loss of protein (amino acids), magnesium,
phosphorous, calcium, and other electrolytes.
The proximal renal tubular cells require an abundant and
steady energy supply.
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Heart
Common Symptoms: Cardiac conduction defects (heart
blocks) and cardiomyopathy.
The sinoatrial and atrioventricular nodes are the most
metabolically active tissues in the body, and the muscular
activity of the heart never ceases. Therefore, cardiac
conduction defects and cardiomyopathy are
complications of mitochondrial dysfunction.
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Liver
Common Symptoms: Hypoglycemia, gluconeogenic
defects, and nonalcoholic liver failure.
Maintenance of glucose homeostasis is the most vital
moment-to-moment function of the liver.
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Eye and Ear

Common Symptoms: Optic neuropathy and Sensoryneural hearing loss
Starting with high-frequency hearing loss, it can progress
to total deafness. A number of mtDNA point mutations are
associated with an extreme otosensitivity to
aminoglycoside antibiotics (streptomycin).
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Hope Springs Eternal

A wide range of seemingly unrelated disorders have
underlying pathophysiological mechanisms in common,
namely reactive oxygen species (ROS) production, the
accumulation of mitochondrial DNA (mtDNA) damage,
resulting in mitochondrial dysfunction.
If in the next 50 years advances in mitochondrial
treatments match the immense increase in knowledge
about mitochondrial function that has occurred in the last
50 years, mitochondrial diseases and dysfunction will
largely be a medical triumph.
Exp Mol Pathol. 2007 Aug;83(1):84-92.
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Handle the difficult while it is still easy.

Handle the big while it is still small.
Difficult tasks begin with what is easy.
Great accomplishments begin with what is small.
Therefore, the wise never strive for the great
and thus achieve greatness.
Lao Tzu
Tao Te Ching
Chapter 63
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Genome Instability
If damage to mitochondria is persistent and defective
mitochondria accumulate in the cell, it would lead to
instability of the nuclear genome.
T Hum Genet. 2009;54:64754.

Gene. 2005;354:1406
Nucleic Acids Res. 2003;31:390917
Mutat Res. 2007;625:11224
Epigenetics. 2012 Apr;7(4):326-34
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Genome Instability
Accumulated nuclear genome instability may help cells
acquire new functions such as resistance to apoptosis,
migration, and invasive characteristics which, in turn,
could induce tumorigenesis.
Epigenetics. 2012 Apr;7(4):326-34
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Epigenetic Influences
Evidence that mitochondrial dysfunction is associated
with epigenomic changes can be found for a wide range
of classical epigenomic diseases.
In cancer, a genetic disease, changes in the epigenome
such as loss of Imprinting (phenomenon by which certain
genes can be expressed in a parent-of-origin-specific
manner is lost) and hypomethylation are common.
Mitochondrion. 10(1): 12-31.
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Mitochondria & nDNA Methylation

An increasing number of studies have identified a
possible effect on the epigenetic landscape of the nuclear
genome as a consequence of mitochondrial dysfunction.
In particular, these studies demonstrate reversible or
irreversible changes in genomic DNA methylation profiles
of the nuclear genome.
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TCA Substrate & Epigenetics

Co-factors, including FAD (Flavin Adenine Dinucleotide)
Cell. 2004;119:94153, acetylCoA Mitochondrion. 2010;10:1231, Science. 2009;324:107680 and ketoglutarate (-KG) are associated with the processes
of active de/methylation or de/acetylation. Epigenetics. 2012 Apr;7(4):326-34
Reduced levels of FAD and -KG due to mitochondrial
impairment/dysfunction could have significant effects on
regulation of the nuclear genome. Eur J Biochem. 2000;267:4888900 Epigenetics.
2012 Apr;7(4):326-34.
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Epigenetic Influences
The chromatin modifications of cancer cells can be
directly modulated by mitochondrial OxPhos.
Cancer Biology and Therapy. 2008;7:11911193

Cancer Biology and Therapy. 2008;7:11821190.
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Hello? Was Anybody Listening?

Normal mitochondria ...
suppress tumorigenesis
because their OxPhos is
sufficient for maintaining
energy homeostasis.

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Then said a teacher,

"Speak to us of Teaching."
And he said: No man can reveal
to you aught but that
which already lies half asleep
in the dawning of our knowledge.
~Khalil Gibran: The Prophet~
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MtDNA Rehabilitation
When mtDNAs were reintroduced into the mtDNAdeficient cancer cells, 30% of the hypomethylated sites
become remethylated.
Thus, there is a direct cause and effect relationship
between mitochondrial function and epigenomic
methylation in cancer cells.
Cancer Biology and Therapy. 2008;7:11911193

Cancer Biology and Therapy. 2008;7:11821190.
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OxPhos-p53 Connection
The p53 protein also regulates OxPhos and it has been
shown that mutational inactivation of p53 in cancer cells
suppresses OxPhos and induces glycolysis.
Science. 2006;312:16501653.
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If mitochondria are so critical for cellular

and overall health of the organism, then it
behooves us to focus ourselves on
mitochondrial biogenesis as a way to
foster overall health of the organism.
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Mitochondrial Biogenesis
Mitochondria cannot be generated de novo; instead, they
proliferate by growth and division of pre-existing
organelles. Nature Rev Mol Cell Biol. 2010;11:872884.
Mitochondria divide during mitosis, providing daughter
cells with a normal complement of mitochondria. Antioxid Redox
Signal. 2012 May 15;16(10):1150-80
There are, however, instances in which mitochondrial

divisions are not tied to cell cycle. Antioxid Redox Signal. 2012 May 15;16(10):1150-80
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Nutrient excess stimulates mitochondrial fission,
fragmented mitochondrial morphology, and an arrest in
oxygen consumption, oxidative phosphorylation,
and
C
Crra
abbt
ATP synthesis. Front Aging Neurosci. 2013 Sep 6;5:48.
trreee
e EE
By contrast, nutrient deficiency triggers mitochondrial
ffffee
cctt
fusion, elongated mitochondrial morphology, and
an
acceleration of mitochondrial respiration and ATP
production. Front Aging Neurosci. 2013 Sep 6;5:48.
Thus, mitochondrial fission and fusion is a fine tuned
process that controls the switches of energy production
with energy demand, thereby maintaining homeostasis.
Commun Integr Biol. 2011 November 1; 4(6): 752754.
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The Biogenesis Big Three

1.Calorie Restriction and Fasting
2.Dietary Polyphenols
3.Endurance Exercise
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Calorie
Restriction/
Fasting
SIRT1
Dietary
Polyphenols
Endurance
Exercise
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SIRT1
SIRT1 stands for silent information regulator type 1.
SIRT1 is an enzyme that deacetylates proteins that
contribute to cellular regulation (reaction to stressors,
longevity). http://www.scientificamerican.com/article.cfm?id=unlocking-the-secrets-of-2006-03&page=3
J Biol Chem. 2005 Apr 22;280(16):16456-60.
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CR/Fasting Targets SIRT1

Sirt1 is activated by calorie restriction in mammals and
acts as a trigger in mitochondrial biogenesis. Am J Physiol Regul Integr
Comp Physiol. 2011 Jul;301(1):R67-75.
BONUS: Upon food withdrawal Sirt1 protein binds to and

represses genes controlled by the fat regulator PPAR-
(peroxisome proliferator-activated receptor-), including
genes mediating fat storage. Nature. 2004 June 17; 429(6993): 771.
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Polyphenols Target SIRT1

Naturally occurring dietary polyphenols, such as
resveratrol, curcumin, quercetin, and catechins, have
antioxidant and anti-inflammatory properties via
modulating different pathways.
In addition, these polyphenols have also been shown to
activate SIRT1 directly or indirectly in a variety of models.
Arch Biochem Biophys. 2010 September 1; 501(1): 7990.
www.drbonci.com
Exercise Targets SIRT1

SIRT1 is increased in response to aerobic exercise. Metabolism
2008; 57: 986-998. Rejuvenation Res 2008; 11: 139-150.
Unlike the increase in mitochondrial content observed

with regular aerobic exercise, resistance training, such as
lifting weights, is associated with an increase in the
contractile machinery. Exercise Physiology:Energy, Nutrition, and Human Performance. 5th ed.
Baltimore: Lippincott Williams & Wilkins; 2001 p. 500-547.
This increase in the production of contractile proteins

results in increased muscle mass with very little
enhancement of mitochondrial production.
www.drbonci.com
Calorie
Restriction/
Fasting
SIRT1
Dietary
Polyphenols
PGC-1
Endurance
Exercise
www.drbonci.com
PGC-1: Master Regulator

PGC-1 = Peroxisome proliferator-activated receptor
gamma coactivator 1-alpha
PGC-1 appears to act as a master regulator of
mitochondrial biogenesis by integrating and coordinating
the activity of multiple transcription factors. Cell 1998;92(6):82939.
Expression levels of PGC-1 are directly related to
mitochondrial biogenesis activity. J Cell Sci. 2012 Nov 1;125(Pt 21):4963-71
www.drbonci.com
Calorie
Restriction/
Fasting
SIRT1
Dietary
Polyphenols
PGC-1
Endurance
Exercise
Mitochondrial
Biogenesis
www.drbonci.com
Benefits of
Increased
Decreased
OxPhos
ROS
Metabolic Efficiency
Oxidative Stress
Energy Level
Body Fat
Lean Body Mass
Disease/Dysfunction
Exercise Performance
Age-related Deterioration
Life Span (?)
www.drbonci.com
Calorie Restriction
In 1935, nutritional scientist Professor Clive M. McCay
(Cornell University) published his seminal paper showing
that rats fed a diet with 30-40% fewer calories lived about
33% longer than rats fed ad libitum.
Proc Nutr Soc 1995; 54: 657-664.
www.drbonci.com
The Responsible Component?

From the beginning, investigators raised the question of
whether it was caloric restriction or a specific dietary
component such as fat, protein, carbohydrate, vitamins,
or antioxidants that was responsible for observed
physiological and metabolic benefits.
After manipulating the various dietary components it was
found that health and longevity effects derived
predominantly from calorie restriction alone.
Proc Nutr Soc 1995; 54: 657-664.
www.drbonci.com
CRON-diet
Calorie Restriction Optimal Nutrition
The CRON-diet involves calorie restriction while
still attempting to provide the recommended daily
amounts of various nutrients.
Proponents recommend a goal of restricting
intake by 20%.
The actual daily amount eaten depends on the
adherent's basal metabolic rate (BMR). A common
daily intake is 1800 calories per day.
http://en.wikipedia.org/wiki/CRON-diet
www.drbonci.com
Roy Lee Walford, M. D. (1924-2004)

Walford found that mice fed
a CRON of 50% normal
caloric intake almost
doubled their expected life
span.
Walford was one of eight
crew members sealed
inside Biosphere 2 where
they lived from Sept 26,
1991 to Sept 26, 1993.
http://en.wikipedia.org/wiki/Roy_Walford
www.drbonci.com
20 Years of CR/CRON Research

[P]rolonged CR appears to extend the lifespan of rhesus
monkeys, which exhibited lower body fat; slower rate of
muscle loss with age; lower incidence of neoplasia,
cardiovascular disease, type 2 diabetes mellitus, and
endometriosis; improved insulin sensitivity and glucose
tolerance; and no apparent adverse effect on bone
health, as well as a reduction in total energy expenditure.
In addition, there are no reports of deleterious effects of
CR on reproductive endpoints, and brain morphology is
preserved by CR.
ILAR J. 2011 February 8; 52(1): 6677.
www.drbonci.com
CRON Weakness
Calorie restrictors are exquisitely aware of exactly how
many calories they are eating at all times.
CRON, in other words, falls prey to one of the biggest
stumbling blocks for any diet: It requires you to constantly
think about the one thing you dont want to be thinking
about: what you can and cant eat.
Johnson M.D., James B. (2008-04-10). The Alternate-Day Diet: Turn on Your "Skinny Gene," Shed the Pounds, and Live a Longer
and HealthierLife (Kindle Locations 242-244). Penguin Group US. Kindle Edition.
www.drbonci.com
Intermittent Fasting
Intermittent fasting (IF) is a pattern
of eating that alternates between
periods of fasting (usually meaning
consumption of water and
sometimes low-calorie drinks such
as black coffee) and non-fasting.
http://en.wikipedia.org/wiki/Intermittent_fasting
www.drbonci.com
Intermittent Fasting
Interestingly, intermittent fasting but
not caloric restriction for 20 weeks
increases hippocampal neuron
tolerance to excitotoxic stress in
mice, suggesting neuroprotective
effects of intermittent fasting.
Proc Natl Acad Sci U S A 100: 62166220.
www.drbonci.com
Alternate Day Fasting

Calorie restriction (CR) and
alternate-day fasting (ADF) represent
2 different forms of dietary restriction
(DR).
The findings in animals suggest that
ADF may effectively modulate
several risk factors, thereby
preventing chronic disease, and that
ADF may modulate disease risk to
an extent similar to that of CR.
Am J Clin Nutr. 2007 Jul;86(1):7-13.
www.drbonci.com
Eat Frequent, Small Meals (?)

The idea that eating little and often is a good
thing has been driven partly by snack
manufacturers and faddish diet books, but it has
also had support from the medical establishment.
Their argument is that it is better to eat lots of
small meals because that way we are less likely to
get hungry and gorge on high-fat junk.
Mosley, Michael; Spencer, Mimi (2013-02-26). The FastDiet: Lose Weight, Stay Healthy, and Live Longer with the
Simple Secret of Intermittent Fasting (p. 14). Atria Books. Kindle Edition.
www.drbonci.com
Eating Between Meals

Once upon a time, parents told their children, Dont eat
between meals.
Recent research in the United States, which compared
the eating habits of 28,000 children and 36,000 adults
over the last thirty years, found that the amount of time
between what the researchers coyly described as eating
occasions has fallen by an average of an hour. In other
words, over the last few decades the amount of time we
spend not eating has dropped dramatically.
Mosley, Michael; Spencer, Mimi (2013-02-26). The FastDiet: Lose Weight, Stay Healthy, and Live Longer with the Simple Secret of
Intermittent Fasting (p. 14). Atria Books. Kindle Edition.
www.drbonci.com
Fasting is Evolutionary
For most animals out in the wild, periods of feast or
famine are the norm.
Our remote ancestors did not often eat four or five times
a day. Instead they would kill, gorge, lie around, and then
have to go for long periods of time without having
anything to eat.
Our bodies and our genes were forged in an environment
of scarcity, punctuated by the occasional massive
blowout.
Mosley, Michael; Spencer, Mimi (2013-02-26). The FastDiet: Lose Weight, Stay Healthy, and Live Longer with the Simple Secret of
Intermittent Fasting (p. 13). Atria Books. Kindle Edition.
www.drbonci.com
Seasonal Expressions
of Mitochondria
When carbohydrates were abundant to our ancestors,
such as during the plant growing season, consumption of
plant starch resulted in increased blood glucose levels.
When glucose is abundant PGC-1 is down-regulated,
mitochondrial OxPhos is depressed, and metabolism
shifts toward glycolysis.
www.drbonci.com
Insulin-Metabolism Response
A rise in serum glucose stimulates the pancreatic -cells
to release insulin.
Insulin signals the availability of carbohydrates to the rest
of the tissues in the body, shifting metabolism toward
glycolysis for ATP generation Mitochondrion. 10(1): 12-31., the storage of
excess calories as fat by activating lipoprotein lipase J Clin
Invest. 1982 May; 69(5): 11191125. and conservation of adipose tissue by
the suppression of cellular [hormone-sensitive] lipase Mol Cell
Biol. 2010 November; 30(21): 50095020. .
www.drbonci.com
Mitochondrial Response
to Glucagon
When carbohydrates are scarce, glucose becomes
limiting to animals, serum glucose levels fall, insulin
secretion declines, and the pancreatic -cells secrete
glucagon.
Glucagon then signals via cAMP to mobilize stored fat
and up-regulate mitochondrial OxPhos to burn fat and
generate energy to survive periods of glucose
deprivation.
Annual Review of Biochemistry. 2007;76:781821.
www.drbonci.com
Carbohydrate Scarcity & PGC-1

[W]hen carbohydrates are limited, the expression of
PGC-1 is doubly induced switching cellular metabolism
toward OxPhos to burn stored fats to survive periods of
carbohydrate deprivation.
www.drbonci.com
Beta-Hydroxybutyric Acid
Beta-hydroxybutyrate, the principal "ketone" body in
starving man, displaces glucose as the predominating
fuel for the brain, decreasing the need for glucose
synthesis in the liver (and kidney) and accordingly spares
its precursor, muscle-derived amino acids.
Trans Am Clin Climatol Assoc. 2003; 114: 149163.
www.drbonci.com
Keystone Ketone of Evolution

[E]volution occurs in long stable periods (equilibrium)
interrupted by brief and rapid changes (punctuation).
This could not have happened without betahydroxybutyric acid supporting survival as a fuel source
during the frequent famines caused by natural
catastrophies as well as those caused by man himself
during hostilities and migrations.
www.drbonci.com
Decreasing food intake decreases the UCPs, coupling
is tighter, and metabolic efficiency is increased.
Increasing the UCPs increases the metabolic rate which
tends to reduce obesity, but it generates more free
radicals.
Walford R. Beyond the 120 Year Diet, 2000. ISBN-10: 1568581572. p. 63.
www.drbonci.com
Fasting State is Protective

Ketones inhibit mitochondrial production of ROS by
enhancing NADH oxidation in the mitochondrial
respiratory chain. Neuroscience. 2007 March 2; 145(1): 256264.
Studies in cardiac tissue have suggested that ketones
reduce oxidative stress IUBMB Life. 2001;51:241247, a pathogenic
process implicated in many disorders ranging from
atherosclerosis and traumatic injuries to diseases more
specific to the nervous system Physiol Rev. 2002;82:4795; Neurology. 2005;64:11521156.
www.drbonci.com
Ketones: the Superfuel

Recent studies have shown that beta-hydroxybutyrate,
the principal "ketone", is not just a fuel, but a "superfuel"
more efficiently producing ATP energy than glucose or
fatty acid.
In a perfused rat heart preparation, it increased
contractility and decreased oxygen consumption.
www.drbonci.com
Successful Fasting as
a Selective Pressure
A normal 70 kg man survives 2-3 months of starvation
[on ketones] instead of several weeks, and obese man
many months to over a year.
Without this metabolic adaptation, homo sapiens could
not have evolved such a large brain.
www.drbonci.com
Take in fewer calories and your body increases its
metabolic efficiency; up your intake and your efficiency
decreases.
Walford R. Beyond the 120 Year Diet, 2000. ISBN-10: 1568581572. p. 63.
www.drbonci.com
Ketoacidosis
In the super-fasted state (the diabetic) where even basal
insulin levels are inadequate, excessive amino acids are
released from muscle, hepatic gluconeogenesis and
ketogenesis increase and levels of glucose and ketones
rise.
These result in progressive hyperglycemia, hyperketosis
and glucosuria and ketonuria.
Diabetes Metab Res Rev 1999;15:412-26.
www.drbonci.com
Ketosis v. Ketoacidosis
Benign dietary ketosis is a
controlled, insulin regulated
process which results in a
mild release of fatty acids
and ketone body production
in response to low
carbohydrate intake.
pH below 7.3
Ketoacidosis occurs when

the body is producing large
quantities of ketone bodies
via the metabolism of fatty
acids (ketosis) and the
body is producing
insufficient insulin to slow
this production.
pH below 7
www.drbonci.com
Simple Starvation
Simple starvation and/or the ketogenic diet produce a
mild but closely regulated metabolic acidosis, compatible
with normal life as evidenced.
www.drbonci.com
CR/Fasting/Ketosis
Protective Effects
Animal models and isolated cells show that ketone
bodies, especially -hydroxybutyrate, confer
neuroprotection against diverse types of cellular injury.
Behav Pharmacol. 2006 September; 17(5-6): 431439.
Nrf2-regulated signaling pathway is critical in protecting

mitochondria from oxidative stress during feed
deprivation, which ensures efficient utilization of fatty
acids. PLoS One. 2013; 8(3): e59122.
www.drbonci.com
Nrf2 Triggers
During periods of oxidative stress, Nrf2 is released from
sequestration in the cytoplasm and translocates to the
nucleus. Nrf2 binds antioxidant response elements
(AREs) in the regulatory regions of target genes and
activates transcription. Toxicol Pathol. 2007 Jun;35(4):459-73.
The Nrf2 antioxidant response pathway is "the primary
cellular defense against the cytotoxic effects of oxidative
stress." N Engl J Med. 2012 Sep 20;367(12):1098-107. Integr Comp Biol. 2010 November; 50(5): 829843.
www.drbonci.com
Three Important Nrf2 Targets

1. Superoxide Dismutase
2. Catalase
3. Glutathione Peroxidase
www.drbonci.com
Superoxide Dismutase
SODs are enzymes that
catalyze the breakdown
of the superoxide anion
into oxygen and
hydrogen peroxide.
Free Radic
Biol Med. 2002 Aug 1;33(3):337-49. CRC Crit Rev Biochem.
1987;22(2):111-80.
SOD enzymes are

present in almost all
aerobic cells and in
extracellular fluids.
Mol Aspects
Med. 2005 Aug-Oct;26(4-5):340-52.
www.drbonci.com
Superoxide Dismutase
Superoxide dismutase enzymes contain metal ion
cofactors that can be copper, zinc, manganese or
iron.
In humans, the copper/zinc SOD is present in the
cytosol, while manganese SOD is present in the
mitochondrion.
CRC Crit Rev Biochem. 1987;22(2):111-80.
There also exists a third form of SOD in

extracellular fluids, which contains copper and
zinc in its active sites.
Int J Biochem Cell Biol. 2005 Dec;37(12):2466-71.
www.drbonci.com
Catalase
Catalases are enzymes
that catalyse the
conversion of hydrogen
peroxide to water and
oxygen, using either an
iron or manganese
cofactor.
Cell Mol Life Sci 61 (2): 192208. Prog

Biophys Mol Biol 72 (1): 1966.
This protein is localized

to peroxisomes in most
eukaryotic cells.
Free Radic Biol Med
13 (5): 55780.
www.drbonci.com
Glutathione Peroxidase
Glutathione peroxidase
is an enzyme containing
four selenium-cofactors
that catalyzes the
breakdown of hydrogen
peroxide and organic
hydroperoxides.
Free Radic Biol Med
27 (910): 95165.
www.drbonci.com
Three Important Interventions

Upregulate Nrf2 Expression
1.Dietary Restriction (DR) in the form of calorie
restriction and fasting.
2.Dietary Polyphenols
3.Aerobic Exercise
www.drbonci.com
CR/Fasting Targets Nrf2

Fasting induces NRF2 target gene expression by at least
1.5 to 5-fold. Antioxid Redox Signal. 2013 Jul 31.
The Nrf2 antioxidant response pathway is "the primary
cellular defense against the cytotoxic effects of oxidative
stress." N Engl J Med. 2012 Sep 20;367(12):1098-107.
Nrf2 is the primary transcription factor that binds to the
antioxidant responsive elements (AREs) and activates
the expression of these genes. It is evident that activation
of ARE-regulated genes contributes to the regulation of
cellular antioxidant defense systems. Curr Pharm Des. 2004;10(8):879-91.
www.drbonci.com
Polyphenols Target Nrf2

Increasing Nrf2 expression or biological activity by small
molecules such as polyphenols among others can be
achieved in various cell types.
Curcumin and resveratrol have been shown to activate
Nrf2 leading to subsequent protection from oxidative
insult and toxins.
Flavonoid polyphenols such as epigallocatechin 3-gallate
(EGCG) and quercetine are potent activators of Nrf2 that
have been shown to be neuroprotective against oxidative
stress in vitro.
Recent Pat CNS Drug Discov. 2012 December; 7(3): 218229.
www.drbonci.com
Aerobic Exercise Targets Nrf2

Exercise activates Nrf2, the master regulator of
antioxidant defenses, and attenuates CVD. Exerc Sport Sci Rev. 2013
Jul;41(3):162-8.
Nrf2 is an important mediator of the antioxidant defense

mechanism that transcriptionally regulates several phase
II antioxidant enzyme-genes, including the glutathione
complexes, superoxide dismutase and others. Am J Physiol Renal
Physiol. 2009 November; 297(5): F1174F1180. Integr Comp Biol. 2010 November; 50(5): 829843.
www.drbonci.com
Recommendations, or ...
www.drbonci.com
Measure with a Micrometer
www.drbonci.com
Mark with Chalk
www.drbonci.com
Cut with an Axe
www.drbonci.com
Hell! Cut with a Chainsaw!!
www.drbonci.com
The Value of RCT

Provides important information about an intervention's
likely outcome in general practice. It should address
margins of efficacy and safety.
A sophisticated marketing strategy employed by
professional elites to control the marketplace. Ian Roberts, PhD
Statistical analysis is often used as a highly effective
propaganda tool. David R. Hawkins, MD, PhD
www.drbonci.com
Single Subject Research Design

Single-subject research is a group of research methods
that are used extensively in the experimental analysis of
behavior and applied behavior analysis with both human
and non-human participants.
The most basic method in this type of research is the AB-A design.
http://en.wikipedia.org/wiki/Single-subject_research
www.drbonci.com
Single Subject Research Design

These methods form the heart of the data collection and
analytic code of behavior analysis.
Behavior analysis is data driven, inductive, and
disinclined to hypothetico-deductive methods.
Statistical methods have been largely ignored.
http://en.wikipedia.org/wiki/Single-subject_research
www.drbonci.com
How Does One Begin?
www.drbonci.com
Begin with a Conversation
www.drbonci.com
What Does DR Look

Like in Practice?
It either looks like counting calories and restricting those
calories over three meals each day, or
It looks like intermittent fasting.
I feel that intermittent fasting is preferable to traditional
CR diets for several reasons.
My major reason in particular is that it appears more
accurately to reflect the large swath of our evolutionary
existence and those adaptive mechanisms.
www.drbonci.com
Carnivore? Herbivore? or ...

Omnivore built for scarcity
This can explain the
Dentition
Digestive tract Length
Gall Bladder Size
www.drbonci.com
Which Supplements
Do You Need to Take?
Dark Berries
Resveratrol
Green Tea (ECGCs)
Turmeric
Vary them from time to time
www.drbonci.com
What Really is Aerobic Exercise?

Aerobic exercise is physical exercise of relatively low
intensity that depends primarily on the aerobic energygenerating processes.
Oxygen supply meets or exceeds the needs of exercising
tissues.
www.drbonci.com
Are there Synergistic Effects?

Voluntary exercise and resveratrol (RSV) treatment
induced mitochondrial biogenesis independent of each
other.
When RSV and exercise were combined, a synergistic
effect was evident, leading to enhanced translocation of
PGC-1 and SirT1 to the nucleus and stimulation of
mitochondrial biogenesis.
Thus, the magnitude of the effect of RSV on muscle
mitochondrial biogenesis is reliant on the cellular
environment and by repeated bouts of exercise.
J Biol Chem. 2013 Mar 8;288(10):6968-79.
www.drbonci.com
Thank You
www.drbonci.com

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The Mitochondrial Factor:

Andrew S. Bonci, BA, DC

A Special Thank You

Missouri State Chiropractic Association

Dr. Robert Riley

Dr. Ron Manfredi

Dr. Russell Matthias

Dr. Doran Nicholson

Get the Notes

Most Humble Dedication

When I sing to make you dance

Most Humble Acknowledgment

Otto Heinrich Warburg

Nat Rev Cancer. 2011 May;11(5):325-37.

Review the Microscopic Anatomy,

The key to growth is the introduction of

Minding My Own Business

And He Says ...

Seyfried, Thomas (2012-05-17T16:00:00+00:00). Cancer as a

Cybrids contain a single

The Secret of Cybrids

Suppression of Malignant State

Nuclei Ain't Nothin'

The Secret of Cybrids

Whiskey Tango Foxtrot?

The Secret of Cybrids

It's About the OxPhos

Seyfried, Thomas. Cancer as a Metabolic Disease: On the Origin,

The Differentiated State

Seyfried, Thomas. Cancer as a Metabolic Disease: On the Origin,

Hello! Is anyone listening?

Seyfried, Thomas. Cancer as a Metabolic Disease: On the Origin,

One More Time Hello?

OxPhos = Mature State

Gylcolysis = Immature State

Cell Stem Cell. 2012 Nov 2;11(5):589-95.

The Warburg Effect

Antioxid Redox Signal. 2012 May 15;16(10):1150-80.

Joshua Lederberg, PhD

Joshua Lederberg, PhD

The Gray Scale of Disease

The word mitochondrion comes from

Of Mitochondria and Chloroplasts

Andreas Schimper (1883) that chloroplasts

Nature. 2010 Oct 21;467(7318):929-34.

Costs of Gene Expression

Nature. 2010 Oct 21;467(7318):929-34.

The Price of Complexity

Growth and replication of the nucleus is limited by

The female oocyte (egg

Whats the Significance for Us?

The Giver of Forms

A Cellular Yin and Yang

Mitochondria is the female energy and giver of forms.

A Cellular Adam and Eve

Eve giver of forms

A Cellular Shiva and Shakti

Shakti mitochondrial giver of forms

Power and Wisdom

"I awoke, only to see the rest of

Adults possess approximately 10 million billion

Mitochondrial Outer Membrane

The outer mitochondrial membrane contains enzyme

Carolyn D. Berdanier. Mitochondria in Health and Disease CRC Press, 2005.

Int. J. Dev. Biol. 56: 799-808 (2012)

Carolyn D. Berdanier. Mitochondria in Health and Disease CRC Press, 2005.

Citric Acid Cycle