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The role of mitochondria in cancer and other chronic diseases

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The role of mitochondria in cancer and other chronic diseases

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Nutrition is the foundation and basis of good health; therefore, it stands to reason that a proper diet would assist in the prevention of common 21st century chronic diseases such as heart disease, diabetes, neurodegenerative diseases, and cancer. In this article we explain the roles of mitochondria in health, and the biochemistry of mitochondria in degenerative disease. We examine the role of oxygen in both (aerobic) oxidative phosphorylation (OxPhos) and (anaerobic) glycolysis, and how the latter may contribute to chronic disease states. We discuss the biochemical mechanisms behind adenosine triphosphate production and the simultaneous production of Reactive Oxygen Species (ROS) (free radicals), and the chronic e!ects of cellular ROS damage. Lastly, we discuss the cellular health-enhancing e!ects of reductive molecules (antioxidants) and an alkaline environment, and how this contrasts with an acidic environment/ diet, which contributes to chronic disease and the pathological state.
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Synthesis Article
JOM Volume 29, Number 4, 2014 157
The Role of Mitochondria in Cancer and
Other Chronic Diseases
Dorothy D Zeviar,1 Michael J Gonzalez?,*2 Jorge R Miranda Massari,2 Jorge
Duconge,2 Nina Mikirova3
1 University of Western States, Portland, OR
2 University of Puerto Rico, Medical Sciences Campus, San Juan, PR
3Riordan Clinic, Wichita, KS * Correspondence should be addressed: Dr. Michael J Gonzalez, University of
Puerto Rico, Medical Sciences Campus School of Public Health, Department of Human Development, Nutri-
tion Program. GPO Box 365067 San Juan PR 00936-5067; email: michael.gonzalez5@upr.edu
Mitochondrial Basics
Mitochondria serve several important
cellular roles, but first, we shall discuss some
background history, structure and the roles
mitochondria play in cellular health. It is
generally recognized and agreed that mito-
chondria originated from an aerobic bacteria
approximately 1-3 billion years ago, which
merged with a pre-existing unicellular organ-
ism. Both organisms developed a symbiotic
relationship which provided a way to create
aerobic cellular respiration and produce much
more energy. is in turn, supports the de-
velopment of complex multi-cellular aerobic
organisms. Mitochondria are the only sub-
cellular organelle/organism with their own
mtDNA.1
Because mtDNA is maternally transmit-
ted by the ovum at conception (inherited from
one’s mother), its genetic defects or variants,
deficiencies (if any) are limited to the mito-
chondria; the cellular-nuclear DNA (nDNA)
is governed by Mendelian inheritance princi-
ples. In contrast to nDNA which is made up
of 3.3 billion base pairs (bp) of genes, mtDNA
is circular and composed of 16,569 bp. ese
bp include 37 genes, of which 24 encode for
mitochondrial translation and 13 encode for
the cellular respiratory chain.2 nDNA is pro-
tected by histones which shield nDNA from
free radical damage, however, mtDNA is
not protected by histones, so they are more
susceptible to oxidative damage.3 mtDNA
may generate up to 10 times the number of
Abstract Nutrition is the foundation and basis of good health; therefore, it stands to reason that
a proper diet would assist in the prevention of common 21st century chronic diseases such as heart
disease, diabetes, neurodegenerative diseases, and cancer. In this article we explain the roles of mi-
tochondria in health, and the biochemistry of mitochondria in degenerative disease. We examine the
role of oxygen in both (aerobic) oxidative phosphorylation (OxPhos) and (anaerobic) glycolysis, and
how the latter may contribute to chronic disease states. We discuss the biochemical mechanisms be-
hind adenosine triphosphate production and the simultaneous production of Reactive Oxygen Species
(ROS) (free radicals), and the chronic effects of cellular ROS damage. Lastly, we discuss the cellular
health-enhancing effects of reductive molecules (antioxidants) and an alkaline environment, and
how this contrasts with an acidic environment/ diet, which contributes to chronic disease and the
pathological state.
Journal of Orthomolecular Medicine Vol 29, No 4, 2014
158
nDNA mutations for two reasons – mtDNA
resides close to the electronic transport system
(ETS) inside the inner mitochondrial mem-
brane and mtDNA lacks repair mechanisms,
so once damaged, the mitochondria may be
slated for apoptosis.4
Mitochondria Structure and Roles
e number of mitochondria per cell is
energy/function dependent; i.e., those cells
that require and expend the most energy
contain the highest number of mitochondria.
Most cells have between a few hundred to
over 20,000 mitochondria; they are concen-
trated most heavily in cells of the heart, brain,
liver, muscles, gastrointestinal tract, and kid-
neys.5
Mitochondria are composed of two
membranes. e more porous outer mem-
brane contains porin and allows molecules
up to approximately 10 kDa to freely diffuse
across the membrane. e inner, more tightly
constructed (less permeable) membrane con-
tains cardiolipin, a phospholipid which has
both a higher affinity for inner membrane
proteins, and, having two unsaturated bonds,
is more susceptible to oxidative damage.
Components of the electron transport system
(ETS) are found along the inner membrane.
e space between the two membranes is the
intermembrane space where Cytochrome c is
found. Inside the inner membrane is the mi-
tochondrial matrix which contains many of
the enzymes necessary for adenosine triphos-
phate (ATP) production (enzymes associated
with the Kreb’s Cycle), as well as the mito-
chondrial genome.6
Mitochondria play many important roles
in human biology, including synthesis of
heme, lipids, amino acids and nucleotides. As
mentioned above, they are involved in initiat-
ing cellular apoptosis. eir most important
role, however, is the production of ATP. Mi-
tochondria generate 95% of the ATP in the
cell, and rely on ATP for its own functions.7 , 8
Due to the location of the ETS adjacent
to the inner mitochondrial membrane, the
generation of free radicals as a normal part
of oxidative phosphorylation (production of
ATP), as well as the lack of histone protec-
tion for mtDNA, much oxidative damage can
occur to mitochondria, and indeed does occur
in normal physiological reactions as well as in
chronic disease. Later, we will discuss the role
that an alkaline diet can play in preventing
much of this oxidative damage.
Review of ATP Biosynthesis
As stated above, the primary role of mi-
tochondria is to synthesize ATP (cellular en-
ergy). is process is also known as cellular
respiration. As humans, we derive all our en-
ergy from the food we eat, which the mito-
chondria metabolize into glucose, amino ac-
ids and fatty acids. Because we derive all our
cellular energy from the food we eat, this fact
emphasizes the point that eating whole food
is necessary for proper ATP production and
general cellular functions. Recent research has
linked all chronic disease, including cancer, to
deficiencies in mitochondrial structure and
function.1
The Role of Oxygen in Both (Aerobic)
Oxidative Phosphorylation and (An-
aerobic) Glycolysis
As presented in Figure 1, (p.159) the
“normal” process of oxidative phosphory-
lation (OxPhos) creates approximately 38
ATPs per glucose molecule and approxi-
mately 90% of the cell’s energy requirements.
Under normal aerobic conditions, pyruvate is
oxidized by NAD+ and a dehydrogenase en-
zyme that converts pyruvate to Acetyl-CoA
and CO2. is reaction requires oxygen to
oxidize NADH back to NAD+ to continue
the metabolic process.9
is section will provide a simplified ex-
planation of the ETS and OxPhos in the in-
ner membrane of the mitochondria. Research
has identified five protein complexes on the
inner mitochondrial membrane related to the
ETS and OxPhos processes; Complexes I, II,
III, IV are part of the ETC, and Complex V
is where OxPhos or the conversion of ADP
to ATP actually takes place. is process re-
quires co-factors that actually carry the elec-
trons “down the ETS such as cytochrome C
and Co-Q, as illustrated in Figure 2. (p.160)
e entire process is actually one of oxidation
159
The Role of Mitochondria in Cancer and Other Chronic Diseases
Figure 1. The oxidative phosphorylation process.
of NADH and FADH2, by-products of the
Kreb’s Cycle, to H2O. 10
Complexes I, III, and IV “pump” protons
from the inner membrane across the mem-
brane into the intermembrane space, creat-
ing a “proton gradient” that is necessary for
ATPase conversion of ADP to ATP (phos-
phorylation). e potential of hepatocytes,
for example, has been measured at 170mV,
but the normal cell potential is 50-70 mV. A
proton gradient is necessary for efficient ETS
function. e combination of movement of
protons “down the ETS and the phospho-
rylation of ADP in Complex V is called the
coupling of cellular respiration with the syn-
thesis of ATP. It is said that the efficiency with
Journal of Orthomolecular Medicine Vol 29, No 4, 2014
160
which foods are metabolized and converted
to energy is determined by the efficiency of
this “coupling” process. It is estimated that
each complex pumps four protons across the
membrane.10,11 e “pumping” of protons into
the intermembrane space helps maintain an
alkaline pH inside the mitochondria, which
then creates a negative potential with respect
to the cytosol.11 Acidic substances, xenobiot-
ics, and drugs can also “uncouple” the ETS
from OxPhos. As previously stated, the entire
ETS and OxPhos process produces approxi-
mately 38 ATP.
Because ATP production occurs in the
cristae of the inner membrane, close to the
ETS where protons are “pumped” and occa-
sionally “lost,” the mitochondria are subject
to great oxidative damage themselves by their
own processes. Although aerobic OxPhos is
the optimal process for producing ATP, it
is not without inherent danger to the mito-
chondria themselves, as it also produces ROS
such as the superoxide radical O2.-, hydrogen
peroxide H2O2, the hydroxyl radical HO. ,the
perhydroxyl radical HO2. , and peroxynitrite
ONOO- . During normal OxPhos, 0.4 – 4%
of all oxygen consumed is converted in mi-
tochondria to superoxide O2.-.1 ese ROS
contribute to enzymatic damage, membrane
damage and subsequent apoptosis. Not only
do ROS accumulate with age, but they nega-
tively affect mtDNA replication and repair
processes. Organelles that have sustained
damage to their DNA, membranes, or re-
spiratory chain (ATP synthesis) proteins will
suffer from a chronic energy shortage and
diminished or nonexistent proton gradient.12
Defective mitochondria accumulate most in
ATP-active organs such as the brain, heart
and muscle, which may partly explain the in-
creasing incidence of chronic diseases involv-
ing these organs. ese ROS can be “paired”
and neutralized in the cell with a diet high in
antioxidants, found in a typical alkaline diet
rich of fresh fruits and vegetables.
Anaerobic Glycolysis
is discussion about ROS damage to
mitochondria relates to anaerobic glycolysis.
From the point in the metabolic pathway
where pyruvate metabolizes to Acetyl-CoA,
pyruvate can also take another form as lac-
tate (C3H5O3-) under conditions of low
oxygen. e attention should be directed to
the one-way arrow emerging from pyruvate
(C3H4O3) to Acetyl-CoA (C21H36N7O16P3S)
to indicate that, at this point in the metabolic
process, pyruvate can only metabolize to
Figure 2. Oxidation of NADH and FADH2.
161
The Role of Mitochondria in Cancer and Other Chronic Diseases
ROS Damage
As stated above, a two-edged sword re-
garding ATP production is the simultane-
ous production of necessary ROS that may
have a role in gene regulation and excessive
damaging ROS leading to the disease state,
under both aerobic and anaerobic conditions.
One explanation for how ROS damage con-
tributes to chronic disease conditions is that
excess calories (or poor quality calories), and
the lack or excess of exercise generate more
electrons than the ETS can handle, leaving
more electrons in the inner membrane space
(because they can’t be pumped back out into
the intermembrane space). is adversely af-
fects the proton gradient necessary for ADP
coupling with P to create ATP, stalling the
ETS process. Additionally, with less oxygen
available to pair with the protons created in
the ETS process, the cells cannot make H2O
as a by-product of OxPhos, so more ROS
accumulate in the cells, contributing further
to mtDNA damage and subsequent nDNA
damage.14 ROS contributes to mtDNA dam-
age/deletions/mutations, and as less ATP
is produced and cellular functions diminish,
subsequent replicated mitochondria become
less and less robust and unable to successfully
carry out cellular and organ functions, thus
contributing to chronic degenerative disease.
Figure 3. Anaerobic glycolysis and disease progression.
Acetyl-CoA in the presence of oxygen. When
muscles have over-exercised and “used up” the
available oxygen, pyruvate cannot convert to
Acetyl-CoA and instead turns to lactic acid
(C3H6O3). is phenomenon occurs dur-
ing heavy exercise or stress, for example, but
can also occur in the initial stages of cancer
and other degenerative and chronic diseases
which affect cellular integrity. Lactic acid cre-
ates an acidic cellular environment that, if
not immediately corrected, contributes to a
chronic acidic cellular environment which is
conducive to cellular breakdown, loss of func-
tion and predisposition to cancer. e usual
disease progression may follow the pattern
depicted in Figure 3. (below)13
Recall that mtDNA lacks protective
histones and repair mechanisms; therefore,
they are more susceptible to oxidative dam-
age. And although each cell contains numer-
ous mitochondria (from hundreds to over
20,000), one would think that occasional mi-
tochondrial damage would not significantly
impact a cell or an organ. And occasional mi-
tochondrial damage does not affect cellular or
organ function. However, years of cumulative
oxidative damage to both mtDNA and sub-
sequently nDNA does indeed adversely affect
cellular and organ function which leads to
disease states, cancer and aging.
Journal of Orthomolecular Medicine Vol 29, No 4, 2014
162
Apoptosis
Recall that another important role of mi-
tochondria is that of regulating cellular apop-
tosis. Because ROS damage negatively impacts
ATP production, necessary for ALL cellular
functions, regulation of apoptosis is also affect-
ed. Apoptosis is the process of programmed
cell death, necessary for the renewal of all body
cells, and for the continuity of life. Approxi-
mately 30-50 billion cells are replaced daily
in the average human. 15 However, too much
apoptosis can cause muscle and organ failure,
and too little may contribute to tumorigenesis.
Recall that the mitochondrial inner
membrane is composed primarily of cardio-
lipin, an easily oxidized phospholipid. When
the mitochondrial membrane is damaged
(due to any of the stressors mentioned above),
apoptotic signals are released which cleave
to nDNA and initiate cell death. e more
membrane damage, the more rapid cellu-
lar degradation occurs. Several proteins and
other substances in the mitochondria initiate
apoptosis. During this process, cytochrome
C is released from the intermembrane space
into the cytosol which causes cell death (after
other substances are triggered and released).
So although 30-50 billion cells are replaced
daily, if apoptosis in one body system is great-
er than the number of cells replaced, systemic
disease and/or organ failure ensues. As cells
continue to die off through apoptosis, tissue
function decreases, which eventually lead to
symptoms and chronic degenerative disease
(refer to boxes 2 and 3 in Figure 3).13
Chronic Disease, Cancer and
Mitochondria
As discussed earlier, lacking histones and
with lowered ATP production, mitochondria
have limited ways of self-repair once damage
from ROS has been inflicted. In this situa-
tion, cells cannot even make the RNA and
DNA they require to function without mito-
chondria. When mtDNA becomes damaged,
it is more difficult to copy accurately, resulting
in errors of transcription, deletions and muta-
tions. Oxidation from ROS results in a series
of cellular insults: cell membranes lose their
integrity, the proton gradient is diminished
causing less ATP to be produced, cellular
proteins necessary for all other cellular func-
tions unfold and lose their affinity for their
enzymes, and cytochrome C is released into
the cytosol stimulating apoptosis, all in a con-
tinuous feed-forward cycle of cellular, tissue
and organ dysfunction (chronic degenerative
disease). Production of ATP is the key differ-
entiator and chief purpose of mitochondria in
the cell; they are the keystone to proper tissue
and organ function and even gene regulation
in humans. is point cannot be over-stated
or over-emphasized; without fully function-
ing mitochondria, we cease to exist. Research
is finding that cancer cells also exhibit in-
creased mitochondrial damage by ROS.9
As discussed above, ROS impedes the ETS,
resulting in not only reduced production of
ATP, but an excess of unoxidized NADH and
pyruvate, which in turn get reduced to lactate.
Additionally, high ROS concentrations per-
mit histone acetylation to predominate, which
accelerates (faulty) nuclear transcription and
thus replication, and initiates the release of
NFkB into the nucleus (a significant pro-
inflammatory cytokine which also damages
nDNA). At the same time, however, cell dif-
ferentiation and apoptosis signals are silenced
with histone acetylation, eventually resulting
in over-replication favoring tumorigenesis. 16
Gonzalez et al further explained the con-
nection between dysfunction in the ETS
and apoptosis: more CO is produced as a
by-product of inefficient cellular respiration,
which also blocks apoptosis. Cancer cells
have a lower proton gradient: only -15 mV
compared to a normal cell of 50-70 mV. A re-
duced gradient simultaneously reduces ATP
output. Complicating this metabolic scenario
is the fact that without sufficient ATP, cells
lose their ability for cell-to-cell communica-
tion, so as “individualized” unicellular cells,
must form colonies to survive, forming what
we know as the tumor. us, cancer is a cell
survival mechanism in a hostile (acidic) envi-
ronment, since cancer cells have a hard time
surviving in an alkaline environment.16 ROS
contributes both to chronic disease manifes-
tation through the mechanisms of mitochon-
drial dysfunction and subsequent tissue/ or-
163
The Role of Mitochondria in Cancer and Other Chronic Diseases
gan loss of function; as well as tumorigenesis
progression through the mechanisms of un-
controlled nDNA replication without differ-
entiation. Cancer cells appear to thrive under
anaerobic conditions; this phenomenon was
first observed by Warburg in the 1930s.
Early History of Cancer Research –
Warburg, Szent-Gyorgyi, and Pauling
According to the CDC, cancer (all forms)
is now the second-leading cause of mortality
among people in the developed world, ex-
ceeded only by heart disease.17 By its nature
and characteristics, cancer is the uncontrolled
overgrowth of cells which we call a tumor.
Normal cellular functions initiated by the
mitochondria such as apoptosis, and cellular
division/ replication are dysfunctional in a
cancerous environment, due to loss of cellular
membrane integrity, and an increasing acidic
cellular environment, as stated above. When
cellular functions no longer operate properly,
the cell accumulates ROS and lactate, leaving
the cell to depend on anaerobic glycolysis for
energy, which generates only two ATPs.10
Our experience has revealed that con-
ventional oncology believes that a significant
proportion of cancers are the result of genet-
ics, yet recent statistics inform us that genet-
ics play a role in only 5% of cases.18 We now
know that mitochondrial activity/ function
determines whether oncogenes get “switched
on” or “off;” an alkaline diet appears to help
keep these genes under control.
Otto Warburg, a German biochemist, was
a pioneer in observing and publishing research
into cellular respiration and the effects on
cancerous cells/ tumor growth; he was award-
ed the Nobel Prize in Physiology in 1931 for
his work. His research concluded that, unlike
normal cells which depend on aerobic oxida-
tive phosphorylation to produce ATP, cancer-
ous cells instead use anaerobic respiration for
energy production. As he wrote and lectured,
“e prime cause of cancer is the replacement
of the respiration of oxygen in normal cells
with the fermentation of sugar. All normal
cells meet their energy needs by respiration of
oxygen, whereas cancer cells meet their ener-
gy needs in great part by fermentation. us,
cancer cells are partial anaerobes.” He added,
“During cancer development aerobic respira-
tion fails, fermentation appears, and highly
differentiated cells are transformed into fer-
menting anaerobes, which retain only the now
useless property of growth.” He concludes,
“Cancer is ultimately a problem of how cells
use or misuse oxygen to burn sugars.”19 S ad ly,
this theory was discounted by the mainstream
medical establishment, continued to be dis-
counted throughout the 1960s when War-
burg lectured internationally, and continues
to be ignored by today’s oncologists who re-
fute the role of anaerobic glycolysis, sugar and
ROS in the creation of cancerous conditions.
Research done by Vaughn and Deshmukh
demonstrate that it is “glucose metabolism
which protects cancer cells from cytochrome
C mediated apoptosis.”20 Albert Szent-Gyor-
gyi, who won the Nobel Prize in Physiology
in 1937 for his work in discovering vitamin
C elucidated what was the theory of cellular
combustion (producing energy), i.e., that “the
combustion of hydrogen is the real energy-
supplying reaction.”25 Empirical experimen-
tation with Hungarian paprika and lemons
had a therapeutic effect on colleagues with
damaged capillary blood vessels; the positive
effect of vitamin C on blood vessel integrity
and wound-healing is well-documented. Vi-
tamin C is also a powerful RedOx agent and
co-factor in many enzymatic reactions.21
Following on the research of Warburg
and Szent-Gyorgyi, in the 1970s Linus Paul-
ing conducted empirical studies of both oral
and IV vitamin C on people with cancer and
the common cold, reasoning that vitamin C
therapy increased survival of cancer patients
by four times compared to control groups.
He co-wrote a book entitled Vitamin C and
Cancer” and with a colleague Ewan Cameron,
but was still labeled a “quack” by the medi-
cal establishment. Gonzalez et al wrote that
ascorbate (vitamin C) may preferentially tar-
get the mitochondria by increasing electron
flux, thus increasing the production of ATP
and thus, the “normalization of the apoptosis
function. ey added that a greater amount of
vitamin C optimizes the production of ATP
as well as cell-to-cell communication and cell
Journal of Orthomolecular Medicine Vol 29, No 4, 2014
164
differentiation.16 Further research remains
important with regards to both the dosage of
vitamin C as well as the timing of application
during oncologic therapies, as Vitamin C can
have both antioxidant and pro-oxidant char-
acteristics.22 RedOx therapy may become the
“medicine of the 21st century.
A recurring theme is that mainstream al-
lopathic oncologists continue to deny the ef-
ficacy of vitamins, minerals, whole foods and
antioxidants on prevention and treatment
of chronic degenerative diseases and cancer.
With the overview of biochemical processes
involved in mitochondrial and cellular dys-
function as outlined in this paper, the evidence
appears to be strong that an alkaline diet high
in antioxidants (fruits and vegetables) would
help prevent chronic degenerative disease and
cancer, and lead to a better quality of life.
The Protective, Preventive Action of
an Alkaline Diet
Prevention of cancer involves two ele-
ments: consumption of the proper diet and
the avoidance of substances that damage the
mitochondria. Damage to mitochondria is
known to have a key role in the pathogenesis
of an extensive amount of disorders such as
schizophrenia, dementia, Alzheimer’s disease,
epilepsy, strokes, neuropathic pain, Parkinsons
disease, ataxia, transient ischemic attack, car-
diomyopathy, coronary artery disease, chronic
fatigue syndrome,bromyalgia and diabetes
among others. A proper diet must include
sufficient nutrients to sustain efficient aerobic
respiration. is includes the macronutrients
that are the energy and macromolecules for
functional and structure and function and the
micronutrients that facilitate efficient func-
tioning of the biochemical pathways to extract
and transform energy into a biologically use-
ful form. ese micronutrients include the B-
complex, various minerals, other cofactors such
as CoQ10, lipoic acid and acetyl L carnitine and
the electrolyte balance to promote the condi-
tions for an efficient physiological functioning.
Risk factors linked with chronic diseases
(e.g., cancer, lung diseases), such as stress, to-
bacco, environmental pollutants, radiation, in-
fection, cause damage to cells through exces-
sive or uncontrolled generation of ROS.23
Xenobiotics that damage mitochondrial
membrane include environmental toxicants
and medications. Tobacco smoke reduces
arterial oxygenation and increases oxidative
stress and decreases cytochrome oxidase in
complex IV if the mitochondria, 25% after 30
minutes of passive smoke and the enzyme ac-
tivity continues to decrease with time.24
Because the mitochondria is crucial in
energy production, the mitochondrial dys-
function can be related to various groups of
diseases including the main killers in our
society cancer and cardiovascular disease.25
Other environmental factors include some
insecticides and pesticides and fat soluble
chemicals with benzene rings such as hair dye
and paint fumes.
Research has demonstrated that medi-
cations are a major cause of mitochondrial
damage, which may explain many adverse
effects. ese offenders include psychotropic
drugs, anticonvulsants, anti-cholesterol medi-
cations, analgesics and anti-inflammatory
agents, antibiotics, steroids, anticancer che-
motherapy, Diabetes medications and HIV/
AIDS medications. While certain nutritional
cofactors might limit the damage caused to
mitochondria by medications, there is still
much research needed in this area.26
Chronic inflammation can stimulate
all stages of tumorigenesis, (DNA damage,
uncontrolled replication, inhibition of apop-
tosis, augmented angiogenesis and tissue in-
vasion/metastasis. Chronic inflammation is
prompted by environmental factors (e.g., in-
fection, tobacco, asbestos) and host gene mu-
tations factors (e.g., Ras, Myc, p53). Despite
the extensive research published over the last
decade, many of the precise molecular mech-
anisms are still in elucidation and discussion.
It has been proposed that activation of
Ras, Myc, and p53 cause mitochondrial dys-
function, which then causes mitochondrial re-
active oxygen species (ROS) production and
consequent signaling transcription factors
(eg, NFkappaB, STAT3, etc.) that promote in-
flammation-associated cancer.27 However, the
bioenergetic theory of carcinogenesis28 pro-
poses that mitochondrial dysfunction could
165
The Role of Mitochondria in Cancer and Other Chronic Diseases
be the original insult that induces signaling
that activates the oncogenes and transcription
factors. Inflammation-associated cancers pro-
duced from signaling from the mitochondrial
are being identified that may prove useful for
developing innovative strategies for both can-
cer prevention and cancer treatment.
Diet and Biochemical Conditions
Neustadt suggests that because the major
reason and root cause for mitochondrial dys-
function (and thus chronic disease and cancer)
lies in a surplus of ROS that cannot effectively
be neutralized, that RedOx therapy (IV vita-
min C, alkaline diet, supplements, enzymes,
etc) may be a viable lifestyle option for both
prevention and treatment. Because research is
still lacking in the dosage and timing of reduc-
tive therapy, the best way to determine vita-
min and supplement needs is through urinary
organic acid testing. Optimal mitochondrial
function is dependent upon sufficient vita-
mins, minerals, enzymes, co-factors and all the
nutrients necessary for optimal cellular func-
tion, all of which are found in a good alkaline
diet.1 Cancer cannot exist in an alkaline, ox-
ygen-rich environment. To overcome cancer,
we must change our internal environment.9
is is the mitochondrial correction concept.
e co-factors necessary for complete
Kreb’s Cycle metabolism include cysteine, sul-
fur, iron, magnesium, manganese, lipoic acid,
niacin, thiamin, riboflavin, and pantothenic
acid, the last four of which are in the Vitamin
B family. Supplementation with lipoic acid
and acetyl-L-carnitine can improve mito-
chondrial function.29 Carnitine is necessary to
move Acetyl-CoA into the mitochondria with
vitamin C as a co-factor. e ETS requires
both CoQ10 and flavins which include ribofla-
vin, iron-sulfur complexes, copper and heme
molecules. Heme synthesis requires pyridox-
ine (B6), riboflavin (B2), iron, copper, and zinc.
Glutathione is a major anti-oxidant which re-
quires selenium as a co-factor for production.
Deficiencies in any of these substances can
cause increased ROS production and loss of
cellular function. Antioxidant herbs and sup-
plements include such substances as turmeric
(curcumin), green tea, resveratrol, and garden
herbs such as oregano. Anti-inflammatory
substances include Omega-3 fish oil, flax oil,
vitamin E, boswellia, and ginger.1
Alkaline vs Acidic Environment
Average adult humans eating Western di-
ets have chronic, low-grade metabolic acidosis
at a grade that can be estimated by the net rate
of endogenous non-carbonic acid production
(NEAP), which varies with diet. 30 Some age-
related problems such as bone mass decline,
osteoporosis, and decrease in muscle mass.
Chronic, low-grade is in part caused by di-
et-dependent acidosis and may therefore be
improved by diet modification and/or sup-
plementation.
Our current “Standard American Diet”
(SAD) is acidic, made so by over-consumption
of high-glycemic foods, processed foods, sugar,
meats, coffee and alcohol, and anything made
with white flour. Stress and toxins also contrib-
ute to an acidic environment. Mitochondrial
enzymes in the matrix work best in an alkaline
environment, thus optimizing their metabolic
processes.31,32 According to Gonzalez, alkaline
solutions absorb oxygen, whereas acidic envi-
ronments expel oxygen, which explains why
anaerobic organisms thrive in an acidic envi-
ronment, and why tumorigenesis is also fa-
vored in an acidic environment. A lowered pH
contributes to a lowered membrane potential
which results in cellular dysfunction and low-
ered ATP production, again, favoring chronic
disease progression and carcinogenesis.16
e ideal blood pH range is 7.35 to 7.45,
with the majority of holistic health practi-
tioners preferring the higher range, closer to
7.4. One of the chief ways the body creates
homeostasis is to “steal” minerals from bones
and other vital organs. is compensating
mechanism, of course, contributes to loss of
vital co-factors involved in important enzy-
matic reactions, which in turn decreases cel-
lular and organ function eventually leading to
chronic disease and/or cancer.
Concluding Remarks
Developing a healthy lifestyle, with an
emphasis on increasing vegetables in the diet,
would decrease ROS and provide the or-
Journal of Orthomolecular Medicine Vol 29, No 4, 2014
166
ganism with a balance of nutrients that fos-
ters a healthy biochemical environment that
strengthens the composition and function of
the mitochondria should be protective against
chronic diseases such as cancer.
Competing Interests
e authors of this report declare that
they have no competing interests.
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