Mitochondrial Correction: A New Therapeutic Paradigm for Cancer and Degenerative Diseases

Authors: Michael J Gonzalez; Thomas Seyfried; Garth L. Nicolson; Barry J Barclay; Jaime Matta; Alex Vasquez; Dominic D’ Agostino; Jose Olalde; Jorge Duconge; Ron Hunninghake; Miguel J Berdiel; Amanda Cintrón

Published: Journal of Orthomolecular Medicine | August 2018 | Volume 33 Number 4

Introduction

Cancer and other degenerative diseases are increasing to
epidemic proportions in all industrialized countries. Many
of these degenerative diseases show some familial association,
thus a genetic basis has been assumed. Yet, the nature and
frequency of genetic variants in the human population has not
changed significantly in the past 50 years, even though the
incidence of these diseases has climbed continuously
(Wallace, 2005). Therefore, because the increased and increasing
incidence of cancer cannot be attributed to population-wide
genetic change during this short timeframe, the cause must be
external to the genome, in the “environment”, which with relation
to diet and chemical exposures, has altered radically in the past few
decades. Cancer has been widely considered a genetic disease involving
nuclear mutations in oncogenes and tumor suppressor genes; this
view persists despite the numerous inconsistencies associated with
the somatic mutation theory. In contrast to the somatic mutation theory,
emerging evidence suggests that cancer is a mitochondrial metabolic
disease, according to the original theory of Otto Warburg (Warburg, 1956).
Respiratory insufficiency is the origin of cancer according to Warburg’s theory.
We are proposing cancer as a mitochondrial disease where diseased or
damaged mitochondria become more dependent on glucose and glutamine
for fuel. A shift from oxidative phosphorylation to fermentation can cause
cellular de-differentiation, an important characteristic of malignancy.

As described already in the 1920s by Otto Warburg, cancer
cells often show a shift in energy production from mitochondrial
oxidative phosphorylation (OXPHOS) to cytosolic
glycolysis (Warburg, Posener, Negelein & Ueber den Stoffwechsel
der Tumoren, 1924). This so-called aerobic glycolysis,
in which glucose is converted to pyruvate and lactate
in spite of the presence of oxygen, is a major characteristic
of most tumor cells. Importantly, this increase in glycolytic
activity was similar to that observed in early embryonic cells.
Thus cancer cells seem to resume a more primitive metabolic
pattern (Gonzalez et al., 2012). This brings us to Albert
Szent Gyorgi’s elucidation of malignancy as a reversion to
the primordial state (Alpha State) from the oxidative or Beta
State of normal cell functions. We can support these concepts
by providing information about the nature, etiology and
function of mitochondria in normal and cancer cells.
Aerobic glycolysis not only provides the cell with ATP from
the readily available substrate glucose, but the rapid glycolytic
flux can also provide the cells with the necessary substrates
and metabolic intermediates for lipid, amino acid and
DNA synthesis that are needed for growth. For example,
NADPH, ribose, acetyl-CoA and glucose-derived non-essential
amino acids can be provided by aerobic glycolysis.
In addition to an altered use of glucose, cancer cells make
energetically inefficient use of glutamine to supply the nitrogen
for the synthesis of nucleotides and non-essential amino
acids, and to facilitate import of essential amino acids and
support NADPH production. Glycolytic metabolism and the
associated metabolic re-programming not only support rapid
growth, although at the expense of other cells, but they also
make the cancer cell less dependent on oxygen availability
while generating an acidic micro-environment that enhances
malignancy. It has been long appreciated that under hypoxic
conditions glycolytic rates are enhanced, with a resulting
increase in lactate production.

Cancer cells produce far less ATP per molecule of glucose
(i.e., reduced efficiency); nevertheless, they can produce
ATP at a much faster rate due to rapid consumption
of substrates. Cancer cells produce ATP almost a hundred
times faster than normal cells (Demetrius, Coy & Tuszynski,
2010). Cancer cells actively produce more glucose
transporters on their cell surface membranes, so that more
glucose is brought inside the cell. This increase in glucose
metabolism through glycolysis allows the generation of glycolytic
intermediates that funnel into biosynthetic pathways
that support the production of NADPH, lipids, proteins and
nucleotides.

Respiration cannot operate smoothly unless all of the delicate
interior structures inside mitochondria are intact and
functional. Mitochondria have evolved with a process called
retrograde response (RTG), which helps them deal with
temporary stress or damage. The retrograde response was
designed for temporary emergency use, not long-term use,
and yet cancer cells appear to stay in this mode. Whereas
the RTG response evolved to protect cells from sudden
energy failure, a persistent RTG response with inadequate
respiration can cause genomic instability, and eventually
this can result in tumorigenesis (Butow & Avadhani, 2004).
Genome instability is linked to mitochondrial dysfunctions
through retrograde signaling. Thus, this emerging evidence
supports an important role for metabolic aberrancies and
mitochondrial dysfunction in cancer. In general, suggesting
that cancer is primarily a mitochondrial metabolic disease
(Gonzalez et al., 2012; Seyfried & Shelton, 2010).

Mitochondria and Cancer

The mitochondria are ancient bacterial symbionts with their
own mitochondrial DNA (mtDNA), RNA, and protein synthesizing
systems. Each human cell contains hundreds of mitochondria
Margulis theorized that mitochondria are probably
descended from free-living bacteria that survived endocytosis
by a eukaryotic host cell. Such symbiosis is a potent and
largely unappreciated and unrecognized force in evolution.
Mitochondria play a greater physiological role than have
been previously appreciated. Some important mitochondrial
functions are: (a) energy conversion with production of adenosine
triphosphate (ATP), (b) regulation of membrane potential,
(c) signaling and messaging through reactive oxygen
species, (d) calcium signaling, (e) apoptosis and autophagy,
(f) cellular metabolism, (g) iron metabolism and heme synthesis,
and (h) steroid synthesis (Seyfried & Shelton, 2010).
Mitochondria synthesize the universal energy molecule
ATP. They accomplish this through glycolysis, oxidative
phosphorylation (OXPHOS) and electron transport in conjunction
with the oxidation of metabolites by the Kreb’s cycle
and the breakdown of fatty acids by Beta oxidation. Because
of their capacity to generate ATP, mitochondria are known
exclusively for their ability to produce ATP, the main fuel for
the basic energy demands of the cell. We inherit our mitochondrial
DNA from our mothers. Although mitochondria are
present in sperm, they are not transferred to the ova during
the process of fertilization since most of them are in the tail
which is lost in the process.

Mitochondria are so efficient at producing energy that their
arrival on the evolutionary scene is thought to be responsible
for the increase in complexity of living things. Building
and supporting elaborate new creatures with specialized
organs and capabilities requires a superabundance of energy
(for organization, compartmentalization, order, and communication).
If large quantities of energy are not constantly
produced to maintain form, function, order and organization;
then complex organisms will gradually succumb to entropy
or chaos. For cells, this will mean that they regress, and as
their DNA becomes unstable; they can lose their cellular
shape, they become more disorganized, inter-cell communication
is impaired, and they start reproducing uncontrollably
as a survival mechanism (Gonzalez et al., 2010).

Mitochondria are active, mobile intracellular organelles
that undergo constant fission and fusion. They form an interconnected
network with other cellular organelles; and their
functions extend beyond the cell membranes to include influence
on the organism’s entire physiology by affecting communication
between cells, tissues and organs. Unsurprisingly
therefore, any small defect in any of these functions could
elicit mitochondrial dysfunction and promote a combination of
diseases including cancer, metabolic disorders, and neurodegenerative
diseases (Elliott, Jiang & Head, 2015).

Mitochondria are continually confronted with factors that
can jeopardize how well they function. These factors in
clude: chronic stress, sleep disturbances, hyperglycemia,
xenobiotics such as drugs, antibiotics, organic pollutants
and environmental toxins. These factors can cause mitochondrial
dysfunction, which can be characterized by any of
four ways; (a) insufficient number of mitochondria, (b) insufficient
substrate or nutrient co-factors needed for oxidative
phosphorylation, (e.g., nutrient deficiency due to poor diet or
drug-induced nutrient depletion), (c) acquired dysfunction
in the ATP synthesis machinery, or (d) damage to the mitochondrial
membranes. Mitochondrial dysfunction results in
a number of cellular consequences, including: (i) decreased
ATP production; (ii) increased reliance on alternative anaerobic
energy sources; and (iii) increased production of reactive
oxygen species (ROS) and reactive nitrogen species
(RNS). Of interest is that ROS/RNS can also have a variety
of normal roles, which include regulation of gene expression
(Turpaev, 2002; Dalton, Shertzer & Puga , 1999). At physiological
concentrations, ROS/RNS function as “redox messengers”
in intracellular signaling and regulation. ROS/RNS
molecular recognition occurs at both the atomic and at the
macromolecular level which expands the potential number
of ROS/RNS-specific receptors and interaction sites. Nevertheless
an unbalanced production of ROS/RNS can be
detrimental to mitochondrial function and viability.

At the molecular level, a reduction in mitochondrial function
occurs as a result of the following changes: (a) a loss of maintenance
of the electrical and chemical transmembrane potential
of the inner mitochondrial membrane, (b) alterations in the
function of the electron transport chain, including those due to
insufficiencies of nutrients and cofactors/coenzymes essential
for mitochondrial function such as magnesium, thiamine,
ubiquinone, lipoic acid or (c) a reduction in the transport of
critical metabolites into mitochondria. In turn, these changes
result in a reduced efficiency of oxidative phosphorylation and
a reduction in the production of ATP (Nicolson, 2014a). Many
of the organic cofactors/coenzymes and structural fatty acids
and phospholipids essential for mitochondrial function are
damaged or destroyed. Several components of this system
require routine replacement, and this need may be facilitated
with specific dietary/substrate supplements.

Proof of the importance of metabolic and mitochondrial
dysfunction in the cellular etiology of cancer is evidenced
by the observations that damaged mitochondria can turn
healthy cells into transformed cells, and that healthy mitochondria
can reverse cancerous behavior in tumor cells.
These observations provide an insight that cancer is not
simply or exclusively a genetic disease, but more so a mitochondrial
disease (Gonzalez et al., 2012; Seyfried & Shelton,
2010). Mitochondrial dysfunction plays a central role in a
wide range of diseases in addition to cancer. These diseases
include: neurodegenerative diseases, such as Alzheimer’s
disease, Parkinson’s disease, Huntington’s disease,
amyotrophic lateral sclerosis, and Friedreich’s ataxia; cardiovascular
diseases, such as atherosclerosis and other heart
and vascular conditions; diabetes and metabolic syndrome;
autoimmune diseases, such as multiple sclerosis, systemic
lupus erythematosus, and type 1 diabetes; neurobehavioral
and psychiatric diseases, such as autism spectrum disorders,
schizophrenia, and bipolar and mood disorders; gastrointestinal
disorders; fatiguing illnesses, such as chronic
fatigue syndrome and Gulf War illnesses; musculoskeletal
diseases, such as fibromyalgia and skeletal muscle atrophy;
and chronic infections (Pagano et al., 2014).

Many pharmaceuticals have been identified as mitochodrial
toxicants (Meyer et al.,2013; Goodson et al., 2015;
Narayanan et al., 2015). The high lipid content of mitochondrial
membranes facilitates accumulation of lipophilic compounds
and also of organic chemicals, particularly amphiphilic
xenobiotics such as pharmacologic agents, including
anti-bacterials, anti-psychotics, anti-depressants, anti-arrhythmics,
anorexic agents, cholesterol-lowering agents,
and others. Cationic metal ions, such as lead, cadmium,
mercury, and manganese, have also been shown to accumulate
in mitochondria. Another factor contributing to mitochondrial
susceptibility is the presence of cytochrome P450s
in mitochondria, which can activate chemicals that are relatively
non-reactive prior to metabolism. At the same time,
mitochondria can also be protected in several ways, including
greater redundancy of their contents, ability to replace
defective components; via mitophagy, biogenesis, complementation
and apoptosis.

An important property in mitochondria is their controlled
leak of matrix protons. Leaky mitochondria cause uncoordinated
electron transport that causes energy to be wasted as
heat instead of being converted into ATP. This mitochondrial
uncoupling has been shown in faster-growing tumors that
are actually warmer because of this effect. Increased proton
leak will increase oxygen consumption (uncoupled respiration,
UCR) and the energy will be dissipated as heat instead
of being trapped as useful energy.

Metabolic normalization of cancer cells and concomitant inhibition
of carcinogenesis may potentially also be attained by
induction of mitochondrial biogenesis and mitochondrial correction.
Moreover, studying the role of mitochondria in cancer cell
de-differentiation/differentiation processes may allow further insight
into the pathophysiology of transformation, and could lead
to the development of new cancer therapies. Increases in mitochondrial
respiration, restoration of mitochondrial membrane
potential, increases the population doubling times, and reduction
of cell proliferation may be important steps in overcoming
the cancer state. By restoring failing mitochondrial energetics
cancer morphogenesis may be reversed.

An example of the process of cancer re-differentiation via
mitochondrial correction is the repair of aconitase dysfunction
using frataxin that reverses cell transformation (Schulz
et al., 2006; Ristow et al., 2002). Aconitase is an enzyme
that catalyses the stereo-specific isomerization of citrate
to isocitrate via cis-aconitate in the tricarboxylic acid cycle
within the mitochondria. Frataxin, a highly conserved protein
found in prokaryotes and eukaryotes, is required for efficient
regulation of cellular iron homeostasis and functions
to activates mitochondrial energy conversion and oxidative
phosphorylation. Frataxin functions as an activator of oxidative
phosphorylation, leading to an increased mitochondrial
membrane potential and an elevated cellular ATP content.

Additional evidence exist showing that normalizing mitochondrial
function is capable of suppressing tumorigenesis.
The strongest evidence that cancer may be a mitochondrial
disease has been demonstrated by nuclear-cytoplasm
transfer studies. Many of these studies, even those done in
cell cybrids, have shown that a nucleus from a malignant cell
when placed in a cell with normal cytoplasm will not produce
malignant daughter cells; (i.e., mutations in nuclear DNA are
insufficient to cause cancer when placed within a normally
functioning cellular context with normal mitochondria). It
was also shown that normal cell nuclei could not suppress
tumorigenecity when placed in tumor cell cytoplasm, (i.e.,
in the context of dysfunctional metabolism and mitochondria,
cancer can be induced despite normal nuclear DNA).
Therefore, in these studies, normal nuclear gene expression
was unable to suppress malignancy. These studies showed
that it was the cytoplasm and not the nucleus that dictated
the malignant state of the cell (McKinnell, Deggins & Labat,
1969; Mintz & Illmensee, 1975; Li, Connelly, Wetmore,
Curran & Morgan, 2003; Minocherhomji, Tollefsbol & Singh,
2012; Elliott, Jiang & Head, 2015; Parikh et al., 2009).
If this is the case, and tumor cells are defective as Warburg
suggested, then malignant suppression should result
from the introduction of normal mitochondria from normal
cells to a malignant cell. Indeed these nuclear-cytoplasmic
transfer studies in various cell types confirm that the integrity
of mitochondrial respiration prevents carcinogenesis. In
other words, cancer arises from respiratory insufficiency just
as Warburg postulated many decades ago (John, 2001). In
summary, the origin of tumorigenesis requires damaged or
ineffective mitochondria in the cytoplasm. Normal isolated
mitochondria co-cultured with cancer cells could be taken
into the cancer cells, where they can then reverse aerobic
glycolysis and inhibit cell growth (Anand et al., 2008; Shanmugam,
Reddy, Guha & Natarajan, 2003; Wen et al., 2006;
Dandona, Chaudhuri, Ghanim & Mohanty, 2007; Klement &
Kämmerer, 2011; Pollak, 2008).

Mitochondrial Correction

The first step in correcting damaged mitochondria involves
addressing lifestyle factors. Studies show that increasing
physical activity improves mitochondrial function, so encouraging
regular moderate exercise is essential (Anand et al.,
2008; Klement & Kämmerer, 2011; Seyfried, 2015). Combining
exercise with a diet rich in organic vegetables and
moderated in organic, grass-fed meats, free range poultry
and wild caught fish and very low in refined carbs and sugar
may be essential. In addition, implementing reduced stress
practices, such as meditation or yoga, as well as ensuring
good sleeping habits are also important. Finally, detoxifying
the body by removing fat-stored xenobiotics that inhibit mitochondrial
function while replacing essential components
should substantially help improve mitochondrial function.

When the mitochondria become unable to adequately
perform their functions, cells will either die, become dormant,
or undergo malignant transformation. The possibility exists
to cause such cells to revert to normal aerobic cells, capable
of normal function via metabolic and mitochondrial correction,
which can be accomplished in a number of ways. The
current genocentric pharmacologic approach has been to kill
such cells with toxic therapies chemotherapy and radiation
rather than attempt to reconvert them back to normal function.
This cytotoxic approach has been largely unsuccessful,
therefore, considering other paradigms that yield alternative
approaches may prove to be useful and less damaging.

Diet

Nutrition is an important part of cancer treatment because
the components of the diet are determinants of cell functionality.
For cancer patients, eating the right kinds of foods can
help them feel better, stay stronger and most importantly,
survive the disease. All tumors depend heavily on glucose
for survival. Research shows a strong connection between
high blood sugar (hyperglycemia), diabetes, and cancer.
High blood glucose raises insulin levels. High blood glucose
also raises levels of Insulin-like Growth Factor 1 (IGF-1).
Cancer cells with receptors on their surfaces for IGF-1 grow
more rapidly because IGF-1 activates metabolic pathways
that drive tumor cell growth (Shanmugam, Reddy, Guha,&
Natarajan, 2003; Wen, 2006; Dandona, Chaudhuri, Ghanim
& Mohanty, 2007).

Studies have consistently estimated that 30% or more
of all cancers may be due to dietary factors (Anand et al.,
2008). Bioactive food components that affect various aspects
of metabolism may be important tools to reverse glycolytic
to oxidative metabolism and enhance sensitivity to
apoptosis. The success of such a strategy may depend on
several factors, acting in concert. Glycolytic metabolism and
the associated metabolic reprogramming not only support
rapid growth of cancer cells, but they also make the cancer
cells less dependent of oxygen availability and generate a
favorable (acidic) micro-environment. Inhibition of glycolysis
may have therapeutic implications in cancer treatment as a
strategy to suppress or even eliminate cancer cells. Such a
strategy may also make use of bioactive food components.

One class of bioactive food components that affect energy
metabolism and may have anti-cancer effects are polyphenols.
Quercetin, a polyphenol present in apples, onions, tea
and wine, affects energy metabolism. Another polyphenol
with anti-cancer potential is resveratrol. Resveratrol is well
known as a compound that is present in red wine. Bioactive
food molecules, that affect energy metabolism, may
also function as anti-cancer agents using mechanisms distinct
from their effect on energy metabolism. Despite being
categorized as antioxidants, most dietary anti-oxidant
compounds exhibit their functional effects through specific
cellular mechanisms, rather than though general, direct anti-
oxidants effects. Mechanisms such as cancer cell growth
limitation, anti-angiogenesis and normalization of the glycolytic
metabolism are possible.

Carbohydrates provide rapidly usable cellular energy but,
unlike proteins and fat, also stimulate potent insulin signals
that can be powerful mitogens. A carbohydrate-restricted
diet will slow cancer growth in patients by decreasing the
secretion and circulating levels of insulin. Tumor glucose uptake
can be stabilized and decreased with a carbohydrate
restricted diet. Hyperglycemia activates monocytes and
macrophages to produce inflammatory cytokines that play
an important role in the progression of cancer (Shanmugam,
Reddy, Guha & Natarajan, 2003, Wen et al., 2006; Dandona,
Chaudhuri, Ghanim & Mohanty, 2007; Klement & Kämmerer,
2011; Pollak, 2008; Seyfried, 2015; Tisdale & Brennan,
1983). High plasma glucose concentrations elevate the levels
of circulating insulin and free IGF1, two potent anti-apoptotic
and growth factors for most cancer cells (Pollak, 2008).

Paleolithic-type diets that by definition exclude grain
products, have been shown to improve glycemic control
therefore are expected to help against cancer. A low carbohydrate,
high fat diet to increase the blood levels of ketones,
along with supplements or foods rich in citric acid, can impair
glycolysis and may prove a beneficial adjunct in the treatment
of many cancers (Klement & Kämmerer, 2011).

A ketogenic diet characterized by minimal carbohydrate
intake, a moderate amount of protein, and higher amounts of
fat seems to limit cancer cell growth. This shift in macronutrients
causes the body to switch to utilizing ketones (produced
by burning fats) instead of glucose as its primary source of
fuel. Ketones (e.g., acetoacetate, ß-hydroxybutyric acid and
acetone) are produced in the liver when lipids are burned
instead of glucose. Low-carbohydrate diets reduce the extreme
glucose peaks and help patients avoid both hyperglycemia
and rebound hypoglycemia, providing more sustained
energy throughout the day. Ketones are efficiently used for
the generation of ATP (energy) in mitochondria. Cancer cells
cannot use ketones as an energy source (Zhou et al., 2007).
The ketogenic diet mimics the metabolic state of starvation,
forcing the body to utilize fat as its primary source of energy.

The Ketogenic diet may be beneficial in optimizing mitochondrial
function. The transition from glucose metabolism
to ketone metabolism is also a powerful anti-inflammatory
strategy. The goal of this diet is to shift the body from
burning mostly glucose (sugar) to burning mostly ketones
(fat). The quickest way to get into the therapeutic zone is to
start by fasting (water only) for 3-5 days. During the induction
phase, carbohydrate withdrawal symptoms may occur,
which typically include lightheadedness, nausea, and headaches
(Keto Flu). An alternative to this fasting is to limit carbohydrates
to less than 12 grams per day and limit protein
to 0.8 to 1.2 grams per kg body weight per day (0.4 to 0.6
grams per pound bodyweight). With this less extreme plan,
patients may need up to several weeks to reach the recommended
therapeutic zone values. Ketogenic diets may
also facilitate easier surgical reduction in tumor burden, as
ketosis can reduce blood vessel mass, inflammation, and
tumor size; thereby facilitating surgical removal of the tumor
mass. The increase of ketones in the blood can also inhibit
the activity of phosphofructokinase, an enzyme that plays a
key role in the regulation of glycolysis. Citric acid, an intermediary
product of the Krebs cycle metabolism, has also
been reported to block the actions of phosphofructokinase.

To support mitochondrial function, our patients are advised
to eat 8–12 servings daily of a variety of whole, colorful
vegetables and fruits; among different plants, color variation
indicates phytochemical variety, thereby allowing the diet
to provide a wide range of anticancer and metabolism-enhancing
phytochemicals. Vegetables should be the primary
focus, especially the bitter foods in the cruciferous family
(such as broccoli, watercress and arugula), as these foods
provide numerous anticancer benefits. Coconut oil, a brainhealthy
saturated fat that contains medium-chain triglycerides
(MCTs), also supports mitochondrial function via production
of ketones.

Calorie and carbohydrate restriction, along with eating
lean, clean (pesticide and toxin-free) proteins, high-quality
fats and oils, and more plant foods may help to prevent or
slow down all degenerative diseases. All grains are minimized
or avoided on a Mitochondria restoration diet in order
to achieve the desired goals of mild ketosis and low glycemic
impact. Most malignant cells lack key mitochondrial enzymes
necessary for conversion of ketone bodies and fatty
acids to ATP (Pollak, 2008; Seyfried, 2015; Tisdale & Brennan,
1983).

Maintaining a lower and consistent insulin level is key to
optimal mitochondrial health. A heavily processed, high-glycemic
load diet of too many grains and added sugars can
lead to increased insulin and inflammation with associated
and accelerated mitochondrial dysfunction. Minimizing grains,
especially highly processed ones, and using low-glycemic
vegetables and fruits as the main source of carbohydrates
helps to stabilize blood sugar and protect mitochondria.

High quality proteins are the best choice, including grassfed,
organic, non-genetically modified organism (GMO)
sources. For fish, patients should choose wild-caught
salmon as farmed salmon may contain hormones and toxic
chemicals. We encourage the consumption of minimally
refined, cold-pressed, organic, non GMO fats and liquid oils
whenever possible. When possible, we advise phytonutrient-
dense, unfiltered, extra-virgin olive oil, Avocado oil or
Coconut oil, add to dress salads and vegetables. Medium
Chain Triglycerides (MCT) oil is another option that can also
be used for cooking and for dressings.

Cancer patients should aim for a minimum of 4–6 servings
of organic vegetables every day (ideally, 10–12 servings
per day). A serving is only ½ cup of cooked vegetable or 1 cup
of raw leafy greens. Patients get four servings of vegetables in
one meal, by filling your plate with vegetables or eating a hearty
salad. All greens (including collard, dandelion, kale, mustard,
and turnip greens), along with chard/Swiss chard, spinach, sea
vegetables, and the many green vegetables in the cruciferous
family have been found to support the mitochondria via effects
such as antioxidant protection, anti-inflammatory benefits and
enhancement of xenobiotic clearance.

Patients are instructed to eat a rainbow of colors: red
peppers, tomatoes, and radishes; orange carrots, peppers,
and pumpkin; yellow summer squash and peppers; green
asparagus, avocado, and green beans; blue/purple eggplant
and cabbage; and white/tan mushrooms, jicama, and
onions. Patients are also counsel to purchase organic vegetables
(and fruits) when possible. Foods should be “organic”
grown without chemical pesticides; given that many
pesticides are neurotoxins, mitochondrial toxins, carcinogens
and endocrine disruptors.

Fruits with a low to moderate glycemic response can be
consumed when patients are feeling the need for something
sweet. All berries along with pomegranate seeds and grapes
with the skin have shown to increase levels of glutathione in
the body. Fruit juices are not encouraged as they are dense
sources of sugar and can increase blood sugar levels, thereby
promoting oxidative stress, immunosuppression and hyperinsulinemia.

Patients should to drink plenty of pure, filtered water daily.
It is generally recommended to drink at least six to eight
glasses. (One glass = 1 cup = 8 ounces). For variety and
additional antioxidant and anticancer benefits, patients consider
adding at least 2 cups of green tea daily with the general
recommendation being Include herbal teas, especially
those prepared from adaptogenic herbs like cordyceps,
schizandra, ginseng, astragalus, and licorice can be used
as desired and tolerated. The importance of pesticide and
toxin-free food from local, free-range, grass-fed, and organic
sources cannot be stressed enough.

Dietary Supplementation: Descriptions and Adult Doses

Several supplements are important in any regimen designed
to boost mitochondrial health (Zhou, 2007). Dietary
supplements can reduce the oxidative burden of ATP generation,
provide additional substrate for oxidative phosphorylation,
and repair leaky membranes which interrupt the electron
transport system. In addition, mitochondrial biogenesis,
or the generation of new mitochondria, can also be encouraged
(Tarnopolsky, 2008).

CoQ10 (Ubiquinone)

Coenzyme Q10 (CoQ) is a small lipophilic molecule critical
for the transport of electrons from complexes I and II to
complex III in the mitochondrial respiratory chain. Furthermore,
CoQ is essential for the stability of complex III in the
mitochondrial respiratory chain, functions as an antioxidant
in cell membranes, and is involved in multiple aspects of
cellular metabolism. CoQ10 also reduces lactic acid levels,
improves muscle strength, and decreases muscle fatigability.
CoQ10 protects against beta-amyloid-induced mitochondrial
malfunction. Statin drugs are thought to cause mitochondrial
damage in part by lowering levels of CoQ10, and
supplementation with CoQ10 has been shown to counteract
some of the negative effects of statins and is an important
supplement to counteract the adverse effects of cancer therapy
(Conklin & Nicolson, 2008). CoQ10 is probably the most
widely used cofactor for treating mitochondrial-related diseases.
CoQ10 is also a strong antioxidant in its reduced
form, and it can affect the expression of certain genes involved
in cell signaling, metabolism, and transport. However,
the main role of CoQ10 is its involvement in the transfer
of electrons along the multiple complexes of the mitochondrial
electron transport chain. In combination with lipoic acid,
CoQ10 may have had the ability to increase ATP production,
resulting in decreased utilization of alternative energy sources
and a decrease in resting plasma lactate concentrations
(Zhou et al., 2007; Rodriguez et al., 2007).

Ubiquinone: 100 mg tid.

L-Carnitine (3-hydroxy-4-Ν-trimethylaminobutyrate)

L-carnitine is a naturally occurring fatty acid transporter. It
is directly involved in the transport of fatty acids into the
mitochondrial matrix for subsequent β-oxidation, but it also
functions in removal of excess acyl groups from the body
and in the modulation of intracellular coenzyme A (CoA)
homeostasis. L-carnitine helps fatty acids cross the inner
mitochondrial membrane to be used as energy. It also
scavenges reactive oxygen and binds iron. L-carnitine
also has been shown to prevent the damaging effects of
statins on the mitochondria. L-carnitine protects against
mitochondrial dysfunction associated with oxidative
stress caused by a series of conditions such as aging,
ischemia reperfusion, inflammation, degenerative diseases,
cancer and drug toxicity (Nicolson, 2014a; Rodriguez
et al., 2007; Nicolson, 2013). L-carnitine has been used to
increase the rate of mitochondrial oxidative phosphorylation.
L-carnitine also is essential for the detoxification of
environmental pollutants, meaning it can protect the mitochondria
on a number of levels.

L-Carnitine: 500 mg bid

Acetyl-L-Carnitine

Acetyl-L-Carnitine (ALCar) is an ester of the trimethylated
amino acid L- carnitine, and it is better absorbed and
more efficiently crosses the blood-brain barrier as compared
to L-carnitine. Dietary supplementation with Acetyl-L-Carnitine
might reverse age-related mitochondrial changes. ALCar
helps to restore mitochondrial membrane potential and
Cardiolipin levels. Cardiolipin is an important component of
the inner mitochondrial membrane, and it constitutes about
20% of the total lipid composition. ALCar facilitates fatty acid
transport into mitochondria, and it increases overall cellular
respiration. ALCar enhances cognitive performance, increased
production of neurotransmitters, and helps restores
levels of certain hormone receptors to more youthful levels.
ALCar reverses many aspects of age-related cellular dysfunction,
principally through maintenance of mitochondrial
function (Ames & Liu, 2004).

Acetyl-L-Carnitine: 250 mg bid

Idebenone (2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-
1,4-benzoquinone)

Idebenone is a CoQ10 analog that, while sharing some
of CoQ10s properties, offers unique mitochondrial-protective
benefits on its own. Idebenone is a powerful mitochondrial
free radical quencher that reduces the ever-increasing
damage to mitochondrial membrane and DNA that occurs
with age. Idebenone has also been shown to be more effective
than CoQ10 in protecting the electron transport chain.
When cellular oxygen levels are low, idebenone is actually
superior to CoQ10 for preventing free radical damage while
helping cells maintain relatively normal ATP levels (Giorgio
et al., 2012).

Idebenone: 150 mg qd

N-Acetyl Cysteine

N-Acetyl Cysteine (NAC) is the acetylated precursor of
both the amino acid L-cysteine and reduced glutathione
(GSH). A major cause of mitochondrial dysfunction is due
to changes that take place in the respiratory chain where
oxidative phosphorylation occurs. NAC has a positive effect
on key elements of the respiratory chain. It increases
the activities of mitochondrial Complexes I, IV and V. NAC
also helps maintain levels of glutathione, an important antioxidant
capable of preventing damage to important cellular
components caused by reactive oxygen species. NAC protects
cells by promoting oxidative phosphorylation, improving
mitochondrial membrane integrity, and enhancing mitochondrial
homeostasis (Banaclocha, 2001).

N-Acetyl Cysteine: 600 mg qd

(R) Alpha Lipoic Acid (1,2-dithiolane-3-pentanoic acid)

Alpha-lipoic acid (ALA) is a potent antioxidant, transition
metal ion chelator, redox transcription regulator, and
anti-inflammatory agent. It acts as a critical cofactor in
mitochondrial α-keto acid dehydrogenases, and thus it is
important in mitochondrial oxidative-decarboxylation reactions.
ALA is an amphipathic molecule with both hydrophilic
and hydrophobic properties. This makes ALA a perfect molecule
to establish communication between the cytoplasm
and mitochondria. ALA acid may also have mitochondrial
resuscitating properties. By providing ALA for two weeks
mitochondrial oxygen consumption was completely restored.
It was also found that ALA, like ALCar, increased
mitochondrial membrane potential of by up to 50 percent.
ALA supplementation also increased mitochondrial glutathione
and vitamin C concentrations, indicating ALA may
have the ability to reverse the age-associated decline in
low molecular weight antioxidants, therefore reducing the
risk for oxidative damage that occurs with aging. ALA supplementation
improves mitochondrial function, alleviates
some of the age-related loss of metabolic activity, increases
ATP synthesis and aortic blood flow, and increases glucose
uptake. Furthermore ALA supplementation may be
a safe and effective means to improve general metabolic
function (Hagen et al., 1999).

(R) Alpha Lipoic Acid: 300 mg bid

Omega 3 Fatty Acids (Eicosapentaenoic acid (EPA) and
Docosahexaenoic acid (DHA))

Omega-3 fatty acids from fish oils are cardio-protective.
They minimize d the increase in mitochondrial calcium content,
increase d levels of phosphatidylcholine, and prevent s
the decrease in cardiolipin content. Omega-3’s may also be
important in mitochondrial membrane restoration. An ome
ga-3 rich diet directly increases mitochondrial membrane
cardiolipin concentrations, increases the ratio of mitochondrial
membrane omega-3 to omega-6, and increases tolerance
of the heart to ischemia and reperfusion (Hansford,
Naotaka & Pepe, 1999). The propensity for ROS/RNS
emissions increases with omega-3 supplementation, although
there are no changes in markers of lipid or protein
oxidative damage. These results demonstrate that omega-
3 supplementation improves mitochondrial ADP kinetics,
suggesting post-translational modification of existing
proteins (Herbst et al., 2014).

Omega 3 Fatty Acids: 1g tid (molecularly distilled)

Vitamin C (Ascorbic Acid)

Vitamin C may improve mitochondrial function by providing
needed H from the conversion of ascorbic acid to
dehydroascorbic acid (Herbst et al., 2014). Also related to
Vitamin C’s electron moving ability it may be considered
an ergogenic aid (Gonzalez, Miranda & Riordan, 2005).
Vitamin C is taken up by the mitochondria and is able to
preserve mitochondrial membrane potential (Gonzalez et
al., 2010; Ohta, 2012; Heaney et al., 2008). Even modest
blood glucose elevations as they typically occur after a
Western diet meal competitively impair the transport of
ascorbic acid into immune cells (Ohta, 2012; Heaney et
al., 2008). Vitamin C is structurally similar to glucose so
it competes for the Glut receptors (Krone & Ely, 2005; Ely
& Krone, 2002; KC, Cárcamo & Golde, 2005; Gonzalez et
al., 2005).

Vitamin C: 500 mg tid. Consider bowel tolerance dosing or
intravenous administration

B-Complex Vitamins

The B vitamins are water-soluble vitamins required as
cofactors for enzymes essential in cell function and energy
production (Depeint, Bruce, Shangari, Mehta & O’brien,
2006).

Thiamine (Vitamin B1)

Thiamin is active in the form of thiamin pyrophosphate
(TPP). As a cofactor, TPP is essential to the activity of cytosolic
transketolase and pyruvate dehydrogenase, as well as
mitochondrial dehydrogenases -ketoglutarate dehydrogenase
and branched chain keto acid dehydrogenase. Large
doses of thiamine (vitamin B1) have been used to stimulate
NADH, which then augments oxidative phosphorylation
at Complex I (Depeint, Bruce, Shangari, Mehta & O’brien,
2006; Lou, 1981).

Thiamine: 100 mg qd

Riboflavin (Vitamin B2)

Riboflavin is a precursor to flavin adenine dinucleotide
(FAD) and flavin mononucleotide (FMN). As prosthetic
groups they are essential for the activity of flavoenzymes
including oxidases, reductase and dehydrogenases. Riboflavin
is a water-soluble B vitamin (B2). It is a key
building block in complex I and II and a cofactor in several
other key enzymatic reactions involving fatty acid oxidation
and the Krebs cycle. Riboflavin improved exercise
capacity in a patient with a mitochondrial myopathy due
to a Complex I dysfunction (Arts, Scholte, Bogaard, Kerrebijn
& Luyt-Houwen, 1983; Driver & Georgiou, 2002).

Riboflavin 100 mg qd

Niacin (Vitamin B3)

Niacin is a precursor to reducing groups nicotinamide
adenine dinucleotide (NAD+) and nicotinamide adenine
dinucleotide phosphate (NADP+). These molecules are
involved in more than 500 enzymatic reactions. For the
focus of this review, it is important to note that NAD/
NADP are involved in reactions pertaining to mitochondrial
respiration, glycolysis or even lipid Beta-oxidation.
Niacin ameliorated age-related changes in bioenergy
(Driver & Georgiou, 2002; Huskisson, Maggini & Ruf,
2007).

Niacin: 50 mg qd

Pantothenic Acid (Vitamin B5)

Pantothenic acid is the precursor of coenzyme A
(CoA), a molecule essential for 4% of known enzymatic
reactions. In the interest of this review it is important to
note the role of CoA in heme synthesis, lipid metabolism
or as a prosthetic group in the TCA cycle (Bratman &
Kroll, 2000).

Pantothenic Acid: 50 mg qd?

Magnesium

Magnesium ion plays an important role in a wide variety
of biochemical processes including optimizing mitochondrial
function and the creation of ATP, regulation of
blood sugar, and the activation of muscles and nerves.
Magnesium ions are critical for the optimization of the
mitochondria, which have enormous potential to influence
cancer. In fact, optimizing mitochondrial metabolism
may be at the core of effective cancer treatment
(Gröber, Schmidt & Kisters, 2015).

Magnesium (Citrate 500 mg tid. Dose may be reduced
as needed per osmotic laxative effect.

Phospholipids

Phospholipids are an important class of lipids found in
all cellular membranes. Glycerolphospholipids, the type of
phospholipid found in cellular and intracellular membranes,
are made up of two fatty acids (long chains of hydrogen and
carbon molecules), which are attached to a glycerol ‘head.’
The glycerol molecule is also attached to a phosphate
group, and this is the hydrophilic part of the molecule. The
glycerolphospholipids help cellular membranes and act not
only as diffusion barriers but also as dynamic cell organelles,
contributing to the synthesis of intracellular mediators, such
as arachidonic acid and inositol phosphates. Glycerolphospholipids
interact and work with integral membrane proteins
to modulate various cellular activities. As membrane phospholipids
are known to be essential to cellular membrane
function and cell viability, their modification and restoration
by exogenous dietary phospholipids remains a useful approach
for maintaining and restoring cellular membrane
function.

Cell membranes control a variety of cellular processes,
as well as the maintenance of a structural and ionic barriers
and intercellular communication networks (as mentioned
above). They are also involved in cell transport, secretion,
recognition, adhesion and other important cell functions.
Membrane lipids provide at least four major requirements
for cellular health. They are used as: (1) an important energy
storage reservoir; (2) the matrix for all cellular membranes,
enabling separation of enzymatic and chemical
reactions into discrete cellular compartments; (3) bioactive
molecules in certain signal transduction and molecular recognition
pathways; and (4) important functional molecules
that undergo interactions with other cellular constituents,
such as proteins and glycoproteins. This latter characteristic
is an absolute requirement for the formation, structure and
activities of biological membranes (Nicolson, 2013; Nicolson
& Ash,2014; Nicolson et al., 2016; Nicolson, 2014b). Phospholipids
contribute to the physicochemical properties of the
membrane and thus influence the conformation and function
of membrane-bound proteins, such as receptors, ion channels,
enzymes, and transporters, and they also influence
cell function by serving as precursors for prostaglandins and
other signaling molecules. Finally, they can modulating gene
expression through the activation of transcription.

One of the fundamental biochemical differences between
tumor cells and normal cells is the composition of the membrane
lipid matrix, including glycophospholipids and other
lipids and their oxidation state. Membrane peroxidation can
modify phospholipid structure, affecting lipid fluidity, permeability
and membrane function (Nicolson & Ash, 2014;
Nicolson et al., 2016; Nicolson, 2014b). In addition, the intracellular
trafficking of phospholipids, which plays a crucial
role in phospholipid homeostasis, can also be modified by
peroxidation events. In the mitochondria the activities of the
enzymes involved in cellular respiration are markedly influenced
by the composition and oxidation state of the phospholipids
of the inner mitochondrial membrane. Oxidation of
inner mitochondrial membrane phospholipids can result in
increased leakiness of the inner mitochondrial membrane.
Leaky mitochondrial membranes cause mitochondrial impairment
and loss in the production of ATP. When there is
progressive functional loss of mitochondrial function, such
as in the excessive oxidative modification of the mitochondrial
membrane phospholipids, can cause changes in health
that could progress to disease.

The outer mitochondrial membrane encloses the entire
organelle and has a protein-to-phospholipid ratio similar to
that of eukaryotic plasma membranes. The outer mitochondrial
membrane contains transport proteins called porins
(Kühlbrandt, 2015). The inner mitochondrial membrane is
rich in the phospholipid cardiolipin, which is characteristic of
the bacterial plasma membrane and is important in electron
transport function and provides yet more evidence suggesting
the mitochondrion’s bacterial origin.

Maintenance of the appropriate phospholipid composition
in the mitochondrial membranes is essential for mitochondrial
structure and function. Thus, mitochondria depend on
phospholipid metabolism, the transport of phospholipids into
mitochondria, and supply of appropriate lipids from the diet.
Regulation of the synthesis, trafficking, and degradation of
phospholipids is essential to maintain phospholipid homeostasis
in the mitochondria. An important element of phospholipid
homeostasis is that the phospholipids in the mitochondria
can be modified by dietary glycerolphospholipids
and fatty acids.

Membrane Lipid Replacement (MLR), the use of functional
oral supplements containing cell membrane glycerolphospholipids
and antioxidants, can safely replace damaged
membrane phospholipids. Most if not all clinical conditions
are characterized by membrane phospholipid oxidative
damage, resulting in loss of membrane and cellular function
(Nicolson & Ash, 2014; Nicolson et al., 2016; Nicolson,
2014b). Orally ingested phospholipids can be degraded into
their constituent parts and absorbed; they can be taken in
as intact molecules without degradation, or they can be absorbed
as small phospholipid droplets and micelles (Nicolson
& Ash, 2014; Nicolson et al., 2016; Nicolson, 2014b).
Eventually they are delivered to tissues and cells where they
are transferred by membrane contact and carrier or transport
proteins to various cellular and organelle membranes.

MLR plus antioxidants has been used to reverse ROS/
RNS damage and increase mitochondrial function in certain
clinical disorders, such as chronic fatigue, CFS and Fibromyalgia
(Nicolson & Ash, 2014; Nicolson et al., 2016; Nicolson,
2014b). In these disorders MLR has been found to be effective
in preventing ROS/RNS-associated changes and reversing
mitochondrial damage and loss of function (Nicolson & Ash,
2014). MLR is possible because cellular lipids are in dynamic
equilibrium in the body. Thus functional oral MLR supplements
containing cell membrane glycerolphospholipids and antioxidants,
has been used to replace damaged, usually oxidized,
membrane glycerophospholipids that accumulate during aging
and in various clinical conditions. Once delivered to membrane
sites, they naturally replace and stimulate removal of damaged
membrane lipids. Various chronic clinical conditions are characterized
by membrane damage, mainly oxidative but also
enzymatic, resulting in loss of cellular function. This is readily
apparent in mitochondrial inner membranes where oxidative
damage to phospholipids like cardiolipin and other molecules
results in loss of transmembrane potential, electron transport
function and generation of high-energy molecules.

Phospholipids (mixed): 1g tid for anti-aging and 2g tid fo r
chronic illnesses.

Ginkgo Biloba (Salisburia Adiantifolia)

Ginkgo biloba is one of the oldest living tree species. It is
also one of the best-selling herbal supplements in the United
States and Europe. Ginkgo leaves contain flavonoids and
terpenoids. A growing volume of data confirms that Ginkgo
biloba extract (GBE) reduces oxidative stress and improves
mitochondrial respiration (Eckert, 2012). Ginkgo biloba extract
has been found to protect mitochondrial DNA (MtDNA)
against oxidative damage and oxidation of mitochondrial
glutathione (Eckert et al., 2003).

Ginko Biloba: 40 mg bid.

Succinate (Succinic acid)

Succinate is a tricarboxylic acid (Krebs) cycle intermediate
that donates electrons directly to Complex II. Succinates
have been widely used for their alleged ability to enhance
athletic performance (Sastre, Pallardo, De la Asuncion &
Vina, 2000; Nowak, Clifton & Bakajsova, 2008). Succinate
Ameliorates Energy Deficits (Nowak, Clifton & Bakajsova,
2008). It seems that the use of succinates is even more
effective when a balance of several salts is used, especially
combinations of magnesium and potassium.

Succinate: 125 mg qd.

Pyrroloquinoline Quinone (PQQ)

PQQ is a small molecule that has act as a Redox agent in
cells, it can modify cell signaling and support mitochondrial
function. PQQ is reported to participate in a range of biological
functions. PQQ protects mitochondria from oxidative
stress. It also promotes the spontaneous generation of new
mitochondria, a process known as mitochondrial biogenesis
or mitochondriogenesis (Rucker, Chowanadisai & Nakano,
2009; Stites, Mitchell & Rucker, 2000; Chowanadisai, Bauerly,
Tchaparian & Rucker, 2007). This effect is an improvement
in mitochondrial function.

Pyrroloquinoline Quinone: 20 mg qd.

Sodium Bicarbonate

Sodium bicarbonate (NaHCO3) is a salt composed of
sodium ions and bicarbonate ions. The glycolytic nature of
malignant tumors contributes to high levels of extracellular
acidity in the tumor microenvironment. The extracellular pH
of malignant tumors is acidic (pH 6.5-6.9) compared to normal
tissue (pH 7.2-7.4). Tumor acidity is a driving force for
cellular division, invasion and metastases (Griffiths, 1991;
Vaupel, Kallinowski & Okunieff, 1989; Wike-Hooley, Haveman
& Reinhold, 1984; Robey & Martin, 2011). Recently,
it has been shown that buffering of extracellular acidity
through systemic administration of oral bicarbonate may
inhibit the spread of metastases.

Dose to individualized effect to achieve urine pH of 7.5-8,
while not consuming excess sodium.

Nicotinamide Adenine Dinucleotide (NADH)

NADH functions as a cellular redox cofactor in over 200
cellular redox reactions and as substrate for certain enzymes.
NADH delivers electrons from metabolite hydrolysis
to the electron transport chain, but in its reduced form, it
can also act as a strong antioxidant. Pyruvate is converted
to lactate, which requires all the glycolytic NADH output to
be converted to NAD+, and this lactate is then excreted
from the cell. Thus, aerobic glycolysis does not produce
any net output of NADH. NADH can be successfully administered
orally or by intravenous/intraperitoneal infusion
(Rex, Hentschke & Fink, 2002).

NADH: 20 mg qd.

D-Ribose

Ribose is a naturally occurring 5-carbon sugar produced
in the body from glucose. In addition to serving as the carbohydrate
backbone for ribonucleic acid (RNA) and deoxyribonucleic
acid (DNA), ribose is also an essential ingredient
in the manufacture of ATP. Thus ribose provides the
key building block of ATP. The mitochondria of high-energy
output organs such as the heart, liver, adrenals, GI tract,
brain, muscles and endocrine glands utilize two methods
for building or conserving cyclic nucleotides like ATP, ADP
and AMP. The first process by which these nucleotides are
synthesized is the de novo pathway, in which nucleotides
are made using ribose. This is the slower of the two pathways.
The second or faster pathway is the salvage pathway,
in which the mitochondria pick up ATP metabolites to
form new ATP. In this manner ribose enables the cells to
more quickly and efficiently recycle (i.e., salvage) the end
products formed by the breakdown of ATP to form new ATP
molecules. Thus, the ribose salvage pathway is known as
the salvage pathway of ATP formation. Ribose is essential
for both the salvage and de novo reactions to work, and it
is formed in the body from glucose, through the pentose
phosphate pathway. Aside from this relatively time-consuming
pathway, there are no foods that are able to provide
enough ribose to rapidly restore ribose levels, should the
need arise, as when exercising or working, and especially
during a heart attack or stroke.

D-ribose is another excellent addition to the mitochondrial
resuscitation regimen. D-ribose reduces markers of
oxidative stress that can form after high-intensity exercise
(Seifert et al., 2009). It also boosts post-exercise ATP
levels (Dhanoa & Housner, 2007) and has shown to have
beneficial effects in heart disease patients (MacCarter et
al., 2009). D-ribose replenishes low myocardial energy
levels, improving cardiac dysfunction following ischemia.
Studies also have shown it can improve ventilation efficiency
in patients with heart failure (Seifert et al., 2009).
The presence of ribose in the cell stimulates the metabolic
pathway to actually produce ATP. If the cell does not
have enough ribose, it cannot make ATP.

Oral or intravenous ribose has been found to rapidly
restore ribose levels in nerves and muscles. Ribose supplementation
can dramatically improve recovery of failing
ATP levels during and following acute or chronic anoxia
or ischemia. Research has shown that taking ribose has a
positive effect on ATP production in all muscle fiber types,
especially the heart. Ribose supplementation increases
the de novo production of ATP through oxidative phosphorylation
by more than 300 percent. Ribose also activates
the salvage pathway, causing nucleotides to be revitalized
into the manufacture of ATP by over 500 percent (Berg,
Tymoczko & Stryer, 2002).

Ribose has also been shown to increase athletic performance.
Supplementation (ten grams per day) in young male
recreational bodybuilders resulted in significant increases
in muscular strength and total work performance after four
weeks, compared with pre-treatment levels. No changes
were noted in those using a placebo (Van Gammeren, Falk
& Antonio, 2002).

D-Ribose: 5g qd.

Citrate

A citrate is a derivative of citric acid. Citric acid is a weak
organic tricarboxylic acid. It occurs naturally in citrus fruits.
It is an intermediate in the citric acid cycle, which occurs
in the metabolism of all aerobic organisms. Citrate inhibits
the phosphofructokinase enzyme blocking glycolysis at the
start; citrate also inhibits the pyruvate dehydrogenase enzyme
complex. Citrate also inhibits the succinate dehydrogenase
enzyme. These citrate or citric acid properties have
the capacity to inhibit glycolysis and a step in Krebs cycle;
the citrate inhibits three base enzymes in the mitochondrial
metabolism of Krebs cycle (Tornheim & Lowenstein, 1976;
Taylor & Halperin, 1973; Hillar, Lott & Lennox, 1975; Velichko,
Trebukhina & Ostrovskii, 1981; Bucay, 2007).

Citrate: No suggested dose.

Creatine

Creatine is an essential, natural substance that is synthesized
in the body from three amino acids: glycine, arginine,
and methionine. Creatine plays a very powerful role in energy
metabolism as a muscle fuel in its role in regenerating
ATP. Creatine combines with phosphate in the mitochondria
to form phosphocreatine. It serves as a source of high-energy
phosphate, released during anaerobic metabolism. It
also acts as an intracellular buffer for ATP and as an energy
shuttle for the movement of high-energy phosphates from
mitochondrial sites of production to cytoplasmic sites of utilization
(Keys, 1943; Kreider et al., 1998; Vandenberghe et
al., 1997; Stone et al., 1999; Urbanski, Vincent & Yuaspelkis,
1999; Volek et al., 1997; Cooke et al., 2014; Ferraro et al.,
1996; Tarnopolsky, 2000; Hespel, 2000; Cooper, Naclerio,
Allgrove & Jimenez, 2012). Operating through the ATP/ADP
cycle, creatine phosphate maintains ATP levels by serving
as a reservoir of high-energy phosphate bonds in muscle
and nerve tissues. The energy required to rephosphorylate
ADP into ATP depends on the amount of phosphocreatine
(PCr) stored in muscle tissues. As phosphocreatine is depleted
during exercise, energy availability declines due to a
loss of ability to resynthesize ATP at the rate required.

In 1943, it was shown that creatine supplementation extended
the cycling times of athletes (Keys, 1943). Creatine
enhances both strength and endurance in athletes (Keys,
1943; Kreider et al., 1998; Vandenberghe et al., 1997; Stone
et al., 1999; Urbanski, Vincent & Yuaspelkis, 1999; Volek
et al., 1997; Cooke et al., 2014; Ferraro et al., 1996; Tarnopolsky,
2000; Hespel, 2000; Cooper, Naclerio, Allgrove &
Jimenez, 2012). Some researchers have shown strength
gains with as little as five to seven days of supplementation
(Cooper, Naclerio, Allgrove & Jimenez, 2012). In a double
blind study that examined the effects of creatine in a
weight training program in men over 70 It was shown that
creatine had a significant advantage over placebo in terms
of increased lean body mass, reduction in body fat, and increased
muscular strength, and endurance (Cooke et al.,
2014; Tarnopolsky, 2000). In Italy, physicians administered
six grams of creatine each day to 13 patients hospitalized
with congestive heart failure. After four days, they noted a
reduction in heart size, reduced vascular resistance, and
increased ejection fraction, all indicators of improved heart
function (Ferraro et al., 1996).

In a review article, Tarnopolsky concluded that creatine
monohydrate supplementation results in an increase in skeletal
muscle total and phosphocreatine concentrations, increased
fat-free mass, and enhanced high-intensity exercise
performance in young healthy men and women (Tarnopolsky,
2000). He also noted neuroprotective effects, which have been
proposed to be of benefit in Parkinson’s disease, Alzheimer’s
disease, ALS, and after ischemia. He concluded that creatine
appeared to have potential to attenuate age-related muscle atrophy
and strength loss, as well as to protect against neurodegenerative
disorders. The U.S. FDA has granted orphan drug
status to creatine as a treatment for patients with amyotrophic
lateral sclerosis (Lou Gehrig’s disease), based on creatine’s
demonstrated ability to enhance cellular energy production. In
addition, a European patent has also recently been issued for
the use of creatine compounds to prevent aging effects and to
treat muscle atrophy (Hespel, 2000).

Creatine: 5g qd.

Shilajit

Shilajit is a thick, sticky tar-like substance with a color
ranging from white to dark brown (the latter is more common)
found predominately in Himalaya and Tibet mountains. It is an
ancient Indian adaptogen. Shilajit enhances CoQ10’s mitochondrial
benefits and supports levels of the active ubiquinol
form. Components of shilajit can serve as electron reservoirs,
replenishing electrons lost by CoQ10 and allowing this vital
coenzyme to remain active longer (Surapaneni, 2012).

Shalajit: 200 mg qd.

Mushrooms

Coriolus versicolor (Turkey tail), is a mushroom of the
Basidiomycetes class from which the extracts Polysaccharide-
K and Polysaccharide-Peptide (PSK, PSP, respectively)
have demonstrated to inhibit various carcinomas in animals
and humans. This is achieved by inducing apoptosis and
activating a cascade of pathways involving the activation
of p38 MAPK signaling cascades and over-expression of
pro-apoptotic protein Bax (Kobayashi, Matsunaga & Oguchi,
1995). PSK was approved for clinical use in various cancers
in Japan in the 1980s. Other mushrooms that seem to have
analogous effects on mitochondria are Reishi (Ganoderma
lucidum; Ko & Leung, 2007; Cherian, Sudheesh, Janardhanan
& Patani, 2009; Sudheesh, Ajith, Mathew, Nima &
Janardhanan, 2012) Maitake (Grifola frondosa; Soares et al.,
2011; Zhang et al., 2017) Shiitake (Lentinula edodes; Fang
et al., 2006), Cordyceps (Ophiocordyceps sinensis; Lee et
al., 2015), Chaga (Inonotus obliquus, Sun et al., 2011), Lion’s
Mane (Hericium erinaceus; Kim, Nam & Friedman, 2013).

Mushrooms: No suggested dose.

Herbs

Certain herbs such as Rhodiola rosea (Abidov, Crendal,
Grachev, Seifulla & Ziegenfuss, 2003), Leuzea carthamoides
(Azizov, Seifulla & Chubarova, 1997), Eleutherococus senticosis
(Eschbach, Webster, Boyd, McArthur & Evetovich,
2000) and Schisandra chinensis (Panossian & Wikman,
2008) have shown certain capacity to activate synthesis and
resynthesis of ATP.

Rhodiola has been taken 200 mg qd of an extract standardized
to contain rosavins and salidrosides in a 3:1 ratio: For the
rest of the herbs there is no suggested dose.

Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is a methoxyindole,
which is synthesized in the pineal gland of vertebrates
through a multistep process starting from hydroxylation
of tryptophan and culminating with transformation of
serotonin to N-acetyl serotonin followed by methylation to
the final substance melatonin. Melatonin is a ubiquitous molecule
with a variety of functions including potent reductive
properties. Due to its lipophilic character, it easily crosses
cellular and intracellular membranes and reaches all subcellular
organelles. Melatonin has been shown to protect
the bio-energetic function of mitochondria (Acuña-Castroviejo
et al., 2001; León et al., 2005; Petrosillo et al., 2006;
Kleszczyński, Zillikens & Fischer, 2016).

Melatonin: 10 mg qd before sleep.

Arginine

Arginine is a basic amino acid and is classified as a conditionally
essential amino acid. One of the main functions of
arginine is its participation in protein synthesis. Arginine is
utilized by a number of metabolic pathways that produce a
variety of biologically active compounds such as nitric oxide,
creatine, agmatine, glutamate, polyamines, ornithine, and
citrulline. Also, arginine is involved in a number of roles in
the body such as the detoxification of ammonia formed during
the nitrogen catabolism of amino acids via the formation
of urea; its potential to be converted to glucose (hence its
classification as a glycogenic amino acid); and its ability to
be catabolized to produce energy (Nagaya et al., 2001; Xu
et al., 2016). Many of the benefits of arginine stem from its
ability to generate nitric oxide, aided by an enzyme called
nitric oxide synthase. Nitric oxide (NO) acts as a signaling
molecule that induces smooth muscle cells to relax, expanding
the blood vessels (vasodilation), blood pressure drops
and blood flow is improved. More blood is delivered to the
tissues, which are then better nourished with oxygen.

Arginine: 700 mg tid.

Resveratrol

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a
plant-derived polyphenol that exerts diverse physiological
activities, mimicking some of the molecular and functional
effects of dietary restriction. Resveratrol has been shown to
increase cellular mitochondrial content and induce apoptosis
(Lagouge et al., 2006; De Oliveira, Nabavi, Manayi, et al.,
2016; Ungvari, Sonntag, de Cabo, Baur & Csiszar, 2011).

Resveratrol: 20 mg qd.

Quercetin

Quercetin is a naturally occurring flavonoid which has a
broad spectrum of bioactive effects. Among these, quercetin
can impact mitochondrial biogenesis by modulating enzymes
and transcription factors. Quercetin is now recognized as a
phytochemical that can modulate pathways associated with
mitochondrial biogenesis, mitochondrial membrane potential,
oxidative respiration and ATP anabolism, intra-mitochondrial
redox status, and subsequently, mitochondria-induced
apoptosis (De Oliveira, Nabavi, Braidy, et al., 2016).

Quercetin: 500 mg bid.

Glutathione

Glutathione (GSH) is the major intracellular thiol compound,
is an ubiquitous tripeptide produced by most mammalian
cells and it is the main mechanism of antioxidant
defense against reactive oxygen species (ROS) and electrophiles.
GSH versatility permits it to counteract hydrogen
peroxide, lipid hydroperoxides, or xenobiotics, mainly as
a cofactor of enzymes such as glutathione peroxidase or
glutathione-S-transferase (GST). GSH (γ-glutamyl-cysteinyl-
glycine) serves as a cofactor for a number of antioxidant
and detoxifying enzymes. GSH in the mitochondrial matrix
plays a key role in defense against respiration-induced ROS
and in the detoxification of lipid hydroperoxides and electrophiles.
Moreover, as mitochondria play a central strategic
role in the activation and mode of cell death, mitochondrial
GSH has been shown to critically regulate the level of sensitization
to secondary hits that induce mitochondrial membrane
permeabilization and release of proteins confined in
the intermembrane space necessary to induce cell death
(apoptosis; Ribas, García-Ruiz & Fernández-Checa, 2014).

Oral glutathione supplementation does not efficiently increase
intracellular glutathione levels, it can be absorbed
intact into the blood stream. Since increased glutathione
levels in the blood have been shown to slow the breakdown
of nitric oxide, glutathione supplementation may be useful to
augment nitric oxide boosters such as L-Citrulline or L-Arginine.
N-Acetylcysteine (NAC) is a prodrug for L-cysteine,
which is used for the intention of allowing more glutathione
to be produced when it would normally be depleted. Through
glutathione buffering, NAC provides antioxidative effects
and other benefits, so is both more efficient and cheaper
than glutathione. Liposome-encapsulated glutathione (Lypo-
GSH) seems to be a more effective way to supplement
this nutrient.

Glutathione: 250 mg qd.

Dichloroacetate (DCA)

DCA is a potent lactate-lowering drug. It activates the
pyruvate dehydrogenase complex by inhibiting the activity of
pyruvate dehydrogenase kinase, which normally phosphorylates
and inhibits the enzyme. The ability of DCA to keep
the pyruvate dehydrogenase complex in an active state reduces
the accumulation of lactate in body tissues (Parikh
et al., 2009; Khan, Govindaraj, Meena & Thangaraj, 2015;
Avula, Parikh, Demarest, Kurz & Gropman, 2014). DCA can
switch a cell from aerobic glycolysis to oxidative respiration.
This drug induced apoptosis of cancer cells (Bonnet
et al., 2007) by reducing mitochondrial membrane potential,
blocking aerobic glycolysis (Warburg effect), and activating
mitochondrial potassium-ion channels (Khan, Marier, Marsden,
Andrews & Eliaz, 2014). Other mechanisms of DCA action
against cancer cells have also been proposed. These
include: (a) inhibition of angiogenesis; (b) alteration of expression
of hypoxia-inducible factor 1-α (HIF1-α),21; and (c)
alteration of pH regulators vacuolar-type H+-ATPase (V-ATPase)
and monocarboxylate transporter 1 (MCT1) and other
regulators of cell survival, such as p53-upregulated modulator
of apoptosis (PUMA), glucose transporter 1 (GLUT1),
B-cell lymphoma 2 (BCL2) protein, and cellular tumor antigen
p53 (127).

An oral DCA regimen that included the natural neuroprotective
medications acetyl-L-carnitine, R-α-lipoic acid, and
benfotiamine (DD) has been used clinically. IV DCA up to
100 mg/kg/dose that have confirmed its safety. Shifts in ATP
production from glycolysis to oxidative phosphorylation by
inhibition of PDK1 with dichloroacetate (DCA) was shown to
shift metabolism from glycolysis to glucose oxidation. Treatment
with DCA increased mitochondrial production of ROS/
RNS in all tested cancer cells, but not in normal cells (Michelakis,
Webster & Mackey, 2008).

It is important to mention that DCA in high doses can
damage mitochondria and produce peripheral neuropathy.
Peripheral neuropathy is not uncommon with prolonged
DCA treatment.

Dichloroacetate: No suggested dose.

3-Bromopyruvate

Bromopyruvic acid and its alkaline form, bromopyruvate,
are synthetic brominated derivatives of pyruvic acid. They are
lactic acid and pyruvate analogs. 3-Bromopyruvate (BP) has
been shown by others to inhibit hexokinase (Ihrlund, Hernlund,
Khan & Shoshan, 2008). Being a lactate analogue, it
is likely taken up by cells via lactate transporters which are
overexpressed in tumor cells (Ihrlund, Hernlund, Khan & Shoshan,
2008). This drug may have significant side effects.

3-Bromopyruvate: No suggested dose.

2-Deoxyglucose

2-deoxyglucose (DG) is a non-metabolizable glucose analogue.
DG is a glucose analogue which is easily taken up by
tumor cells via glucose transporters and is then phosphorylated
by hexokinase, but it is not further metabolized in the glycolytic
process (Pedersen, 2007). DG will thus titrate endogenous
glucose and thereby block glycolysis (Zhao, Wieman,
Jacobs & Rathmell, 2008; Cantor & Sabatini, 2012).

2-Deoxyglucose: No suggested dose.

EPI-743

EPI-743 is a new drug that is based on vitamin E. EPI-
743 is a para-benzoquinone analog. Tests have shown that
it can help improve the function of cells with mitochondrial
problems. It works by improving the regulation of cellular
energy metabolism by targeting an enzyme NADPH quinone
oxidoreductase (Enns & Cohen, 2017).

EPI-743: No suggested dose.

Lifestyle and mitochondria

Exercise

Dietary interventions are just one part of the overall picture
of optimizing mitochondrial function. Other lifestyle considerations
like exercise, movement, stress and sleep also play
a role in mitochondrial health. Exercise and movement has
been shown to improve cellular energy production (Sahlin,
2014). Both aerobic and anaerobic exercise should be performed
on a regular basis. Exercise also has an important
role in mitochondrial disease therapy, as it has been shown
to reduce the burden of unhealthy mitochondria; increase
the percentage of healthy, non-mutated mitochondrial DNA
(mtDNA); and improve endurance and muscle function.

Suggested exercise, combine aerobic exercises (such as
cycling, walking, running, hiking, and playing tennis, basketball
that focus on increasing cardiovascular endurance) and
anaerobic exercises ( such as weight training to increase
muscle strength) for 45 min 3x a week.

Hyperbaric (high pressure, 100%) Oxygen Therapy
(HBOT)

Hyperbaric oxygen treatment (HBOT) involves inhaling up
to 100% oxygen at a pressure greater than one atmosphere
(ATM) in a pressurized chamber. Excess oxygen reduces the
activity of an enzyme called hexokinase II, which grabs onto
glucose after it enters cells and traps it inside so it can be
burned for energy. Also HBOT significantly ameliorates mitochondrial
dysfunction (Dave et al., 2003; Rossignol et al.,
2012; Palzur, Zaaroor, Vlodavsky, Milman & Soustiel, 2008;
Moen & Stuhr, 2012; Poff, Ari, Seyfried & D’Agostino, 2013;
Poff, Ward, Seyfried, Arnold & D’Agostino, 2015). When cells
are proliferating and DNA is unwound, unprotected and being
replicated: if high ROS levels are sensed at this time, the process
is aborted and the cell can be driven into apoptosis.

Treatment: 45 min 1.5-2.5 ATM twice a week

Intravenous Laser Therapy (IVLT)

Laser Therapy works on the principle of inducing a biological
response through energy transfer, in that the photonic
energy delivered into the tissue by the laser modulate the
biological processes within the tissue. Light energy transmitted
through space as waves that contain tiny “energy packets”
called photons (Duality). Each photon contains a definite
amount of energy depending on its wavelength (color).

Intravenous or intravascular laser blood irradiation involves
the in-vivo illumination of the blood by feeding low
level laser light. It is a minimally invasive laser procedure in
which a small needle is placed into the vein in the forearm,
under the assumption that any therapeutic effect will be circulated
through the circulatory system.

It works similar to photosynthesis; the correct wavelengths
and power of light at certain intensities for an appropriate period
of time can increase ATP production and cell membrane
alterations could lead to permeability changes and second
messenger activity resulting in functional changes (Ferraresi
et al., 2015; Xu, Zhao, Liu & Pan, 2008; Momenzadeh et al.,
2015; Huang et al., 2012).

Acupuncture treatment (needles in cardinal points), increases
the patient’s energy but only by mobilizing reserve
energy (meridians), in contrast Laser therapy introduces additional
energy into the system.

Mitochondria are the key to photobiomodulation. The
cytochrome c oxidase can absorb red light converting the
photonic energy into biological energy ATP. Cytochrome
c oxidase is commonly accepted as a photo acceptor that
catalyzes cellular level activity when exposed to red to
near-infrared red light.

The absorption of different colors within the mitochondrial
respiratory chain:

Complex 1 (NADH dehydrogenase) absorbs blue and ultraviolet
light.

Complex 3 (cytochrome c reductase) absorbs green and
yellow light.

Complex 4 (cytochrome c oxidase) absorbs red and infrared
light.

Mitochondria changed to “giant mitochondria” after laser-
irradiation with activation of various metabolic pathways
and increased production of ATP due to activation of the
respiratory chain and increased ATP-synthesis. ATP is also
used as a signaling molecule in communications between
nerve cells and other tissues.

There is a normalization of the tissue metabolism due to increased
O2. There is also an increase of enzymes. An increase
of ATP-synthesis occurs with a normalization of cell membrane
potential. Irradiation in the red range is effective to increase the
absorption spectrum of cytochrome-C-oxidase in the respiratory
chain with a concomitant stimulation of the ATP-synthesis.

There is an increased change of the redox potential in mitochondria
and cytoplasm by oxidation at the NADH. Thereby
the proton motor force is increased which drives the backflow
of the protons into the matrix and by doing so increases the
ATP turnover. In addition the electron transfer is accelerated,
both effects cause an increase of ATP synthesis.

IVLT has Pleiotropic action that produces a cascade of
events due to increased Energy.

Treatment: IVLT 10 min of each color twice a week.
This therapy be accompanied by mitochondria-supporting
supplements.

Conclusions

Mitochondrial dysfunction has been identified as one of
the principal causes of bioenergetic decline. Although there
is no single silver bullet or an exact combination of substances
or supplements that will unfailingly resuscitate all aspects
of failing mitochondria, it has been reported that a number
of nutrients, supplements and prescription substances may
alleviate or restore many aspects of mitochondrial failure.
Combinations of these, acting on multiple targets, may normalize
and/or improve mitochondrial function, increase cellular
and systemic energy production, alleviate mitochondrial-
related disease, and delay age-related decline in many
organs and systems of the body.

The rise in the incidence of cancer and deaths from cancer
not only parallels the rise in the development and use of
toxic chemicals and materials in the environment, but also
toxins in our food and water supplies and pharmaceuticals.
The rise in cancer incidence and deaths is thought to be directly
caused by such toxic ingestion and the body’s increasing
inability to cope with the toxic overload of xenobiotics that
profoundly affects the mitochondria. It is conceivable that
combinations of various mitochondrial enhancers/resuscitators,
acting on various portions of the mitochondrial energy
production pathway will have complementary/additive effects
and decrease the cancer incidence and death rates.

Here we have proposed a combination of diet, exercise
and supplements containing a mixture of nutrients mentioned
herein to significantly enhance mitochondrial function
to help restore oxidative respiration to a level of favoring malignant
cell re-differentiation or to at least restore apoptotic
mechanisms since the intrinsic apoptotic pathway in cells is
regulated largely by functional mitochondria. When restoring
mitochondrial function, we may reverse aerobic glycolysis,
inhibit cancer cell growth and possibly, reverse malignancy.

Scientific support for the use of vitamin-based and cofactor-
based mitochondrial therapies is accumulating. This
Mitochondrial Correction (Mitochondrial Rescue, Mitochondrial
repair) approach is intended to promote critical enzymatic
reactions, reduce putative sequelae of excess free
radicals, and scavenge toxic metabolic molecules, which
tend to accumulate in mitochondrial diseases. Some supplements
also may act as alternative energy fuels or may
bypass biochemical blocks within the respiratory chain. We
believe this concept can have an important repercussion in
the treatment of degenerative diseases.

References:

Abidov, M., Crendal, F., Grachev, S., Seifulla, R., & Ziegenfuss,
T. (2003). Effect of extracts from Rhodiola rosea
and Rhodiola crenulata (Crassulaceae) roots on ATP
content in mitochondria of skeletal muscles. Bull Exp Biol
Med, 136(6), 585-7.
Acuña-Castroviejo, D., Martín, M., Macías, M., Escames,
G., León, J., Khaldy, H., & Reiter, R.J. (2001). Melatonin,
mitochondria, and cellular bioenergetics. J Pineal Res,
30(2), 65-74.
Ames, B.N., & Liu, J. (2004). Delaying the mitochondrial decay
of aging with acetyl L-Carnitine. Ann NY Acad Sci,
1033, 108–116.
Anand, P., Kunnumakara, A.B., Sundaram, C., Harikumar,
K.B., Tharakan, S.T., & Lai, O.S. (2008). Cancer is a preventable
disease that requires major lifestyle changes.
Pharm Res, 25(9), 2097–2116.
Arts, W.F.M., Scholte, H.R., Bogaard, J.M., Kerrebijn, K.F., &
Luyt-Houwen, I.E.M. (1983). NADH-CoQ reductase deficient
myopathy: Successful treatment with riboflavin. Lancet,
2, 581-82.
Avula, S., Parikh, S., Demarest, S., Kurz, J., & Gropman, A.
(2014). Treatment of Mitochondrial Disorders. Current
treatment options in neurology, 16(6), 292.
Azizov, A.P., Seifulla, R.D., & Chubarova, A.V. (1997). Effects
of leuzea tincture and leveton on humoral immunity of athletes.
Eksp Klin Farmakol, 60(6), 47-8.
Banaclocha, M. (2001). Therapeutic potential of N-acetylcysteine
in age-related mitochondrial neurodegenerative
diseases. Med Hypotheses, 56(4), 472-477.
Berg, J.M., Tymoczko, J.L., & Stryer, L. (2002). Biochemistry.
5th edition. New York: W H Freeman.
Bonnet, S., Archer, S.L., Allalunis-Turner, J., Haromy, A.,
Beaulieu, C., Haromy, A., Beaulieu, C., Thompson, R.,
Lee, C.T., Lopaschuk, G.D., Puttagunta, L., Bonnet, S.,
Harry, G., Hashimoto, K., Porter, C.J., Andrade, M.A., Thebaud,
B., & Michelakis, E.D. (2007). A mitochondria-K+
channel axis is suppressed in cancer and its normalization
promotes apoptosis and inhibits cancer growth. Cancer
Cell,11(1), 37-51.
Bratman, S., & Kroll, D. eds. (2000). Pantothenic acid and
pantethine. Natural Health Bible. Roseville, CA: Prima
Publishing, 275-276.
Bucay, A.H. (2007). The biological significance of cancer:
Mitochondria as a cause of cancer and the inhibition of
glycolysis with citrate as a cancer treatment. Med Hypotheses,
69, 826–828.
Butow, R.A., & Avadhani, N.G. (2004). Mitochondrial signaling:
the retrograde response. Mol Cell, 14, 1–15.
Cantor, J.R., & Sabatini, D.M. (2012). Cancer Cell Metabolism:
One Hallmark, Many Faces. Cancer discovery,
2(10), 881-898.
Cherian, E., Sudheesh, N.P., Janardhanan, K.K., & Patani, G.
(2009). Free-radical scavenging and mitochondrial antioxidant
activities of Reishi-Ganoderma lucidum (Curt: Fr)
P. Karst and Arogyapacha-Trichopus zeylanicus Gaertn
extracts. J Basic Clin Physiol Pharmacol, 20(4), 289-307.
Chowanadisai, W., Bauerly, K., Tchaparian, E., & Rucker,
R.B. (2007). Pyrroloquinoline quinone (PQQ) stimulates
mitochondrial biogenesis. FASEB J, 21, 854.
Conklin, K.A., & Nicolson, G.L. (2008). Molecular replacement
in cancer therapy: reversing cancer metabolic and
mitochondrial dysfunction, fatigue and the adverse effects
of therapy. Curr Cancer Therapy Rev, 4, 66-76.
Cooke, M.B., Brabham, B., Buford, T.W., Shelmadine, B.D.,
McPheeters, M., Hudson, G.M., Stathis, C., Greenwood,
M., Kreider, R., & Willoughby, D.S. (2014). Creatine supplementation
post-exercise does not enhance training-induced
adaptations in middle to older aged males. Eur J
Appl Physiol, 114(6), 1321-1332.
Cooper, R., Naclerio, F., Allgrove, J., & Jimenez, A. (2012). Creatine
supplementation with specific view to exercise/sports
performance: an update. J Intl Soc Sports Nutr, 9, 33.
Dalton, T.P., Shertzer, H.G., & Puga, A. (1999). Regulation of
gene expression by reactive oxygen. Ann Rev Pharmacol
Toxicol, 39, 67–101.
Dandona, P., Chaudhuri, A., Ghanim, H., & Mohanty, P. (2007).
Proinflammatory effects of glucose and anti-inflammatory
effect of insulin: relevance to cardiovascular disease. Am
J Cardiol, 99(4A), 15B-26B.
Dave, K.R., Prado, R., Busto, R., Raval, A.P., Bradley, W.G.,
Torbati, D., & Pérez-Pinzón, M.A. (2003). Hyperbaric oxygen
therapy protects against mitochondrial dysfunction
and delays onset of motor neuron disease in Wobbler
mice. Neuroscience, 120(1), 113–120.
De Oliveira, M.R., Nabavi, S.F., Manayi, A., Daglia, M., Hajheydari,
Z., & Nabavi, S.M. (2016). Resveratrol and the
mitochondria: From triggering the intrinsic apoptotic pathway
to inducing mitochondrial biogenesis, a mechanistic
view. Biochim Biophys Acta, 1860(4), 727-45.
De Oliveira, M.R., Nabavi, S.M., Braidy, N., Setzer, W.N.,
Ahmed, T., & Nabavi, S.F. (2016). Quercetin and the mitochondria:
A mechanistic view. Biotechnol Adv, 34(5), 532-
549.
Demetrius, L.A., Coy, J.F., & Tuszynski, J.A. (2010). Cancer
proliferation and therapy: the Warburg effect and quantum
metabolism. Theoretical Biology & Medical Modelling, 7, 2.
Depeint, F., Bruce, W.R., Shangari, N., Mehta, R., & O’brien,
P.J. (2006). Mitochondrial function and toxicity: role of the
B vitamin family on mitochondrial energy metabolism.
Chem Biol Interact,163(1-2), 94–112.
Dhanoa, T.S. & Housner, J.A. (2007). Ribose: more than a
simple sugar? Curr Sports Med Rep, 6(4), 254-7.
Driver, C., & Georgiou, A. (2002). How to re-energize old mitochondria
without shooting yourself in the foot. Biogerontology,
3, 103-106.
Eckert, A. (2012). Mitochondrial effects of Ginkgo biloba extract.
Int Psychogeriatr, 24(Suppl 1), S18–S20.
Eckert, A., Keil, U., Kressmann, S., Schindowski, K., Leutner,
S., Leutz, S., & Müller, W.E. (2003). Effects of EGb 761
Ginkgo biloba extract on mitochondrial function and oxidative
stress. Pharmacopsychiatry, 36(1), S15–S23.
Elliott, R.L., Jiang, X.P., & Head, J.F. (2015). Mitochondrial
organelle transplantation: introduction of normal epithelial
mitochondria into human cancer cells inhibits proliferation
and increases drug sensitivity. Breast Cancer Res Treat,
136(2), 347-54.
Elliott, RL, Jiang XP, & Head, J.F. (2015). Mitochondria organelle
transplantation: A potential cellular biotherapy for
cancer. J Surgery 2015; S(2), 9.
Ely, J.T., & Krone, C.A. (2002). Glucose and cancer. N Z Med
J,115, U123.
Enns, G.M., & Cohen, B.H. (2017). Clinical trials in mitochondrial
disease: An update on EPI-743 and RP103. J Inborn
Errors Metab and Screening, 5.
Eschbach, L.F., Webster, M.J., Boyd, J.C., McArthur, P.D., &
Evetovich, T.K. (2000). The effects of Siberian ginseng
(Eleutherococcus senticosus) on substrate utilization and
performance. Int J Sport Nutr Exerc Metab, 10(4), 444-
451.
Fang, N., Li, Q., Yu, S., Zhang, J., He, L., Ronis, M.J., &
Badger, T.M. (2006). Inhibition of growth and induction of
apoptosis in human cancer cell lines by an ethyl acetate
fraction from Shiitake mushrooms. J Altern Complement
Med, 12(2), 125-32.
Ferraresi, C., Kaippert, B., Avci, P., Huang, Y.Y., de Sousa,
M.V., Bagnato, V.S., Parizotto, N.A., & Hamblin, M.R.
(2015). Low-level laser (light) therapy increases mitochondrial
membrane potential and ATP synthesis in C2C12
myotubes with a peak response at 3-6 hours. Photochemistry
and Photobiology, 91(2), 411-416.
Ferraro, S., Codella, C., Palumbo, F., Desiderio, A., Trimigliozzi,
P., Maddalena, G., & Chiariello, M. (1996). Hemodynamic
effects of creatine phosphate in patients with
congestive heart failure: a double-blind comparison trial
versus placebo. Clin Cardio, 19(9), 699-703.
Giorgio, V., Petronilli, V., Ghelli, A., Carelli, V., Rugolo, M.,
Lenaz, G., & Bernardia, P. (2012). The effects of idebenone
on mitochondrial bioenergetics. Biochimica et Biophysica
Acta, 1817(2), 363-369.
Gonzalez, M.J., Massari, J.R.M., Duconge, J., Riordan, N.H.,
Ichim, T., Quintero-Del-Rio, A.I., & Ortiz, N. (2012). The
bio-energetic theory of carcinogenesis. Med Hypotheses,
79, 433–439.
González, M.J., Miranda-Massari, J.R., Mora, E.M., Guzmán,
A., Riordan, N.H., Riordan, H.D., Casciari, J.J., Jackson,
J.A., & Román-Franco, A. (2005). Orthomolecular oncology
review: Ascorbic acid and cancer 25 years later. Integr
Cancer Ther, 4, 32–44.
González, M.J., Miranda, J.R., & Riordan, H.D. (2005). Vitamin
C as an ergogenic aid. J Orthomolec Med, 20(2), 100-102.
González, M.J., Rosario-Pérez, G., Guzmán, A.M., Miranda-
Massari, J.R., Duconge, J., Lavergne, J., Fernandez,
N., Ortiz, N., Quintero, A., Mikirova, N., Riordan, N.H., &
Ricart, C.M. (2010). Mitochondria, Energy and Cancer:
The Relationship with Ascorbic Acid. J orthomolec Med,
25(1), 29-38.
Goodson, W.H. III, Lowe, L., & Carpenter, D.O., et al. (2015).
Assessing the carcinogenic potential of low-dose exposures
to chemical mixtures in the environment: the challenge
ahead. Carcinogenesis, 36(suppl 1), S254–S296.
Griffiths, J.R. (1991). Are cancer cells acidic? Br J Cancer,
64(3), 425-427.
Gröber, U., Schmidt, J., & Kisters, K. (2015). Magnesium in
Prevention and Therapy. Nutrients, 7(9), 8199-8226.
Hagen, T.M., Ingersoll, R.T., Lykkesfeldt, J., Liu, J., Wehr,
C.M., Vinarsky, V., Bartholomew, J.C., & Ames, A.B.
(1999). (R)-alpha-lipoic acid-supplemented old rats have
improved mitochondrial function, decreased oxidative
damage, and increased metabolic rate. FASEB J, 13(2),
411-8.
Hansford, R., Naotaka, T., & Pepe, S. (1999). Mitochondria in
heart ischemia and aging. Biochem Soc Symp, 66, 141-
147.
Heaney, M.L., Gardner, J.R., Karasavvas, N., Golde, D.W.,
Scheinberg, D.A., Smith, E.A., & O’Connor, O.A. (2008).
Vitamin C antagonizes the cytotoxic effects of antineoplastic
drugs. Cancer Res, 68(19), 8031-8038.
Herbst, E.A., Paglialunga, S., Gerling, C., Whitfield, J., Mukai,
K., Chabowski, A., Heigenhauser, G.J., Spriet, L.L., &
Holloway, G.P. (2014). Omega-3 supplementation alters
mitochondrial membrane composition and respiration
kinetics in human skeletal muscle. J. Physiol, 592 Pt 6,
1341–1352.
Hespel, P.J.L. (2000). KU Leuven Research & Development,
Belgium. Creatine compounds for prevention of aging effects
and treatment of muscle atrophy. Eur Pat Appl. EP
2000,1,002, 532, 24 May.
Hillar, M., Lott, V., & Lennox, B. (1975). Correlation of the effects
of citric acid cycle metabolites on succinate oxidation
by rat liver mitochondria and submitochondrial particles. J
Bioenerg, 7(1), 1–16.
Huang, S.F., Tsai, Y.A., Wu, S.B., Wei, Y.H., Tsai, P.Y., &
Chuang, T.Y. (2012). Effects of Intravascular Laser Irradiation
of Blood in Mitochondria Dysfunction and Oxidative
Stress in Adults with Chronic Spinal Cord Injury. Photomed
and Laser Surg, 30(10), 579–586.
Huskisson, E., Maggini, S., & Ruf, M. (2007). The Role of Vitamins
and Minerals in Energy Metabolism and Well-Being.
J Intern Med Res, 35, 277-289.
Ihrlund, L.S., Hernlund, E., Khan, O., & Shoshan, M.C.
(2008). 3-Bromopyruvate as inhibitor of tumour cell energy
metabolism and chemopotentiator of platinum drugs.
Mol Oncol, 2, 94–101.
John, A.P. (2001). Dysfunctional mitochondria, not oxygen
insufficiency, cause cancer cells to produce inordinate
amounts of lactic acid: the impact of this on the treatment
of cancer. Medical Hypotheses, 57(4), 429–431.
KC, S., Cárcamo, J.M., & Golde, DW. (2005). Vitamin C enters
mitochondria via facilitative glucose transporter 1
(Glut1) and confers mitochondrial protection against oxidative
injury. FASEB J, 19, 1657–67.
Keys, A. (1943). Physical performance in relation to diet. Fed
Proc, 2, 164.
Khan, A., Marier, D., Marsden, E., Andrews, D., & Eliaz, I.
(2014). A Novel Form of Dichloroacetate Therapy for Patients
With Advanced Cancer: A Report of 3 Cases. Altern
Ther Health Med, 20(suppl 2), 21-28.
Khan, N.A., Govindaraj, P., Meena, A.K., & Thangaraj, K.
(2015). Mitochondrial disorders: Challenges in diagnosis
& treatment. Indian J Med Res, 141(1), 13-26.
Kim, S.P., Nam, S.H., & Friedman, M. (2013). Hericium erinaceus
(Lion’s Mane) mushroom extracts inhibit metastasis
of cancer cells to the lung in CT-26 colon cancer-tansplanted
mice. J Agric Food Chem, 61(20), 4898-904.
Klement , R.J., & Kämmerer, U. (2011). Is there a role for
carbohydrate restriction in the treatment and prevention
of cancer? Nutr Metab (Lond), 8, 75.
Kleszczyński, K., Zillikens, D., & Fischer, T.W. (2016). Melatonin
enhances mitochondrial ATP synthesis, reduces
reactive oxygen species formation, and mediates translocation
of the nuclear erythroid 2-related factor 2 resulting in
activation of phase-2 antioxidant enzymes (γ-GCS, HO-1,
NQO1) in ultraviolet radiation-treated normal human epidermal
keratinocytes (NHEK). J Pineal Res, 61(2), 187-97.
Ko, K.M., & Leung, H.Y. (2007). Enhancement of ATP generation
capacity, antioxidant activity and immunomodulatory
activities by Chinese Yang and Yin tonifying herbs. Chinese
Medicine, 2,3.
Kobayashi, H., Matsunaga, K., & Oguchi, Y. (1995). Antimetastatic
effects of PSK (Krestin), a protein-bound polysaccharide
obtained from basidiomycetes: an overview. Cancer
Epidemiol Biomarkers Prev, 4(3), 275-81.
Kreider, R.B., Ferreira, M., Wilsoln, M., Grindstaff, P., Plisk, S.,
Reinardy, J., Cantler, E., & Almada, A.L. (1998). Effects of
creatine supplementation on body composition, strength,
and sprint performance. Med Sci Sports, 30, 73-82.
Krone, C.A., & Ely, J.T. (2005). Controlling hyperglycemia as
an adjunct to cancer therapy. Integr Cancer Ther,4, 25-31.
Kühlbrandt, W. (2015). Structure and function of mitochondrial
membrane protein complexes. BMC Biology, 13, 89.
Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H.,
Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert,
P., Elliott, P., Geny, B., Laakso, M., Puigserver, P., & Auwerx,
J. (2006). Resveratrol improves mitochondrial function
and protects against metabolic disease by activating
SIRT1 and PGC-1alpha. Cell, 127(6), 1109-22.
Lee, H.H., Lee, S., Lee, K., Shin, Y.S., Kang, H., & Cho, H.
(2015). Anti-cancer effect of Cordyceps militaris in human
colorectal carcinoma RKO cells via cell cycle arrest and
mitochondrial apoptosis. DARU Journal of Pharmaceutical
Sciences, 23(1), 35.
León, J., Acuña-Castroviejo, D., Escames, G., Tan, D.X.,
& Reiter, R.J. (2005). Melatonin mitigates mitochondrial
malfunction. J Pineal Res, 38(1), 1-9.
Li, L., Connelly, M.C., Wetmore, C., Curran, T., & Morgan,
J.I. (2003). Mouse embryos cloned from brain tumors.
Cancer Res., 63(11), 2733–2736.
Lou, H.C. (1981). Correction of increased plasma pyruvate
and lactate levels using large doses of thiamine in patients
with Kearns-Sayre Syndrome. Arch Neurol, 38, 469.
MacCarter, D., Vijay, N., Washam, M., Shecterle, L., Sierminski,
H., & St Cyr, J.A. (2009). D-ribose aids advanced
ischemic heart failure patients. Int J Cardiol, 137, 79–80.
McKinnell, R.G., Deggins, B.A., & Labat, D.D. (1969). Transplantation
of pluripotential nuclei from triploid frog tumors.
Science, 165, 394–396.
Meyer, J.N., Leung, M.C.K., Rooney, J.P., Sendoel, A., Hengartner,
M.O., Kisby, G.E., & Bess, A.S. (2013). Mitochondria
as a target of environmental toxicants. Toxicol Sci,
134(1), 1–17.
Michelakis, E.D., Webster, L., & Mackey, J.R. (2008). Dichloroacetate
(DCA) as a potential metabolic-targeting therapy
for cancer. Br J Cancer, 99, 989–994.
Minocherhomji, S., Tollefsbol, T.O., & Singh, K.K. (2012). Mitochondrial
regulation of epigenetics and its role in human
diseases. Epigenetics, 7(4), 326–334.
Mintz, B., & Illmensee, K. (1975). Normal genetically mosaic
mice produced from malignant teratocarcinoma cells.
Proc Natl Acad Sci (USA), 72, 3585–3589.
Moen, I., & Stuhr, L.E.B. (2012). Hyperbaric oxygen therapy
and cancer—a review. Targeted Oncology, 7(4), 233-242.
Momenzadeh, S., Abbasi, M., Ebadifar, A., Aryani, M., Bayrami,
J., & Nematollahi, F. (2015). The Intravenous Laser
Blood Irradiation in Chronic Pain and Fibromyalgia. J Lasers
in Med Sci, 6(1), 6-9.
Nagaya, N., Uematsu, M., Oya, H., Sato, N., Sakamaki, F.,
Kyotani, S., Ueno, K., Nakanishi, N., Yamagishi, M., & Miyatake,
K. (2001). Short-term oral administration of L-arginine
improves hemodynamics and exercise capacity in
patients with precapillary pulmonary hypertension. Am J
Resp Crit Care Med, 163, 887-91.
Narayanan, K.B., Ali, M., & Barclay, B.J., et al. (2015). Disruptive
environmental chemicals and cellular mechanisms
that confer resistance to cell death. Carcinogenesis,36(-
Suppl 1), S89-S110.
Nicolson, G.L. (2014a). Mitochondrial dysfunction and natural
supplements. Integr Med., 13(4), 36-43.
Nicolson, G.L. (2014b). Mitochondrial Dysfunction and Chronic
Disease: Treatment with Natural Supplements. Integr
Med: A Clinician’s Journal, 13(4), 35-43.
Nicolson, G.L., & Ash, M.E. (2014). Lipid Replacement Therapy:
A natural medicine approach to replacing damaged
lipids in cellular membranes and organelles and restoring
function. Biochim Biophys Acta, 1838, 1657–1679.
Nicolson, G.L., Rosenblatt, S., Ferreira de Mattos, G., Settineri,
R., Breeding, P.C., Ellithorpe, R.R., & Ash, M.E.
(2016). Clinical Uses of Membrane Lipid Replacement
Supplements in Restoring Membrane Function and Reducing
Fatigue in Chronic Diseases and Cancer. Discoveries,
4(1), e54.
Nicolson, GL. (2013). Mitochondrial dysfunction and chronic
disease: treatment with natural supplements. Altern Ther
Health Med, :at5027.
Nowak, G., Clifton, G.L., & Bakajsova, D. (2008). Succinate
Ameliorates Energy Deficits and Prevents Dysfunction
of Complex I in Injured Renal Proximal Tubular Cells. J
Pharmacol Exp Therapeut, 324(3), 1155-1162.
Ohta, S. (2012). Molecular hydrogen is a novel antioxidant
to efficiently reduce oxidative stress with potential for the
improvement of mitochondrial diseases. Biochim Biophys
Acta, 1820, 586–594.
Pagano, G., Talamanca, A.A., Castello, G., Cordero, M.D.,
d’Ischia, M., Gadaleta, M.N., Pallardó, F.V., Petrović, S.,
Tiano, L., & Zatterale, A. (2014). Oxidative stress and
mitochondrial dysfunction across broad-ranging pathologies:
toward mitochondria-targeted clinical strategies.
Oxid Med Cell Longev, 541230.
Palzur, E., Zaaroor, M., Vlodavsky, E., Milman, F., & Soustiel,
J.F. (2008). Neuroprotective effect of hyperbaric oxygen
therapy in brain injury is mediated by preservation of mitochondrial
membrane properties. Brain Res, 1221, 126–
133.
Panossian, A., & Wikman, G. (2008). Pharmacology of
Schisandra chinensis Bail: an overview of Russian research
and uses in medicine. J Ethnopharmacol, 118(2),
183-212.
Parikh, S., Saneto, R., Falk, M.J., Anselm, I., Cohen, B.H.,
& Haas, R. (2009). Medicine Society TM. A modern approach
to the treatment of mitochondrial disease. Curr
Treat Options Neurol, 11(6), 414-30.
Pedersen, P.L. (2007). The cancer cell’s ‘‘power plants’’ as
promising therapeutic targets: An overview. J Bioenerg
Biomembr, 39, 1–12.
Petrosillo, G., Di Venosa, N., Pistolese, M., Casanova, G.,
Tiravanti, E., Colantuono, G., Federici, A., Paradies, G.,
& Ruggiero, F.M. (2006). Protective effect of melatonin
against mitochondrial dysfunction associated with cardiac
ischemia- reperfusion: role of cardiolipin. FASEB J, 20(2),
269-76.
Poff, A.M., Ari, C., Seyfried, T.N., & D’Agostino, D.P. (2013).
The ketogenic diet and hyperbaric oxygen therapy prolong
survival in mice with systemic metastatic cancer.
PLoS One, 8, e65522.
Poff, A.M., Ward, N., Seyfried, T.N., Arnold, P., & D’Agostino,
D.P. (2015). Non-toxic metabolic management of metastatic
cancer in VM mice: novel combination of ketogenic
diet, ketone supplementation and hyperbaric oxygen therapy.
PLoS One, 10, e0127407.
Pollak, M. (2008). Insulin and insulin-like growth factor signaling
in neoplasia. Nat Rev Cancer, 8(12), 915-928.
Rex, A., Hentschke, M.P., & Fink, H. (2002). Bioavailability
of Reduced Nicotinamide-adenin-dinucleotide (NADH)
in the Central Nervous System of the Anaesthetized Rat
Measured by Laser-Induced Fluorescence Spectroscopy.
Pharmacol Toxicol, 90(4), 220-225.
Ribas, V., García-Ruiz, C., & Fernández-Checa, J.C. (2014).
Glutathione and mitochondria. Frontiers in Pharmacology,
5,151.
Ristow, M., Pfister, M.F., Yee, A.J., Schubert, M., Michael, L.,
Zhang, C.Y., Ueki, K., Michael, II M.D., Lowell, B.B., &
Kahn, C.R. (2002). Frataxin activates mitochondrial energy
conversion and oxidative phosphorylation. Proc Natl
Acad Sci (USA), 97(22), 12239–12243.
Robey, I.F. & Martin, N.K. (2011). Bicarbonate and dichloroacetate:
Evaluating pH altering therapies in a mouse model
for metastatic breast cancer. BMC Cancer, 11, 235.
Rodriguez, M.C., MacDonald, J.R., Mahoney, D.J., Parise,
G., Beal, M.F., & Tarnopolsky, M.A. (2007). Beneficial effects
of creatine, CoQ10, and lipoic acid in mitochondrial
disorders. Muscle Nerve, 35(2), 235-42.
Rossignol, D.A., Bradstreet, J.J., Van Dyke, K., Schneider,
C., Freedenfeld, S.H., O’Hara, N., Cave, S., Buckley, J.A.,
Mumper, E.A., & Frye, R.E. (2012). Hyperbaric oxygen
treatment in autism spectrum disorders. Med Gas Res,
2, 16.
Rucker, R., Chowanadisai, W., & Nakano, M. (2009). Potential
physiological importance of pyrroloquinoline quinone.
Altern Med Rev, 14(3), 268-77.
Sahlin, K. (2014). Muscle Energetics during Explosive Activities
and Potential Effects of Nutrition and Training. Sports
Med, 44(Suppl 2), 167-173.
Sastre, J., Pallardo, F., De la Asuncion, J., & Vina, J. (2000).
Mitochondria, oxidative stress and aging. Free Radical
Res, 32,(3), 189-198.
Schulz, T.J., Thierbach, R., Voigt, A., Drewes, G., Mietzner,
B., Steinberg, P., Pfeiffer, A.F., & Ristow, M. (2006). Induction
of oxidative metabolism by mitochondrial frataxin
inhibits cancer growth: Otto Warburg revisited. J Biol
Chem, 281, 977-981.
Seifert, J.G., Subudi, A.W., Fu, M.X., Riska, K.L., John, J.C.,
Shecterle, L.M., & St Cyr, J.A. (2009). The role of ribose
on oxidative stress during hypoxic exercise: a pilot study.
J Med Food, 12, 690–693.
Seyfried, T.N. (2015). Cancer as a mitochondrial metabolic disease.
Frontiers in Cell and Developmental Biology,3, 43.
Seyfried, T.N., & Shelton, L.M. (2010). Cancer as a metabolic
disease. Nutr. Metab, 7, 7.
Shanmugam, N., Reddy, M.A., Guha, M., & Natarajan, R.
(2003). High glucose-induced expression of proinflammatory
cytokine and chemokine genes in monocytic cells.
Diabetes, 52(5), 1256-1264.
Soares, R., Meireles, M., Rocha, A., Pirraco, A., Obiol, D.,
Alonso, E., Joos, G., & Balogh, G. (2011). Maitake (D
fraction) mushroom extract induces apoptosis in breast
cancer cells by BAK-1 gene activation. J Med Food, 14(6),
563-72.
Stites ,T.E., Mitchell, A.E., & Rucker, R.B. (2000). Physiological
importance of quinoenzymes and the O-quinone family
of cofactors. J Nutr, 130, 719–727.
Stone, M.H., Sanborn, K., Smith, L.L., O’Bryant, H.S., Hoke,
T., Utter, A.C., Johnson, R.L., Boros, R., Hruby, J.,
Pierce, K.C., Stone, M.E., & Garner, B. (1999). Effects of
in-season (5 weeks) creatine and pyruvate supplemen
tation on anaerobic performance and body composition
in American football players. Int J Sport Nutr, 9, 146-165.
Sudheesh, N.P., Ajith, T.A., Mathew, J., Nima, N., & Janardhanan,
K.K. (2012). Ganoderma lucidum protects liver
mitochondrial oxidative stress and improves the activity
of electron transport chain in carbon tetrachloride intoxicated
rats. Hepatol Res, 42(2), 181-91.
Sun, Y., Yin, T., Chen, X.H., Zhang, G., Curtis, R.B., Lu, Z.H.,
& Jiang, J.H. (2011). In Vitro Antitumor Activity and Structure
Characterization of Ethanol Extracts from Wild and
Cultivated Chaga Medicinal Mushroom, Inonotus obliquus
(Pers:Fr.) Pilát (Aphyllophoromycetideae). International
Journal of Medicinal Mushrooms, 13(2), 121-30.
Surapaneni, D.K., Adapa, S.R., Preeti, K., Teja, G.R.,
Veeraragavan, M., & Krishnamurthy, S. (2012). Shilajit
attenuates behavioral symptoms of chronic fatigue syndrome
by modulating the hypothalamic-pituitary-adrenal
axis and mitochondrial bioenergetics in rats. J Ethnopharmacol,
143, 91–99.
Tarnopolsky, M.A. (2000). Potential benefits of creatine
monohydrate supplementation in the elderly. Curr Opin
Clin Nutr Metab Care, 3(6), 495-502.
Tarnopolsky, M.A. (2008). The mitochondrial cocktail: Rationale
for combined nutraceutical therapy in mitochondrial
cytopathies. Adv Drug Delivery Rev, 60(13-14),
1561–1567.
Taylor, W.M., & Halperin, M.L. (1973). Regulation of pyruvate
dehydrogenase in muscle. Inhibition by citrate. J
Biol Chem, 248(17), 6080–3.
Tisdale, M.J., & Brennan, R.A. (1983). Loss of acetoacetate
coenzyme A transferase activity in tumours of peripheral
tissues. Br J Cancer, 47(2), 293-297.
Tornheim, K., & Lowenstein, J.M. (1976). Control of phosphofructokinase
from rat skeletal muscle. Effects of fructose
diphosphate, AMP, ATP and citrate. J Biol Chem,
251(23), 7322–8.
Turpaev, K.T. (2002). Reactive oxygen species and regulation
of gene expression. Biochemistry, 67(3), 281–292.
Ungvari, Z., Sonntag, W.E., de Cabo, R., Baur, J.A., &
Csiszar, A. (2011). Mitochondrial Protection by Resveratrol.
Exercise and Sport Sci Rev, 39(3), 128-132.
Urbanski, R.L., Vincent, W.J., & Yuaspelkis, B.B. (1999).
Creatine supplementation differentially affects maximal
isometric strength and time to fatigue in large and small
muscle groups. Int J Sport Nut, 9, 136-145.
Van Gammeren, D., Falk, D., & Antonio, J. (2002). The Effects
of Four Weeks of Ribose Supplementation on Body
Composition and Exercise Performance in Healthy,
Young, Male Recreational Bodybuilders: A Double-Blind,
Placebo-Controlled Trial. Curr Therapeut Res, 63(8),
486-495.
Vandenberghe, K., Goris, M., Van Hecke, P., Van Leemputte,
M., Vangerven, L., & Hespel, P. (1997). Long-term
creatine intake is beneficial to muscle performance during
resistance training. J Appl Physiol, 83, 2055-2063.
Vaupel, P., Kallinowski, F., & Okunieff, P. (1989). Blood flow,
oxygen and nutrient supply, and metabolic microenvironment
of human tumors: a review. Cancer Res, 49(23),
6449-6465.
Velichko, M.G., Trebukhina, R.V., & Ostrovskii, IuM. (1981).
Features of pyruvate and lactate metabolism in tumor-
bearing rats following citrate administration. Vopr
Med Khim, 27(1), 68–72.
Volek, J.S., Kraemer, W.J., Bush, J.A., Boetes, M., Incledon,
T., Clark, K.L., Lynch, J.M. (1997). Creatine supplementation
enhances muscular performance during
high intensity resistance exercise. J Am Diet Assoc, 97,
765-770.
Wallace, D.C. (2005). A mitochondrial paradigm of metabolic
and degenerative diseases, aging, and cancer: A dawn
for evolutionary medicine. Ann Rev Genet, 39, 359–407.
Warburg, O. (1956). On the Origin of Cancer Cells. Science,
123(3191), 309–14.
Warburg, O., Posener K., Negelein, & Ueber den Stoffwechsel
der Tumoren, E. (1924). Biochemische Zeitschrift,
152, 319-344. (German). Reprinted in English in the
book: On Metabolism of Tumors by O. Warburg, Publisher:
Constable, London, 1930.
Wen, Y., Gu, J., Li, S.L., Reddy, M.A., Natarajan, R., & Nadler,
J.L. (2006). Elevated glucose and diabetes promote
interleukin-12 cytokine gene expression in mouse macrophages.
Endocrinol, 147(7), 2518-2525.
Wike-Hooley, J.L., Haveman, J., & Reinhold, H.S. (1984).
The relevance of tumour pH to the treatment of malignant
disease. Radiother Oncol, 2(4), 343-366.
Xu, W., Ghosh, S., Comhair, S.A.A., Asosingh, K., Janocha,
A.J., Mavrakis, D.A., Bennett, C.D., Gruca, L.L., Graham,
B.B., Queisser, K.A., Kao, C.C., Wedes, S.H., Petrich,
J.M., Tuder, R.M., Kalhan, S.C., & Erzurum, S.C.
(2016). Increased mitochondrial arginine metabolism
supports bioenergetics in asthma. J Clin Invest, 126(7),
2465-2481.
Xu, X., Zhao, X., Liu, T.C., & Pan, H. (2008). Low-intensity
laser irradiation improves the mitochondrial dysfunction
of C2C12 induced by electrical stimulation. Photomed
Laser Surg,26(3), 197-202.
Zhang, Y., Sun, D., Meng, Q., Guo, W., Chen, Q., & Zhang, Y.
(2017). Grifola frondosa polysaccharides induce breast
cancer cell apoptosis via the mitochondrial-dependent
apoptotic pathway. Int J Mol Med, 40(4), 1089–1095.
Zhao, Y., Wieman, H.L., Jacobs, S.R., & Rathmell, J.C.
(2008). Mechanisms and Methods in Glucose Metabolism
and Cell Death. Methods in enzymology, 442, 439-
457.
Zhou, W., Mukherjee, P., Kiebish, M.A., Markis, W.T., Mantis,
J.G., & Seyfried, TN. (2007). The calorically restricted
ketogenic diet, an effective alternative therapy for malignant
brain cancer. Nutri & Metabol, 4, 5.