Send Orders for Reprints to reprints@benthamscience.

ae
32 Central Nervous System Agents in Medicinal Chemistry, 2015, 15, 32-41

Beyond Mitochondria, What Would be the Energy Source of the Cell?

Arturo S. Herrera1, María del C.A. Esparza1, Ghulam Md. Ashraf2, Andrey A. Zamyatnin Jr.3,4 and
Gjumrakch Aliev5,6*

1
Human Photosynthesis Study Center, R & D & I Department, López Velarde 108, Centro, Aguascalientes,
Aguascalientes, C.P. 20000, México; 2King Fahd Medical Research Center, King Abdulaziz University, P.O.
Box 80216, Jeddah 21589, Saudi Arabia; 3Department of Cell Signalling, Belozersky Institute of Physico-
Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia; 4Institute of Molecular
Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia; 5GALLY Interna-
tional Biomedical Research Consulting LLC., 7733 Louis Pasteur Drive, #330, San Antonio, TX 78229,
USA; 6School of Health Science and Healthcare Administration, University of Atlanta, E. Johns Crossing,
#175, Johns Creek, GA 30097, USA

Abstract: Currently, cell biology is based on glucose as the main source of energy. Cellular bioenergetic pathways have
become unnecessarily complex in their eagerness to explain that how the cell is able to generate and use energy from the
oxidation of glucose, where mitochondria play an important role through oxidative phosphorylation. During a descriptive
study about the three leading causes of blindness in the world, the ability of melanin to transform light energy into chemi-
cal energy through the dissociation of water molecule was unraveled. Initially, during 2 or 3 years; we tried to link to-
gether our findings with the widely accepted metabolic pathways already described in metabolic pathway databases,
which have been developed to collect and organize the current knowledge on metabolism scattered across a multitude of
scientific articles. However, firstly, the literature on metabolism is extensive but rarely conclusive evidence is available,
and secondly, one would expect these databases to contain largely the same information, but the contrary is true. For the
apparently well studied metabolic process Krebs cycle, which was described as early as 1937 and is found in nearly every
biology and chemistry curriculum, there is a considerable disagreement between at least five databases. Of the nearly
7000 reactions contained jointly by these five databases, only 199 are described in the same way in all the five databases.
Thus to try to integrate chemical energy from melanin with the supposedly well-known bioenergetic pathways is easier
said than done; and the lack of consensus about metabolic network constitutes an insurmountable barrier. After years of
unsuccessful results, we finally realized that the chemical energy released through the dissociation of water molecule by
melanin represents over 90% of cell energy requirements. These findings reveal a new aspect of cell biology, as glucose
and ATP have biological functions related mainly to biomass and not so much with energy. Our finding about the unex-
pected intrinsic property of melanin to transform photon energy into chemical energy through the dissociation of water
molecule, a role performed supposedly only by chlorophyll in plants, seriously questions the sacrosanct role of glucose
and thereby mitochondria as the primary source of energy and power for the cells.
Keywords: Energy, human photosynthesis, mitochondria, melanin, water dissociation.

INTRODUCTION
The puzzle of how the cells get energy from food contin-
ues to fascinate researchers. Science try to exudate an aura
based in the solidity of its facts, however, the study of energy
transformations in the cell is far from this image. Anyone
who is not thoroughly confused just not understands the
situation.
Metabolism has been studied for decades already, and to
collect our ever-increasing but scattered knowledge on me-
tabolism, pathways databases like the Kyoto Encyclopedia of
*Address correspondence to this author at the “GALLY” International
Biomedical Research Institute Inc., 7733 Louis Pasteur Drive, #330, San
Antonio, TX, 78229 USA; Tel: +440-263-7461;
E-mails: aliev03@gmail.com; cobalt55@gallyinternational.com
Genes and Genomes have been created [1]. The number of
pathway databases describing the metabolic network of one
or more organisms is growing rapidly [2]. For many organ-
isms, there are multiple databases describing the metabolic
network and providing a holistic view, which are thus rou-
tinely used to provide context for the analysis and interpreta-
tion of high-throughput molecular data [3]. In silica models
of the metabolic network can be used (theoretically) to gen-
erate experimentally verifiable hypotheses such as potential
drug target, or to simulate the effect of network perturba-
tions, such as loss of function. However, expected results
were not obtained, as the level of agreement among the
metabolic network descriptions of the same organism given
by the various pathway databases is surprisingly low [4]. For
example, five pathway databases that describe the human

1875-6166/15 $58.00+.00 © 2015 Bentham Science Publishers

Beyond Mitochondria, What Would be the Energy Source
metabolic network were shown to agree on only 199 (≈3%)
of the total 7000 reactions contained by these databases [5].
Databases differ not only in the way they retrieve infor-
mation to build the metabolic network and in the way the
network is curated, but also in the way that many metabolic
pathways have entirely theoretical components. Moreover,
despite being curated by selected experts and peer reviewed,
different values for the same reaction have been obtained in
metabolic pathway databases. Furthermore, the proposed
metabolic pathways have numerous inconsistencies; the vol-
ume of the matrix fraction of mitochondria is not correlated
to the amount of Krebs cycle enzyme, and it seems theoreti-
cally reasonable to assume that they do not fill the matrix
[6]. However, it is a concept that has not been proven yet, as
other potential side measurements of enzyme equilibrium
have always been difficult and prone to large errors [7].
Hence, the level of agreement among pathways databases is
surprisingly low. For example, while evaluating the descrip-
tion of the well-known tricarboxylic acid (TCA) pathways,
Stobbe and coworkers found that in 10 human metabolic
pathways, none of the descriptions given by these databases
is entirely correct [8]. This might be either due to an inaccu-
rate representation of the knowledge described in scientific
literature or due to lack of conclusive literature evidence in
some cases, and were thus referred as “unconfirmed” de-
scription. The degree of impact of this lack of consensus in
database network on the scientific research is still unknown,
but is surely expected to be quite detrimental.
Solving the dilemma of the lack of consensus is a formi-
dable challenge because if we would simply combine the
different descriptions of human metabolism provided by the
databases, we neither resolve conflicting information nor
filter out mistakes. The study of normal metabolism is full of
theories, dogmas, which make it even harder trying to ad-
vance in knowledge. Theoretically, cells depend on the reac-
tions that produce adenosine triphosphate (ATP), which is so
far considered as the primary energy-carrying molecule. Our
body uses ATP to walk, to grasp, to speak, to swallow, to
drink, to blink, to inhale, to pump blood, to pump liquids,
and to concentrate molecules which do not tend to concen-
trate on their own, rather they tend to disperse.
Concentrating the molecules by actively transporting
them inside a membrane requires energy. Thus, the focus of
research has always been the process whereby cells convert
energy from Krebs cycle into usable form. However, after
decades of research about intermediate metabolites with dis-
heartening results, Peter Mitchel introduced a novel hypothe-
sis based on his observations on cell membranes. Certain
molecules enter cells while others do not; therefore the fluid
inside a membrane is different from the fluid outside. Some
molecules pass through membranes easily, whilst other need
energy to actively cross the osmotic barrier. Mitchell, who
was working with bacteria and not so with mitochondria
inferred that if the concentration of protons was greater than
one side of the membranes, cell could transform chemical
energy into mechanical energy and synthesize ATP. Krebs
cycle, theoretically, channels energy in the form of high en-
ergy electrons attached to electron-carrier molecules known
as NAD and FAD. A high energy electron is defined as an
electron whose probabilistic cloud is farthest from the nu-
Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1 33
cleus of the atom in question as a difference of a low-energy
electron, whose probability cloud is closer from the nucleus
of the atom. They are electrons that are exchanged easily for
what is considered as not belonging to an atom or molecule
in particular. Thereafter, NAD and FAD transfer their high-
energy electrons to a series of molecules in the inner mito-
chondrial membrane known as electron transport chain. In
this oxidation chain, the electrons shift to successively lower
energy states as they move from molecule to molecule. At
the same time, energy is released and produces ATP. Elec-
trons eventually reach their lowest energy level and combine
with oxygen and protons forming water. When oxygen is
absent, electrons stop flowing and no ATP is made. The
electron transport chain (theoretically) creates a proton im-
balance, and then the protons would move to restore the bal-
ance by traveling through an enzyme, ATP synthase. Recall
that hydrogen is the simplest and smallest atom, and has a
diameter of 1Å, so it is very difficult to confine. It is difficult
to accept that the only or even the primary function of this
complicated chain of reactions is to produce protons at the
right place.
Leaving aside for the moment the inconsistencies of the
Mitchell´s chemiosmotic theory, we will continue with ATP.
It is widely accepted that all organisms use ATP as their
primary energy currency. The low energy covalent-bonds of
nutrients must be translated to high energy bonds and this is
the role of ATP. Theoretically, ATP degrades to ADP by
releasing energy in the form of heat which in turn is trans-
ported by electromagnetic radiations. But this argument
lacks the deeply rooted concept that human body cannot use
electromagnetic radiation as source of energy, because pho-
tosynthesis occurs only in plants. Once ATP is spent, then
the ADP is vertiginously recycled in the mitochondria, given
that for each ATP, the terminal phosphate is added and re-
moved three times each minute. At any instant each cell con-
tains about one billion of ATP molecules. However, this
amount is sufficient only for few minutes and must be recy-
cled rapidly because it is estimated that an average body con-
tains one sextillion ATP molecules. The total ATP content in
human body is only about 50 grams, but total ATP require-
ments of a body is about 180 kg every 24 hours; a fact that is
very difficult to explain so far.
Another serious inconsistency is that the daily heart con-
sumption of energy is about 6 kg of ATP, but the normal
content is approx. 700 mg. This monumental difference has
been tried to be explained in different ways. One theory says
that heart is an efficient omnivore, the other theory says that
is heart has very efficient anapleurotic (intermediate metabo-
lites) pathways, besides the heart high content of phos-
phocreatine (PCr), creatine kinase, adenylate kinase, etc.
However, these explanations make no sense due to the fact
that it is not possible to get, from any system, more energy
than it actually has. On the other hand more intermediate
steps imply more intermediate molecules and more enzymes
to catalyze each reaction and thereby more energy expendi-
ture. Therefore, we believe that our discovery of the intrinsic
property of melanin to transform light energy into chemical
energy is a disruptive discovery something which allow a
better understanding of the complexities, mysteries and nu-
merous contradictions related to cell metabolism.
34 Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1
The previously unknown fact that the melanin in our
body is able to absorb electromagnetic radiation and uses the
energy contained in them to dissociate the water molecule
like plant chlorophyll breaks the paradigm. Moreover, hu-
man eukaryotic cell also has the equivalent of the first reac-
tion of the photosynthetic process in plants.
METHODOLOGY
Subjects
In 1990, we started an observational, descriptive, longi-
tudinal study about morphological characteristics of the tiny
vessels of the optic nerve in the subjects. Our working hy-
pothesis was that adequate magnification and digital record-
ing of the anatomical changes in blood vessels of the optic
nerve eventually allow us to identify variations in their ana-
tomical characteristics that could be validated and therefore
eventually used as indicators of early disease, which would
permit us to develop new treatment approaches or at least
institute early treatment. The retina angiographic studies
were performed in subjects attending our service of angi-
ography, most of them were referred by other physicians or
institutions, and signed informed consent was obtained from
each one of them.
The study was done on population that required ocular
fundus study (fluorescein angiography) for any reason. The
patients were sent by ophthalmologist of several local hospi-
tals in city of Aguascalientes to our retina medical service
(Centro de Estudios de la Fotosíntesis Humana. S.C. Human
Photosynthesis Study Center, Aguascalientes, México). The
magnifications and scans were made in all the subjects that
were routinely sent to our angiography service. During the
period of 12-15 years, our angiographic service was the best,
and a routine angiographic fluorescein study was optimized.
Two to three subjects for a period of 12 years made it ap-
prox. 6000. The digital file allowed the selection of patients
with diseases that interest us and they logically were the
causes of more frequent consultation. Each digital file con-
tained brief data of patient information such as age, sex, date
of the study, current diagnosis (systemic and ophthalmologi-
cal), pathological history in the case of chronic patients (dia-
betes mellitus, systemic arterial hypertension, arthritis, kid-
ney etc), time of evolution, used treatments, as well as a his-
tory of other illnesses, treatments or surgeries. Alcoholism
and smoking were also registered.
Due to the socio-economic characteristics of the subjects
who were sent to us, it was methodologically difficult to
form a cohort in particular for each disease, mainly glau-
coma, diabetes and macular degeneration. So we included all
the subjects in the study, and then selected the digital file of
the patients with above mentioned diseases; which were the
most numerous. However, since the description of optic
nerve blood vessels were not reported in as much detail as
we wanted, so we included all the subjects who participated
in the study. This resulted to our advantage, especially when
the presence of melanin near the optic nerve began to be the
primary endpoint in our study, followed by characteristics of
the vessels.
Measurement of blood vessels were not done through
instruments of measurement since the size of the image is
Herrera et al.
different in each patient. Furthermore, eyes of same patient
can also be different. For example, the image we could get in
myopic eyes of a patient is larger than normal eye and the
image in hyperopic eye of a patient is smaller than normal
eye. In astigmatic eyes obtained image is distorted. There-
fore, the evaluation of vessels was mainly based on the expe-
rience of the examiner, who assessed the direction of vessels,
number of vessels (if it was rectified) and features of vessels
(wavy, dilated, occluded etc).
Magnification of Optic Nerve and the Role of Melanin
The first problem to solve was to obtain a proper magni-
fication of the optic nerve (ON) in live subjects, because the
ON average diameter (1200 microns) is equivalent to twelve
human hairs together. We made adaptations in our diagnostic
equipment methods and obtained appropriate magnification
of the structures under study in a relatively short time of
three months (Fig. 1, 2). While digitally recording the tiny
blood vessels of the optic nerve (the main variable under
study), we began to detect another element (melanin) that we
had not taken into account earlier. However, we found mela-
nin as a nuisance because many times it appeared in front of
the blood vessels, thus disturbing the proper observation
(Fig. 3, 4). But the appearance of melanin in virtually all the
patients (Fig. 5, 6) we studied developed tremendous curios-
ity in our minds. On the other side, we thought that this
molecule could have great significance, which so far has
been considered just as a simple sunscreen molecule located
in a region 2.5 cm behind the pupil. So we decided to include
it in our study as the main variable along with the blood ves-
sels (Fig. 5, 6). But as the study progressed, our doubts kept
growing and the omnipresence of melanin in almost all the
patients studied puzzled us a lot. It was not only the constant
presence of melanin (Fig. 7, 8) that intrigued us because we
also perceived that adjacent tissues seemed to respond to its
presence. And the blood vessels were no exception, as we
began to notice that more the melanin less was the number
and size of blood vessels and vice versa. This association
was very consistent, because we could identify it in indi-
viduals as well as diseased patients. Despite repeated litera-
ture searches, we could not find a satisfactory explanation
for such a large effect size. During the first three years of the
study, which spanned a total of twelve years, we reached two
important conclusions: melanin is found in or nearby optic
nerve of all patients and has a strong anti-angiogenic effect.
Anti-angiogenic Effect of Melanin
In order to demonstrate the anti-angiogenic effect of
melanin, we designed an experiment in laboratory animals.
We formed five groups of animals, each consisting of ten
Wistar male rats, each two months old. We then applied a
drop of an aqueous solution containing 50% of C6H7O, a
selectively toxic compound, to the melanocytes in the right
eye of four groups. The left eye was used as control in all
groups. There was no other intervention, all groups were fed
the same way and were provided unrestricted water and food
ad libitum, with the general conditions (12/12 daylight hours,
number of animals in each cage, etc.) being same for all
groups. Photographs of the corneas of both eyes of each ani-
mal were obtained every week. On an average, after 15 days,
vessel growth was noticeable on the surface of the cornea in
Beyond Mitochondria, What Would be the Energy Source
Fig. (1). Photograph of the fundus with polychromatic light in an
apparently healthy patient with skin type V, in the classification
of Fitzpatrick. The predominant tone reddish coffee does not
allow discerning the presence of melanin, which only can be seen
as a discrete dark thread on the temporal edge of the disc.
Fig. (3). Above patient shows the presence of melanin in the
temporal edge of the optical disk is seen as dark spots.
Fig. (5). Alterations of pigment can be seen with polychromatic
light (white) around both the disc and the rest of the tissues of the
fundus.
Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1 35
Fig. (2). The shape of the optic disc differs from patient to patient
as well as the coloration of the fundus. In this patient with skin
type IV in the classification of Fitzpatrick, were we can see a
“little” more clearly the melanin in the temporal edge of the optic
disc.
Fig. (4). The irregularities in the temporal edge of the optic disc
and therefore melanin were present in almost all patients that
included in our studies.
Fig. (6). The monochromatic light causes some details depending
on the wavelength used; the picture belongs to the same patient as
in Fig. 5, but a pigment irregularity around the optical disk is
observed with greater clarity.
36 Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1
Fig. (7). The presence of melanin is the rule in the back of the
eye, regardless of the disease in question, as in this case of glau-
comatous optic neuropathy.
four out of five animals. This growth was maintained uni-
formly until the end of the experiment which lasted three
months.
RESULTS AND DISCUSSION
In any tissue, vascularization is dependent on the dy-
namic balance between pro- and anti-angiogenic factors. In
eyes, the control of retinal angiogenesis is of critical impor-
tance for the preservation of vision. For example, in the case
of diabetic retinopathy which is the second leading cause of
blindness in the world [9], it has been observed that hypoxia
is the major pro-angiogenic factor, which is attributed to
retinal ischemia, presumably for the loss of an adequate oxy-
gen transport as well as by stimulating the expression of an-
giogenic growth factors and by inhibiting the release of anti-
angiogenic cytokines [10]. Vitreal levels of angiogenic
growth factors have been shown to be directly associated
with the degree of retinal angiogenesis [11]. The ability to
monitor and validate degree of the retinal angiogenesis
within the eye makes the eye an ideal setting to investigate
the delicate balance of new vessel growth and the influence
of specific growth factors in vivo in humans.
The main characteristic of our study is that we did not
study only a specific type of patients; instead we studied all
the subjects attending our fluorangiography service. Hence,
we concluded that melanin was present in patients as well as
healthy subjects, and anti-angiogenic effect was always pre-
sent in greater or lesser degree depending on the underlying
disease. Diabetic retinopathy has been intensively studied
not only from the ophthalmologic viewpoint but also from
systemic point of view. Epidemiologic studies have shown
the effects of hyperglycemia, hypertension, dyslipidaemia,
body-mass index, physical activity and insulin resistance on
the incidence and progression of diabetic retinopathy and
clinically significant macular edema [12]. Data from several
studies also suggest roles for factors such as sleep apnea,
non-alcoholic liver disease, serum prolactin, adinectin, ho-
mocysteine levels, and mutations in the erythropoietin gene
promoter. However, the relative contributions of the overall
Herrera et al.
Fig. (8). Alterations of pigment are most notable in the temporal
edge of the disc during the exploration of the fundus, but not
limited to that area and can be found spread over wide regions of
the fundus.
factors to the risk of retinopathy in populations remain un-
certain due to a poor understanding of the pathophysiology
of diabetic retinopathy. It is striking that melanin is not men-
tioned in the numerous publications about diabetic retinopa-
thy, where it was mostly mentioned as a pigment epithelium-
derived factor (PEDF).
In the first half of the research, we had very clear consen-
sus about the presence of melanin in the fundus of all sub-
jects we reviewed, but the reason was still unclear to us.
Moreover, since there were two main variables (blood ves-
sels and melanin) under study, we observed very powerful
and very consistent anti-angiogenic effect of melanin (Fig. 9,
10). This led us to conclude that it is not carried throughout
factors since the variability in their composition and amino
acid sequence is remarkable and so is at level of membrane
receptors (biological variability), thereby their effect de-
creases significantly, perhaps to less than 30%. But the
melanin anti-angiogenic effect exceeded 90%, and thus
might be exercised through a different mechanism. The pu-
rity of the experimental model obtained also caught our at-
tention because of minimal or no destruction or disorganiza-
tion of corneal tissue (Fig. 11, 12). There was no angiogenesis
at all in the cornea of the control (left eye). It was thus very
clear that the blood vessels grew when melanocytes were
destroyed, thus proving our observation about melanin having
remarkable anti-angiogenic power proved to be correct.
In addition to the above observations, we also began to
notice that possibly there were other effects that could be
classified as “trophic” for tissues with more melanin were
found to be stronger, thicker and were kept in better condi-
tion than tissues with lower melanin content under similar
conditions. So, the puzzle gradually took shape, because mela-
nin was present in all subjects, and the vessels responded to the
presence of melanin, besides the tissues showed several posi-
tive effects that were detectable in form and function. At this
point, melanin for us was no more than just a simple built-in
sunscreen pigment, and our hypothesis started taking
shape. The important role of melanin seemed as fundamen-
tal. The effect of melanin on the blood vessels cannot
Beyond Mitochondria, What Would be the Energy Source
Fig. (9). The laser photocoagulation is a practice that started from
the middle of last century. And to date their effects remain con-
troversial. But the retina is true what we see in the skin, melanin
is activated by electromagnetic radiation. In the upper part of the
photograph the scars of photocoagulation are seen, and activating
melanin and choroidal retinal vessels diminish its light and tend
to fibrosis.
Fig. (11). Example of angiogenesis in the cornea of the right eye
of Wistar rats after 15 days of the application of a drop of an 50%
aqueous solution of C6H6.
be through peptide formation, because melanin neither pos-
sesses subcellular structures such as ribosomes, endoplasmic
reticulum and Golgi apparatus to synthesize peptides, nor
have genes that could hold and transmit the information.
Therefore, the effect of melanin on blood vessels was ex-
pected to be through a very efficient mechanism that did not
involve the presence of receptors and transmitters. Finally,
the presence of melanin is invariably accompanied by sev-
eral positive –trophic- effects on tissues, detectable through
angiography. They also have beneficial effects that occur in
a manner that does not involve synthesis of amino acids or
peptide chains and also not in relation to glucose nor en-
zymes because melanin contains structures with no unusual
characteristics of any enzyme.
The answer to our questions began to emerge while ana-
lyzing the biochemical characteristics of the choroid, and
really caught our attention when the partial pressure of oxy-
gen in the choroidal arteries was found to be 97%, which is
very similar to other arteries in the body. But in the choroidal
Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1 37
Fig. (10). The same case of Fig. 9, which shows that the area
where photocoagulation is applied, the choroidal vessels regress,
no longer have blood passage, only the larger vessels retain some
function. Since there are many confounding factors, it took us a
while to understand that melanin had significant anti-angiogenic
properties.
Fig. (12). Angiogenesis in cornea, right eye, Wistar rats after 15
days of the application of a drop of a solution of C6H6.
veins, it was around 94%, which contrasts with veins from
other tissues where it is close to 60%. We then started de-
termining explanation about the high oxygen levels in the
vortex veins, which is paradoxical because the metabolic
needs of the retina are ten times higher than those of the
cerebral cortex. On the other hand, it is widely accepted that
80% of the oxygen needs of the retina are covered with oxy-
gen coming from the choroidal layer. Since the amount of
oxygen present in choroidal veins could not be explained
from the blood circulation, it was obvious that it was gener-
ated within the same tissue, in this case in the choroid itself.
However, vascular endothelial cells (EC) of the choroid
showed no significant differences in the vascular EC in gen-
eral. Also, there were no other anatomical or functional fac-
tors to which we could attribute such high levels of oxygen
in choroidal veins compared to other tissues, except the huge
content of melanin. After reanalyzing the data published in
different sources, the only significant difference we found
was that the amount of melanin in the choroid was 40%
greater than in the skin. And eventually the answer was
38 Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1
found in February 2002, with the only real option left was
that melanin possessed the ability to dissociate the water
molecule. This explanation was consistent with our findings
from the beginning, as it was important for nature to place
melanin in all optic nerves. And on the other hand, the high
levels of oxygen are known as the most potent anti-
angiogenic factor. So, we had managed to solve part of the
puzzle, but lacked the explanation of the nutritional effect.
So we decided to delve into plant photosynthesis, since the
first chemical reaction is the dissociation of the water mole-
cule and can be written as follows:
2H2O→2H2 + O2
Gradually, we understood that the main product of this
reaction is the diatomic hydrogen, because it is the carrier of
energy for excellence in the entire universe, and on the other
hand oxygen is toxic at any concentration, hence the plant
expels it to atmosphere. Then there was the consistency that
water dissociates in plants and humans in order to transform
light energy into chemical energy which is a very wearable
energy. But there are some important differences, as chloro-
phyll only absorbs the ends of the visible spectrum (red and
blue) and melanin absorbs all of the electromagnetic spec-
trum, i.e. from gamma to radio waves rays [13]. Further-
more, it is also said that melanin is the darkest substance
known [5]. On the other hand, the level of oxygen present in
the choroid tissue are very high, which speaks of constant
dissociation of the water molecule. Had it been only disso-
ciation, the amount of water present in the eye would not be
enough. So, the representation of photosynthesis in humans
should be:
2H2O↔2H2 + O2
But the thermodynamics energy of the reaction involves
generation of high electron when the molecule of water is
annealed, i.e., for every two reformed water molecules
would have four high energy electrons, so the representation
would be:
2H2O↔2H2 + O2 + 4e-
The third equation solved incognita; the free chemical
energy accounted for most tissue integrity, because the cell
uses energy in many ways, besides that the best antioxidant
is the diatomic hydrogen. The intrinsic capacity of melanin
to split and reform the water molecule resolved the puzzle of
the first step of energy transduction in humans, mammals,
and perhaps in all living species.
From these findings some doubts were resolved but a
very important question aroused that if melanin is the source
of energy, then what is the role of mitochondria? Initially,
we tried to concatenate our results with the widely accepted
conventional metabolic pathways, but after some years of
effort we failed. But we were so sure of our results that we
began to doubt the veracity of the role of glucose (and mito-
chondria) as an energy source, and eventually the all impor-
tant question aroused: And if the mitochondria were not a
source of energy?
Mitochondria are unusual organelles, which divide inde-
pendently of the cell on which they reside, meaning mito-
chondrial replication is not coupled to cell division. Since
mitochondria possess their own genome, it is thought that
Herrera et al.
they originated from an ancient symbiosis that resulted when
a nucleated cell for some reasons engulfed an aerobic pro-
karyote. This eventually derives a character highly conserved
in evolution, since theoretically mitochondria use oxygen to
generate energy. Mitochondria is surrounded by two mem-
branes, outer and inner [14]. The outer membrane fully en-
closes the whole organelle, and a small intermembrane space
exists between outer and inner membrane [14]. However the
outer mitochondrial membrane contains a lot of protein-
derived pores that are big enough to allow the passage of
ions and even molecules as large as small proteins [14]. Op-
positely, the inner membrane has much more restricted per-
meability, much like the plasma membrane of a cell. The
inner membrane is also loaded with proteins involved in
electron transport and ATP synthesis. The inner membrane
surrounds the mitochondrial matrix, where the citric acid
cycle produces the electrons that travel from one protein
complex to the next in the inner membrane. At the end of the
chain, the final electron acceptor is oxygen, which ultimately
forms water; and at the same time, the electron transport
chain produces ATP, the so called oxidative phosphorylation
[15]. Thus, mitochondria generate energy as electrons are
passed from donors at lower to acceptors at higher redox
potential through various protein complexes [14]. But the
energy required for this to happen is higher than that ob-
tained, since only protein complexes requires power to main-
tain their shape and functionality. However, the term elec-
tron transport “chain” has been criticized as misleading,
because it implies a linear progression along a single path-
way [16]. During electron transport, the participating protein
complexes push protons from the matrix out to the inter-
membrane space [15]. This creates a concentration gradient
of protons that another protein complex, called ATP syn-
thase, uses to power synthesis of the ATP molecule. The
mitochondrial complex V is capable of “coupling” proton
flow to conversion of ADP to ATP in an intricate manner
that still remains incompletely understood [17].
In the 1950s, there was no more perplexing problem in
all of biochemistry than the nature of energy coupling. How
do living organisms capture the energy available from the
degradation of organic matter, or from the absorption of
light, and harness it for the performance of useful works such
as biosynthesis, membrane transport and movement? In
1961, Peter Mitchell through chemiosmotic theory was the
first one to propose that the mechanism of energy coupling
in oxidative phosphorylation is not chemical in nature but is
effectively electrical [18]. By this proposal, he stirred up a
passionate controversy that embroiled much of the bioener-
getics community for the next fifteen years [18]. Thereby,
mitochondria were established as the source which generates
the bulk of the ATP produced by respiration, via a process
known as oxidative phosphorylation [19]. Apparently, it was
well established that respiration is mediated by a cascade of
redox proteins associated with membranes, which funnel
electrons from NADH to oxygen [20]. The free energy (if
any) available from this “exergonic” reaction is conserved,
and drives the “endergonic” synthesis of ATP from ADP and
inorganic phosphate [21]. The enzyme that catalyzes the
latter reaction, the ATP synthase (F1F0 ATP synthase), had
also been identified [22]. In its native membrane-bound
form, it can generate ATP, whereas the solubilized enzyme
Beyond Mitochondria, What Would be the Energy Source Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1 39

can only break it down [22]. The open question was how understand why diabetic patients are not able to improve
mitochondria harness the free energy of respiration and make their capabilities with the increase of energy (glucose) avail-
it drive ATP synthesis up the thermodynamic hill? Analo- able. With so many uncertainties about the physiology and
gous questions had arisen with respect to photo- function of mitochondria, it is natural that the mitochondria-
phosphorylation and the uptake of metabolites by organelles focused therapy also is full of questions.
and cells [19].
According to Peter Mitchell, both redox chains and the
ATP synthase translocate protons and are linked only though
the proton current [18]. Both redox chain and the role of
ATP synthase require energy to succeed and to perform their
functions, including power required for any molecule. In this
case ATP synthase retains its shape, but the source of energy
remains a mystery till date. It was apparent to Peter Mitchell
from the beginning that proton motive force (proton poten-
tial, proton circulation) could support various kinds of mem-
brane work [18]. For instance, cells that possess the lactose
permease could accumulate β -galactosides to an internal
concentration nearly a thousand-fold higher than that of the
medium, but the energy source was unknown, although un-
doubtedly required [23]. Theoretically, accumulation of the
sugar occurs secondarily, thanks to the electrochemical driv-
ing force exerted upon the proton.
Fig. (13). The schematic drawing how the free chemical energy that
Mitochondria are the main producers of reactive oxygen emanates from the melanin is released symmetrically in all direc-
species (ROS) inside cell as a consequence of fuel oxidation tions, as rising energy spheres alternating nature. For example the
[24], and the amount of ROS contributes to apoptosis [25]. first contains molecular hydrogen and oxygen, the next re-formed
Another condition favoring ROS production is a reduction in water and a higher content of high electron energy, and so on. Our
mitochondrial copy number per cell. Mitochondrial mem- concept of the human body is that we are made up of billions of
brane potential is generated by proton pumping at complexes energy-independent units.
1, III, and IV, and offset by proton transfer in opposite direc-
tion which is referred to as proton leak [16]. This process can
occur in less-defined ways, apparently independent of known
enzymes or carriers [26]. Mitochondrial biology will be dif-
ferent if conceptualized in the manner shown in (Fig. 13),
and then glucose is only source of biomass, but no power
[27]. Oxygen utilization by mitochondria is connected with a
risk of generation of ROS and consequent development of
oxidative stress as a result of oxidative damage. That is why
it was considered that mitochondria are the major site of in-
tracellular superoxide production [28]. However, the exact
quantification is difficult, and the mitochondrial contribution
varies with the respiratory state. Besides there are consider-
able ROS derived from outside this organelle, including
oxygen radicals from peroxisomal β-oxidation of fatty acids,
NAD(P)H oxidase, xanthine oxidase, arachidonic acid me-
tabolism, microsomal P-450 enzymes, and the prooxidant Fig. (14). The single cell, where some are seen as organelles are
heme molecule [29]. Basically, the cell is a black box whose constantly bathed in the free growing areas of chemical energy
operation is extremely complex, thus isolated organelle stud- emanating from melanin, strategically located in the perinuclear
ies provide very limited or even skewed information. Mito- space. By the way the energy emanates from melanin, virtually all
organelles can constantly capture the day and night shifts. Appar-
chondrial alterations are observed in many diseases, but
ently, the organelles with higher requirements, such as the nucleus
more to be a causal factor, perhaps are relatively easy to ob-
and rough endoplasmic reticulum, absorb a large part derived from
serve changes [27, 30].
its position in relation to the melanosomes.
There are several controversial topics including:
“whether diabetes results from perturbed mitochondria or The biochemical processes that lead to cell life requires
vice versa, the importance of mitochondrial dysfunction ver- energy constantly, and the unexpected capacity of melanin to
sus altered numbers of mitochondria, sites of mitochondrial absorb light energy and transform it into chemical energy
ROS production, the role of ROS in diabetes and its compli- involve a substantial change in our conceptualization of cell
cations, and the role of membrane potential in regulating biology. Because of strategic placement of melanin granules
ROS” [16]. Normally, ADP serves to reduce the membrane in the perinuclear space (Fig. 14), the growing areas of free
potential by formation of ATP [16]. Given mitochondrial chemical energy constantly bathe the nucleus and the cyto-
essential function in aerobic metabolism, it is difficult to plasm, since the energy is released symmetrically in all di-
40 Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1
rections. The molecular hydrogen not combined with water
moves easily and reaches even the most remote corner of the
cell carrying their precious cargo of energy. The source of
energy of the nucleus is melanin, so the surrounding merges
the growing areas of energy from various melanin granules
to generate high energy. The endoplasmic reticulum almost
completely surrounds the cell nucleus, and effectively blocks
the energy flow of melanin and is considered the “factory" of
the cell protein. For us, the function of mitochondria is the
regulation of temperature, for although subtle, the data indi-
cate that the clearest skin has more mitochondria than darker
skin, the difference being over 50%, and even 83 % in some
cases. Also, animals believed to have hatched during periods
of glaciations have more mitochondria than animals during
warmer stages of earth's history.
CONCLUSION
Albert Einstein said that the geometry of the universe
depends on the distribution of energy. It is very likely that
the form and function of the cell and the organism depend
also on the distribution of energy; hence the uniformity that
is observed in human beings. There is no biochemistry reac-
tion that can be considered exempt. Any process of the body,
for example the synthesis, storage, release and hormone
function; they require chemical energy.
The thick cloud of doubt surrounding cellular metabolism
undoubtedly change with the surprising finding that our body
is made up of trillions of energy dependent cells, thanks to
the intrinsic property of melanin to transform light energy
into chemical energy. The energy that emanates from the
melanin in the form of molecular hydrogen and high energy
electrons is able to account for the energy required for every
single biochemical reaction that cell´s life requires. The time
that melanin takes to dissociate the water molecule is in the
range of the nano- and pico-seconds.
There are serious inconsistencies in the understanding of
cell metabolism that could be improved if we take in account
the chemical energy of melanin, for instance the Warburg
effect or aerobic glycolysis that is an inefficient way to gen-
erate ATP. It is paradoxical that cells with increased meta-
bolic requirements, such as cancer cell, rely on aerobic gly-
colysis. However there is an interesting observation regard-
ing the cancer cell potential which is about 75 mV, mean-
while normal cells have 120 mV. In our opinion, the voltage
is produced through the chemical energy that comes from
melanin, but when this process is impaired, e.g. cold, aged,
contaminated water, pesticides, herbicides, heavy metals,
etc., and then available chemical energy is not sufficient to
impel adequately the network of biochemical reactions that
mold life. Cells with chronic low levels of chemical energy
tend characteristically to disordered mitosis. Since chemical
energy levels are critical to enable the cell to what he has
done for millions of years, millions of times, we believe that
actually cell is not making mistakes but making its best ef-
fort under given circumstances. But power failures translate
into widespread failures. In our opinion, life is a delicate
balance between mass and energy, as it is the universe.
Based on this study, we are confident that the synthesis
of ATP is intended to supplement the control of the tempera-
ture and phosphate level toxicity, as we have found evidence
Herrera et al.
that energy is released when ADP is converted to ATP, and
energy is absorbed when ATP and ADP degrades. It is con-
ceivable that one of the main effects of the rotations of the
ATP synthase is the generation of heat. So, mitochondrial
temperature rises with the rotation of ATP synthase, but im-
mediately launches contrast mechanism, as is usual in the
body: the degradation of ATP, a process that absorbs heat to
become ADP and occurs within next 20 seconds. Recall that
high ATP levels are toxic to the cell and the organism. With
due regard to the earlier beliefs and findings, the interesting
observations of this study is expected to pave way for a cut-
ting edge research arena.
CONFLICT OF INTEREST
The authors declare that there are no potential conflicts of
interest with respect to the research, authorship, and/or pub-
lication of this article.
ACKNOWLEDGEMENTS
This work was supported by Human Photosynthesis
Study Center, Aguascalientes, México and GALLY Interna-
tional Biomedical Research Consulting LLC, San Antonio,
Texas, USA. Dr. Ghulam Md Ashraf was supported by the
Deanship of Scientific Research (DSR) and King Fahd
Medical Research Center (KFMRC), King Abdulaziz Uni-
versity, Jeddah, Saudi Arabia.
REFERENCES
[1] Kanehisa, M.; Goto, S.; Sato, Y.; Furumichi, M.; Tanabe, M.
KEGG for integration and interpretation of large-scale molecular
data sets. Nucleic Acids Res., 2012, 40(Database issue), D109-114.
[2] Karp, P.D.; Caspi, R. A survey of metabolic databases emphasizing
the MetaCyc family. Arch. Toxicol., 2011, 85, (9), 1015-1033.
[3] Rey, G.; Cesbron, F.; Rougemont, J.; Reinke, H.; Brunner, M.;
Naef, F. Genome-wide and phase-specific DNA-binding rhythms
of BMAL1 control circadian output functions in mouse liver. PLoS
Biol., 2011, 9, e1000595.
[4] Radrich, K.; Tsuruoka, Y.; Dobson, P.; Gevorgyan, A.; Swainston,
N.; Baart, G.; Schwartz, J.-M. Integration of metabolic databases
for the reconstruction of genome-scale metabolic networks. BMC
Syst. Biol., 2010, 4, 114.
[5] Stobbe, M.D.; Houten, S.M.; Jansen, G.A.; van Kampen, A.H.C.;
Moerland, P.D. Critical assessment of human metabolic pathway
databases: a stepping stone for future integration. BMC Syst. Biol.,
2011, 5, 165.
[6] Srere, P.A.; Inman, L.; Liposits, Z.; Sumegi, B. In: Integration of
Mitochondrial Function, Lemasters, J.J.; Hackenbrock, C.R.;
Thurman, R.G.; Westerhoff, H.V., Eds.; Springer US, 1988, pp
279-288.
[7] Miller, S.L.; Smith‐Magowan, D. The Thermodynamics of the
Krebs Cycle and Related Compounds. J. Phys. Chem. Ref. Data,
1990, 19, 1049-1073.
[8] Stobbe, M.D.; Houten, S.M.; van Kampen, A.H.C.; Wanders, R.J.A.;
Moerland, P.D. Improving the description of metabolic networks: the
TCA cycle as example. FASEB J., 2012, 26, 3625-3636.
[9] Diabetic Eye Disease, Facts About [NEI Health Information].
http://www.nei.nih.gov/health/diabetic/retinopathy.asp (Accessed
Dec 12, 2014).
[10] King, G.L.; Suzuma, K. Pigment-epithelium-derived factor--a key
coordinator of retinal neuronal and vascular functions. N. Engl. J.
Med., 2000, 342, 349-351.
[11] Aiello, L.P.; Avery, R.L.; Arrigg, P.G.; Keyt, B.A.; Jampel, H.D.;
Shah, S.T.; Pasquale, L.R.; Thieme, H.; Iwamoto, M.A.; Park, J.E.
Vascular endothelial growth factor in ocular fluid of patients with
diabetic retinopathy and other retinal disorders. N. Engl. J. Med.,
1994, 331, 1480-1487.
Beyond Mitochondria, What Would be the Energy Source
[12] Diabetic Retinopathy | Now@NEJM. http://blogs.nejm.org/now/
index.php/diabetic-retinopathy/2012/03/30/ (Accessed Dec 12, 2014).
[13] De Montellano B.O. Magic Melanin: Spreading Scientific Illiteracy
Among Minorities. Skeptical Inquirer, 16, 1992, 162-166..
[14] Alberts, B.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter,
P. In: Molecular Biology of the Cell, 4th edition. The Transport of
Proteins into Mitochondria and Chloroplasts. Garland Science:
New York, 2002.
[15] Mitochondria, Cell Energy, ATP Synthase | Learn Science at
Scitable. http://www.nature.com/scitable/topicpage/mitochondria-
14053590 (Accessed Dec 12, 2014).
[16] Sivitz, W.I.; Yorek, M.A. Mitochondrial Dysfunction in Diabetes:
From Molecular Mechanisms to Functional Significance and
Therapeutic Opportunities. Antioxid Redox Signal., 2010, 12, 537-
577.
[17] Arechaga, I.; Ledesma, A.; Rial, E. The mitochondrial uncoupling
protein UCP1: a gated pore. IUBMB Life, 2001, 52, 165-173.
[18] Mitchell, P. Chemiosmotic coupling in oxidative and photosynthetic
phosphorylation. 1966. Biochim. Biophys. Acta., 2011, 1807, 1507-
1538.
[19] Harold, F.M. Gleanings of a chemiosmotic eye. BioEssays, 2001,
23, 848-855.
[20] Murphy, Michael P.; Siegel, Richard M. Mitochondrial ROS Fire
Up T Cell Activation. Immunity, 2013, 38, 201-202.
[21] Thauer, R.K.; Jungermann, K.; Decker, K. Energy conservation in
chemotrophic anaerobic bacteria. Bacteriol. Rev., 1977, 41, 100-180.
[22] Weber, J.; Senior, A.E. ATP synthesis driven by proton transport in
F1F0-ATP synthase. FEBS Lett., 2003, 545, 61-70.
Received: December 15, 2014 Revised: January 25, 2015 Accepted: January 28, 2015
DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Edito-
rial Department reserves the right to make minor modifications for further improvement of the manuscript.
Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1 41
[23] Bogdanov, M.; Dowhan, W. Phosphatidylethanolamine is Required
for in vivo Function of the Membrane-associated Lactose Permease
of Escherichia coli. J. Biol. Chem., 1995, 270, 732-739.
[24] Aliev, G.; Obrenovich, M.E.; Tabrez, S.; Jabir, N.R.; Reddy, V.P.;
Li, Y.; Burnstock, G.; Cacabelos, R.; Kamal, M.A. Link between
Cancer and Alzheimer Disease via Oxidative Stress Induced by
Nitric Oxide-Dependent Mitochondrial DNA Overproliferation and
Deletion. Oxid. Med. Cell Longev., 2013, 2013, 962984.
[25] Maassen, J.A.; T Hart, L.M.; Van Essen, E.; Heine, R.J.; Nijpels,
G.; Jahangir Tafrechi, R.S.; Raap, A.K.; Janssen, G.M.C.; Lemkes,
H.H.P.J. Mitochondrial diabetes: molecular mechanisms and
clinical presentation. Diabetes, 2004, 53(Suppl 1), S103-109.
[26] Green, K.; Brand, M.D.; Murphy, M.P. Prevention of mitochondrial
oxidative damage as a therapeutic strategy in diabetes. Diabetes,
2004, 53(Suppl 1), S110-118.
[27] Aliev, G.; Solís-Herrera, A.; Li, Y.; Kaminsky, Y.G.; Yakhno,
N.N.; Nikolenko, V.N.; Zamyatnin, A.A.; Benberin, V.V.;
Bachurin, S.O. Human photosynthesis, the ultimate answer to the
long term mystery of Kleiber’s law or E= M 3/4: Implication in the
context of gerontology and neurodegenerative diseases. Open J.
Psychiat., 2013, 03, 408-421.
[28] Raha, S.; Robinson, B.H. Mitochondria, oxygen free radicals,
disease and ageing. Trends Biochem. Sci., 2000, 25, 502-508.
[29] Morita, T. Heme Oxygenase and Atherosclerosis. Arterioscler.
Thromb. Vasc. Biol., 2005, 25, 1786-1795.
[30] Aliev, G. The Role of Oxidative Stress, Mitochondria Failure, and
Cellular Hypoperfusion in the Context of Alzheimer Disease: Past,
Present and Future. Nova Science Publishers Inc.: New York,
2013.