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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, Mara 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, Lpez Velarde 108, Centro, Aguascalientes,
Aguascalientes, C.P. 20000, Mxico; 2King Fahd Medical Research Center, King Abdulaziz University, P.O.
Box 80216, Jeddah 21589, Saudi Arabia; 3Department of Cell Signalling, Belozersky Institute of PhysicoChemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia; 4Institute of Molecular
Medicine, Sechenov First Moscow State Medical University, 119991, Moscow, Russia; 5GALLY International 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 chemical energy through the dissociation of water molecule was unraveled. Initially, during 2 or 3 years; we tried to link together 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 unexpected 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 continues 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 metabolism, 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
1875-6166/15 $58.00+.00

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 organisms, there are multiple databases describing the metabolic
network and providing a holistic view, which are thus routinely used to provide context for the analysis and interpretation of high-throughput molecular data [3]. In silica models
of the metabolic network can be used (theoretically) to generate experimentally verifiable hypotheses such as potential
drug target, or to simulate the effect of network perturbations, 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

2015 Bentham Science Publishers

Beyond Mitochondria, What Would be the Energy Source

Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1

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 information 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 volume of the matrix fraction of mitochondria is not correlated
to the amount of Krebs cycle enzyme, and it seems theoretically 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 description 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 inaccurate 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 description. 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 formidable 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 advance in knowledge. Theoretically, cells depend on the reactions 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 concentrate 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 disheartening results, Peter Mitchel introduced a novel hypothesis 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 energy 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-

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 highenergy electrons to a series of molecules in the inner mitochondrial 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. Electrons 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 imbalance, and then the protons would move to restore the balance by traveling through an enzyme, ATP synthase. Recall
that hydrogen is the simplest and smallest atom, and has a
diameter of 1, 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
Mitchells 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 transported by electromagnetic radiations. But this argument
lacks the deeply rooted concept that human body cannot use
electromagnetic radiation as source of energy, because photosynthesis 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 removed three times each minute. At any instant each cell contains about one billion of ATP molecules. However, this
amount is sufficient only for few minutes and must be recycled rapidly because it is estimated that an average body contains one sextillion ATP molecules. The total ATP content in
human body is only about 50 grams, but total ATP requirements 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 consumption 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 metabolites) pathways, besides the heart high content of phosphocreatine (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 expenditure. 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 numerous 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, human eukaryotic cell also has the equivalent of the first reaction of the photosynthetic process in plants.
METHODOLOGY
Subjects
In 1990, we started an observational, descriptive, longitudinal study about morphological characteristics of the tiny
vessels of the optic nerve in the subjects. Our working hypothesis was that adequate magnification and digital recording of the anatomical changes in blood vessels of the optic
nerve eventually allow us to identify variations in their anatomical 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 angiography, 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 hospitals in city of Aguascalientes to our retina medical service
(Centro de Estudios de la Fotosntesis Humana. S.C. Human
Photosynthesis Study Center, Aguascalientes, Mxico). 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 approx. 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 contained brief data of patient information such as age, sex, date
of the study, current diagnosis (systemic and ophthalmological), pathological history in the case of chronic patients (diabetes mellitus, systemic arterial hypertension, arthritis, kidney etc), time of evolution, used treatments, as well as a history 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 glaucoma, 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. Therefore, the evaluation of vessels was mainly based on the experience 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 magnification 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 melanin 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 curiosity 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 vessels (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 individuals as well as diseased patients. Despite repeated literature 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 animal were obtained every week. On an average, after 15 days,
vessel growth was noticeable on the surface of the cornea in

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35

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. (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. (3). Above patient shows the presence of melanin in the

temporal edge of the optical disk is seen as dark spots.

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. (5). Alterations of pigment can be seen with polychromatic

light (white) around both the disc and the rest of the tissues of the
fundus.

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

Herrera et al.

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 glaucomatous optic neuropathy.

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.

four out of five animals. This growth was maintained uniformly until the end of the experiment which lasted three
months.

factors to the risk of retinopathy in populations remain uncertain due to a poor understanding of the pathophysiology
of diabetic retinopathy. It is striking that melanin is not mentioned in the numerous publications about diabetic retinopathy, where it was mostly mentioned as a pigment epitheliumderived factor (PEDF).

RESULTS AND DISCUSSION

In any tissue, vascularization is dependent on the dynamic balance between pro- and anti-angiogenic factors. In
eyes, the control of retinal angiogenesis is of critical importance 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 oxygen transport as well as by stimulating the expression of angiogenic growth factors and by inhibiting the release of antiangiogenic 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 present 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, homocysteine levels, and mutations in the erythropoietin gene
promoter. However, the relative contributions of the overall

In the first half of the research, we had very clear consensus about the presence of melanin in the fundus of all subjects we reviewed, but the reason was still unclear to us.
Moreover, since there were two main variables (blood vessels 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 decreases significantly, perhaps to less than 30%. But the
melanin anti-angiogenic effect exceeded 90%, and thus
might be exercised through a different mechanism. The purity of the experimental model obtained also caught our attention because of minimal or no destruction or disorganization 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 condition than tissues with lower melanin content under similar
conditions. So, the puzzle gradually took shape, because melanin was present in all subjects, and the vessels responded to the
presence of melanin, besides the tissues showed several positive 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 fundamental. The effect of melanin on the blood vessels cannot

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37

Fig. (9). The laser photocoagulation is a practice that started from

the middle of last century. And to date their effects remain controversial. 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. (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. (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.

Fig. (12). Angiogenesis in cornea, right eye, Wistar rats after 15

days of the application of a drop of a solution of C6H6.

be through peptide formation, because melanin neither possesses 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 expected 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 several 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 enzymes because melanin contains structures with no unusual
characteristics of any enzyme.

veins, it was around 94%, which contrasts with veins from

other tissues where it is close to 60%. We then started determining 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 oxygen 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 generated 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 general. Also, there were no other anatomical or functional factors 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

The answer to our questions began to emerge while analyzing the biochemical characteristics of the choroid, and
really caught our attention when the partial pressure of oxygen in the choroidal arteries was found to be 97%, which is
very similar to other arteries in the body. But in the choroidal

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 antiangiogenic 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 molecule and can be written as follows:
2H2O2H2 + 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 chlorophyll only absorbs the ends of the visible spectrum (red and
blue) and melanin absorbs all of the electromagnetic spectrum, i.e. from gamma to radio waves rays [13]. Furthermore, 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 dissociation, the amount of water present in the eye would not be
enough. So, the representation of photosynthesis in humans
should be:
2H2O2H2 + 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:
2H2O2H2 + O2 + 4eThe 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 mitochondria) as an energy source, and eventually the all important question aroused: And if the mitochondria were not a
source of energy?
Mitochondria are unusual organelles, which divide independently of the cell on which they reside, meaning mitochondrial 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 prokaryote. This eventually derives a character highly conserved
in evolution, since theoretically mitochondria use oxygen to
generate energy. Mitochondria is surrounded by two membranes, outer and inner [14]. The outer membrane fully encloses the whole organelle, and a small intermembrane space
exists between outer and inner membrane [14]. However the
outer mitochondrial membrane contains a lot of proteinderived pores that are big enough to allow the passage of
ions and even molecules as large as small proteins [14]. Oppositely, the inner membrane has much more restricted permeability, 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 obtained, since only protein complexes requires power to maintain their shape and functionality. However, the term electron transport chain has been criticized as misleading,
because it implies a linear progression along a single pathway [16]. During electron transport, the participating protein
complexes push protons from the matrix out to the intermembrane space [15]. This creates a concentration gradient
of protons that another protein complex, called ATP synthase, 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 bioenergetics 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

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Central Nervous System Agents in Medicinal Chemistry, 2015, Vol. 15, No. 1

can only break it down [22]. The open question was how
mitochondria harness the free energy of respiration and make
it drive ATP synthesis up the thermodynamic hill? Analogous questions had arisen with respect to photophosphorylation and the uptake of metabolites by organelles
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 potential, proton circulation) could support various kinds of membrane work [18]. For instance, cells that possess the lactose
permease could accumulate -galactosides to an internal
concentration nearly a thousand-fold higher than that of the
medium, but the energy source was unknown, although undoubtedly required [23]. Theoretically, accumulation of the
sugar occurs secondarily, thanks to the electrochemical driving force exerted upon the proton.
Mitochondria are the main producers of reactive oxygen
species (ROS) inside cell as a consequence of fuel oxidation
[24], and the amount of ROS contributes to apoptosis [25].
Another condition favoring ROS production is a reduction in
mitochondrial copy number per cell. Mitochondrial membrane potential is generated by proton pumping at complexes
1, III, and IV, and offset by proton transfer in opposite direction 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 different 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 intracellular superoxide production [28]. However, the exact
quantification is difficult, and the mitochondrial contribution
varies with the respiratory state. Besides there are considerable ROS derived from outside this organelle, including
oxygen radicals from peroxisomal -oxidation of fatty acids,
NAD(P)H oxidase, xanthine oxidase, arachidonic acid metabolism, microsomal P-450 enzymes, and the prooxidant
heme molecule [29]. Basically, the cell is a black box whose
operation is extremely complex, thus isolated organelle studies provide very limited or even skewed information. Mitochondrial alterations are observed in many diseases, but
more to be a causal factor, perhaps are relatively easy to observe changes [27, 30].
There are several controversial topics including:
whether diabetes results from perturbed mitochondria or
vice versa, the importance of mitochondrial dysfunction versus altered numbers of mitochondria, sites of mitochondrial
ROS production, the role of ROS in diabetes and its complications, and the role of membrane potential in regulating
ROS [16]. Normally, ADP serves to reduce the membrane
potential by formation of ATP [16]. Given mitochondrial
essential function in aerobic metabolism, it is difficult to

39

understand why diabetic patients are not able to improve

their capabilities with the increase of energy (glucose) available. With so many uncertainties about the physiology and
function of mitochondria, it is natural that the mitochondriafocused therapy also is full of questions.

Fig. (13). The schematic drawing how the free chemical energy that
emanates from the melanin is released symmetrically in all directions, as rising energy spheres alternating nature. For example the
first contains molecular hydrogen and oxygen, the next re-formed
water and a higher content of high electron energy, and so on. Our
concept of the human body is that we are made up of billions of
energy-independent units.

Fig. (14). The single cell, where some are seen as organelles are
constantly bathed in the free growing areas of chemical energy
emanating from melanin, strategically located in the perinuclear
space. By the way the energy emanates from melanin, virtually all
organelles can constantly capture the day and night shifts. Apparently, the organelles with higher requirements, such as the nucleus
and rough endoplasmic reticulum, absorb a large part derived from
its position in relation to the melanosomes.

The biochemical processes that lead to cell life requires

energy constantly, and the unexpected capacity of melanin to
absorb light energy and transform it into chemical energy
involve a substantial change in our conceptualization of cell
biology. Because of strategic placement of melanin granules
in the perinuclear space (Fig. 14), the growing areas of free
chemical energy constantly bathe the nucleus and the cytoplasm, 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 indicate 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 reaction 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 cells 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 generate ATP. It is paradoxical that cells with increased metabolic requirements, such as cancer cell, rely on aerobic glycolysis. However there is an interesting observation regarding the cancer cell potential which is about 75 mV, meanwhile 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 effort 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 temperature 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 conceivable 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 immediately 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 cutting 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 publication of this article.
ACKNOWLEDGEMENTS
This work was supported by Human Photosynthesis
Study Center, Aguascalientes, Mxico and GALLY International 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 University, Jeddah, Saudi Arabia.
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Accepted: January 28, 2015

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