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Book on fructose, mitochondria, and the sickest of mammals
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3-1 Mitochondrdial structures and maintenance
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Sample Chapters -- Book in Progress, pending final editing
LIKE THE OTHER CHAPTERS THE
ILLUSTRATIONS DON'T PASTE NOW
3-1-Mitochondrial
Structures and maintenance 5/19/19 the illustrations in this chapter wont
paste
Chapter 1, Mitochondria
structures and processes 1. MTD basics
2.
Mitochondria structures and functions
3. MTD repair systems 4. Fission
and fusion 5. Mitophagy 5.
Sex hormones are protective 6. ATP
7. add movement through microtubules
Again I must state
that I don’t like the word “probably”,[1] thus I state the
evidence and solution without that word; considered it understood.
Take a deep-deep
breath, because with mitochondrial
dysfunction lowers the use of oxygen, which is used for the production ATP
I scarified style
for teaching, a resource to promote
understanding.
I find a parallel
with Darwin: he faced to opposition from those who
believed that god created everything, and I the opposition from those who
believe in pharma’s version of medical science.
Knowing that faith in the standard theories creates a barrier to a
theory that opposes most of the stand theory, I consume 25% of space in
critical analysis.
I investigate critically nearly everything that in journals promotes the sales
of drugs. With my cherry-picked evidence
from the journal, this work sets out the case for fructose causing MTDD, then
MTDD causing CAWD.
“Mitochondrion ultrastructure (interactive
diagram) A mitochondrion has a double membrane; the inner one contains
its chemiosmotic apparatus
and has deep grooves which increase its surface area. While commonly depicted
as an "orange sausage with a blob inside of it" (like it is here),
mitochondria can take many shapes and
their intermembrane space is quite thin.” [2]
The mitochondrion lies at the heart of cell life
and cell death. To put these structures in context, consider that every child
knows that we must breathe oxygen to stay alive. And why? Because our
mitochondria demand oxygen in order to function. 98% or so of the oxygen that
we breathe is destined to be consumed by our mitochondria. . . . They
provide the energy required for almost
all cellular processes. . . . they also
are exquisitely and intimately involved in a subtle discourse with other
aspects of cell physiology, [As a consequence MTDD is a CC for nearly all the
age related conditions.][3]
1. MTD basics: As developed
in Section 2
the reactive chemical caused by the western diet causes MTDD, which is by far the most significant cause for all of the
CAWD. As
pointed out in 1:1,
over 90% of the population is at risk for CAWD based on a comparison to LSPs
biomarkers. This 90 plus percent through
moderate to severe damage to MTD are at risk well above the LSP for CAWD. To
repeat myself compared
to lean Swedes their fasting insulin is nearly double the Kitavans as too their
fasting glucose; blood pressures is about 20% higher, and so on (1:1). All these factors
are not merely associated with MTDD, but are caused by MTDD and the reactive
sugar fructose in the cytosol. What
follows in this chapter is Section 3 is a detailed picture of the MTD—a look at
the factory. Its sister chapter, 2, is
on the products produced, excluding from metabolism which is covered in 2:1. Chapter 4 is
on
MTDD, and the subsequent chapters are on the major-cellular products are
affected by MTDD and its sidekick fructose. There I present the evidence on how
the reduce production of ATP (RAPT) along with fructosylation affects various
systems such as the hormonal regulation of the rate of metabolism and weight,
the rate of replacement of defective collagen, the rate of catabolism of
glucose and thus cause hyperinsulinemia, the performance of various cellular
repair and replacement systems, to three ways in which every cell are affected
by RPA. Then in the 4th
Section is the evidence for an association of RPA and various conditions such
as dementia, atherosclerosis, and cancer.
Theses 4 areas: population studies, journal articles on MTDD, effects
upon major cellular system, and the association of MTDD with various
conditions, these 4 taken together elevate MTDD from just a theory of CAWD to a
proof. This Section 3
provides the foundation for the claim that MTDD with its RPA causes the
conditions listed in Section 4.
At my website healthfully.org/??? are over 100
journal articles concerning
MTD and MTDD; however, don’t sweat the
details. The details on the mitochondria
structures and functions below are described here for to create an awareness of
the complexity of processes which occur in eukaryotes and some simple forms of
life. Realizing the complexity of
process is an essential part of developing the ability to arrive at reasonable
evidence-based conclusions. Ignorance is
not bliss, and an overload of details creates cognitive dissonance. What should
be taken away from this chapter and the next is that evolution builds many
complex systems to promote survival, and the unhealthful consequence result
from them compromised or their being turned.
These consequences, such as the formation of sharp uric- acid crystal
circulating in the blood and accumulating in certain tissues are a result of
broken systems. MTDD AND RPA are the
demons inside the cells. Having said
this, I am not going to load the reader with genetic information, details about
regulatory systems, the nuts and bolts of metabolism, and like. The object is
to paint a clear picture of
MTDD and RPA and their roles. Section 3 forms
the causal foundation for Section 4 on the CAWD, and 5 on restoring health.
“A mitochondrion generates 150—200 millivolts
across
its 5-nanometre membrane. . . . if the
field strength were measured per meter, a mitochondrion would be producing a
whapping 30 million volts. Lane and
Martin (2010) have estimated for size, a mitochondrion produces as much energy
as a bolt of lightning. . . There are approximately 10 million billion
mitochondria in an adult human, that is estimated to be roughly 10 percent of
total body weight.[4] Found in every eukaryote and have made
possible the complex life forms on this planet; why?
Figure
A, the dots in the upper right are the mtDNA, size 200 nm.
Figure
B), a view of the cytoplasm with the scaffolding for MTD in the upper center
2. Mitochondria structures and functions:
The mitochondria are tiny organelles in all
eukaryotic cells. They number from one
in the tail of a sperm, to 6,000 in very active cells--such as hepatocytes and
some cardiac myocytes[5]
where they comprise nearly 25% of the volume of The cell. “There are about10
million billon MTD. A mitochondrion generates 150-200 volts
across a 5 nanometre membrane, which equal about 300 million volts per meter,
and they constitute 40 percent of cytosolic weight in many cells. . . . Every
day the brain and heart have to
synthesize 13 pounds of ATP [in the MTDs.]” [6] “In humans, 615 distinct types
of protein
have been identified from cardiac
mitochondria--supra, whereas in rats, 940 proteins have been reported” supra. Different
tissues types have different sets of
protein, thereby enabling MTD functions adaption to types of tissues.
By derivative work: Shanel (talk)
Mitochondrial DNA de.svg: translation by Knopfkind; layout by jhc -
Mitochondrial DNA de.svg, CC BY-SA 3.0,
Alexeyev, Mikhail, Inna Shokolenko, et al The Maintenance of Mitochondrial
DNA integrity—critical analysis and
update, 5/2013
“In
most
multicellular organisms, the mtDNA – or mitogenome – is organized as a
circular, covalently closed, double-stranded DNA. In humans there are 100–10,000
separate copies of mtDNA
are usually present per somatic cell
(egg and sperm cells are exceptions). .
. . In mammals,
each double-stranded
circular mtDNA molecule consists of 15,000–17,000[40] base pairs. The two strands of mtDNA are
differentiated by their nucleotide content, with a guanine-rich strand referred to as the heavy strand (or H-strand) and a cytosine-rich strand referred to as the light strand (or L-strand). . . . The light strand encodes 28 genes, and the
heavy strand encodes 9 genes for a total of 37 genes.[4] Of the 37 genes, 13 are for proteins
(polypeptides), 22 are for transfer RNA (tRNA) and two are for the small and
large subunits of ribosomal
RNA (rRNA).” [7]
3. Most of the proteins are
transported into the mitochondria rather than produced there--only about 30 are
produced in the MTD. “Mitochondria possess a harsh protein
folding environment, due to the high levels of reactive oxygen species (ROS),
and the fact that more than 99% of mitochondrial proteins need to be
transported from the cytosol into the mitochondria and correctly folded.”[8] One
reason for the transport is that “some mitochondrial functions are performed
only in specific types of cells. For
example, mitochondria in the liver cells contain enzymes that allow them to
detoxify ammonia, a waste product of protein metabolism.” [9] Since ammonia is very reactive, it
contributes to MTDD, its rapid disposal helps to maintain genome integrity.[10] Given its reactive environment and the lack
of protection compared to nucleus DNA, this import of protein limits the amount
of DNA and thus its damage. The assault
by reactive chemicals, limiting the number of mtDNA genes and mtRNA
transcription factors, limits targets.
Secondly, those genes are far more exposed than those in the nucleus for
several reasons. One is the energy
required to fold and unfold genes would both slow their usage and consume
significant amounts of ATP. Second there
is no chromatin that the chromosomes are fold in in the nucleus protect them
from reactive chemical, thus the exposure of mtDNA is more than in the
nucleus. Third there are few introns
which would be another target for reactive chemicals, one for which such damage
often has negligible effect. Lacking
introns is another CC for the high rate of mtDNA damage. The net effect of these
difference is that
mtDNA mutates 10-20 times faster than nDNA.
. . .” [11]
This high rate of DNA damage entails that MTD are short lived, with those producing
the most ATP have the shortest life (under 2 days), while other with moderate
ATP products would last a couple of months or longer.
Given
the survival pressure of over 1 billion years of evolution, the MTDs are
sculptured to promote the survival of each species. The similarity between of
DNA code between
species is a result of their functions being preserved because they are
essential. However, there is great
variation of mtDNA gene content and size among fungi and plants. “Surprisingly, even those huge mtDNAs
contain the same number and kinds of genes as related plants with much smaller
mtDNAs”, supra. Plants having MTD entails an early inclusion in eukaryotes,
long before the develop of aquatic plants.
“It is generally accepted that they were originally derived from
endosymbiont prokaryotes. . . . proto-mitochondrion was a member of the phylum
Proteobacteria.” [12]
Though MTD was first observed in 1840, and
established as cell organelles in 1890, in 1913 by Otto Warburg were linked to respiration,
in 1939 that oxygen was used in the formation of ATP, but it wasn’t discovered
until 1948 that the MTD are the site of oxidative phosphorylation in eukaryotes.
In 1924 Warburg published his finding that cancers
have disabled MTD’s production of ATP through the Krebs cycle.[13] This enables these abnormal cells to avoid
apoptosis. In spite of his cellular recognition and Nobel award, his efforts
over 4 decades to have suitable research concerning this finding and its
therapeutic consequences, that of starving the cancer through fasting and a
ketogenic diet, his work was mainly ignored.[14] Not surprisingly pharma was able to frame the
cancer topic and ignore the dietary approach to cancer treatment. In around
2000 significant interest in cancer
being a metabolic disease became an area of major research, of which most is in
search of drugs to block minor metabolite glutamine or affect the fermentation
of glucose in the cytosol, which also yield at a far lower rate ATP per
molecule of glucose. The low rate of
production is insufficient—at least in many cases of cancer—to provide
sufficient ATP for cancer cell reproduction, and in some cases results in
destruction of cancer—a cure. The work
of Thomas Seyfried has done much to draw attention to Warburg’s finding, as too
his textbook Cancer as a Metabolic Diseases
(2012). Warburg’s work with Trung Nguyen added as
coauthor, The Metabolism of Tumours
(2018) is the 5th part of
the series Understanding Cancer. As of 2017 I have read that regulatory agencies won’t
allow
a clinical trial of fasting and keto diet for treating cancer, and that if any
are to be approved it must have an adjunct chemotherapy. A friend of mine, the
clinic refused in 2018 to excise his stage 3 rectum cancer because he refused
chemotherapy.
Acetyl-Co-A
Pyruvic
Acid, both an acid and a ketone.
Without the H on the OH group, it is pyruvate.
6.
Being limited to 37 genes with about
16,600 base pairs, the mtDNA encodes 12 proteins essentials for the respiratory
chain functions. Over 600 other proteins
found in the MTD; they are transported from the cell’s cytoplasm. (This
is the
vehicle for glycated proteins to enter the MTD, and through further metabolism
into very reactive
chemical, this process can on a western high sugar diet cause CAWD through
excessive number of damaged MTD and
the accumulation of mutated mtDNA).
6a. MTD in different tissue types have different proteins.[15] These additional complexities exist to expand
the functions of the MTD functions besides the universal ATP production, signaling
for apoptosis (orderly cellular dismantling), calcium signaling, MTD repair,
replication, fusion, and mitophagy, allostasic stability, synthesizing cellular
components, generation of ROS used by the immune, production of heme and of
phosphocreatine for short bust of intense activities, calcium storage and
regulation, assist in the clearance of ammonia by supporting several steps in
the urea cycle, promote steroid synthesis by the production of pregnenolone,
active transport systems, influence cell growth and differentiation.[16] There is also a glycogenic pathway in the
MTD, for when glucose is need during starvation. Most of these processes are
dependent on
nDNA. For example, “mtDNA is dependent
upon nDNA for the production of a number of proteins involved in its
replication, transcription. Translation, repair, and maintenance. . . . Adenine
nucleotide translocator-1 (ANT-1) is an isoform specific to muscle, heart, and
brain.”[17] In a cell, the MTD can change shape and move
within the cell, increase or decrease in numbers as needed, and start the
process of cellular apoptosis. The MTD
mainly in brown fat cells is used to generate heat. Additional functions include
signaling
through ROS, regulation of membrane potential, cellular proliferation
regulation, cellular metabolism, calcium channel signaling, certain types of
heme synthesis, phosphorylation of AMP and ADP to ATP, the synthesis of ATP in
the Krebs cycle, metabolism of ketones, hormonal signal to name the important ones. “Mitochondria can
repair oxidative DNA
damage by mechanisms that are analogous to those occurring in the cell nucleus.
The proteins that are employed in mtDNA repair are encoded by nuclear genes, and are translocated
to the mitochondria”, Wiki supra.[18]
Shows
the scaffolding for MTD, which also provide a means for being moved to where
need.
[1]
““Probably in a phrase when repeated often is a mark of verbosity, a poor style
of writing, and it detracts from the overall thesis by encouraging the reader
to wonder what else. Think of The Origin of Species with
a phrase containing “probably” on
every second page. A work which presents
an alternative thesis is very possible wrong in details, and possible overall
wrong
[3] Duchen, Michael,
Aug 2004. Mitochondria in health
and disease: perspectives on a new mitochondrial biology a seminal
technical article
[4]
Griffith, Mitochondria in disease and health,
P.
17
[6]
Supra
17, It is estimated that an adult
of 30 produces from ADP as to weight of ATP, their own body weight in ATP. The
process of going from ADP to ATP and back
again to ADP occurs in some tissues in less than a second.
[8]
Barbour, Jayne, Nigel Turner, Jan 2914, Mitochondrial stress signaling promotes
cellular adaptations
[9]
Wani Aijaz, Molecular and biochemical
understanding of mitochondrial diseases (book), section 2.3.
[10]
This is the main reason for my following and
recommending a moderate protein diet of around ½ gram per kilo of lean body
weight for adults. For those without
MTDD, a much greater amount of ammonium caused damage will be handled by their
systems. With the low protein diet,
there isn’t excess amino acids for catabolism. Amino
acids are not stored.
[12]
Wani, Aijaz, 2.2 Molecular and biochemical
understanding of mitochondrial diseases
[13]
Hans Adolf Krebs working in Warburg’s laboratory elucidated the cycle for which
he won a Noble award in physiology in 1953.
[14]
In 1984 I bought a Cancer Biology
(1981) by Raymond W. Rubbon, the Director of
Biological Markers Program of the National Cancer Institute. In the books 344
pages there is no reference
to Otto Warburg, mitochondria, defective metabolism, fermentation, and glucose,
yet there in its 8 sections on cancer cells there are sections on transforms,
tumor growth and cellular differentiation.
I had been reading widely on cancer, and in 2015 wrote an article on
cancer for healthfully.org/rh, which took about 6 months of preparation. In
the process I came across Warburg’s work
and another on how a tumor becomes matastic by turning on the genes of the
macrophage and thereby becoming invisible to the immune system. In those years
after 1984 to 2015, I had
repeated visited the topic of cancer, first accepting the multiple mutations,
then the role of stem cells, then stem cells creating of a tumor pluripotent
cells, and finally Warburg and macrophage genes. In the Wiki article Cancer, May 2019, the
same are still missing, Warburg, glucose, macrophage, fermentation, and
mitochondria. The deception lies in what
is not mentioned: “If the error control
processes fail [referring to apoptosis], the mutation will survive and be
passed along to daughter cells. . . . A further mutation may cause loss of a
tumor suppressor gene, disrupting the apoptosis signaling pathway and
immortalizing the cell.” Not mentioned
is the role of the MTDD that shuts down MTD signaling for apoptosis by
mutations that shut down the functions of MTD.
Again I must repeat that pharma frames the discussion.
[15]
“For example, mitochondria in the liver cells contain enzymes that allow them
to detoxify ammonia, a waste prod cut of protein metabolism.” Wani, Aijaz,
Molecular and biochemical
understanding of mitochondrial diseases, 2:2.
[16] Osellame, Laura, Thomas Blacker, et al, Cellular and molecular mechanisms of
mitochondrial function Dec.
2012.
[17]
Wani, Aijaz, 4.3, Molecular and biochemical
understanding of mitochondrial diseases,
[18]
Major articles on repair are Alexeyev, Mikhail, Inna Shokolenko, 5, 2013 et al The Maintenance of Mitochondrial DNA integrity—critical analysis and
update, and Osellame supra.
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3-1-Mitochondrial Structures
and maintenance 5/19/19
Chapter
1, Mitochondria
structures and processes 1. MTD basics
2.
Mitochondria structures and functions
3. MTD repair systems 4. Fission
and fusion 5. Mitophagy 5.
Sex hormones are protective 6. ATP
7. add movement through microtubules
Unfortunately the jpeg illustration on my MS word pages won't now show up
The MTD structures are
relatively simple--not surprisingly given its diminutive size, which is between
0.75 and 3 micrometers. The out wall of
this organelle is between 60 and 75 angstroms thick and is composed of
phospholipids and proteins that from the permeable pores that allow many different
types of molecules that are under 5000 Daltons to freely diffuse both in and
out. Large proteins can enter through a
transport system. The inner membrane,
the cristae. The leaking of protein
through the outer membrane will initiate apoptosis.[1]
The major metabolic
activity occurs inside the inner membrane, known as cristae membrane and the
space between folds, the cristae. The cristae are
numerous pockets/folds within the matrix wherein the production of ATP
occurs. These folds are studded around
F1 particles which serve osmotic functions.
The matrix is the space enclosed by the inner membrane and contains ATP
synthase, along with mtRNA and mtDNA. Pyruvate molecules produced by glycolysis
are actively transported across the inner MTD membrane and into the matrix for
fueling the Krebs cycle, or it can be carboxylated to form oxaloacetate another
fuel for the Krebs cycle. Depending
upon signalling glycogenesis and the product of glucose can also occur. The
MTD in response to hormonal signalling
regulates cellular metabolism, and there are other regulatory functions such as
the storage of calcium.
9 In
addition to that
the MTD there is a cellular scaffolding like structure (the fluorescent photo
above) which functions to maintain structure and serve other functions. The
cytoskeleton is a dynamic network of
interlinking proteins filaments that extend from the cell walls to the nucleus
membrane. They vary according to cell
type and conditions in the cell. The dynein arms[2]
attached to the microtubules function as the molecular motors. The motion of
the cilia and flagella is created by the microtubules sliding past one another,
which requires ATP and function to locate the MTD according to needs. Underperformance
of this system has been linked
to dementia and other neuronal problems to
which hyperposphorylation of the tau proteins are associated with.[3]
The system function provides transport in support of the fusion process of MTD
(3:5).
We can attribute to RATP and fructosylation of proteins as causal for
the assortment diseases and much more as a result of RATP and the
downregulation of the repair processes which includes also the fusion, fission
processes. Fission occurs to replace MTD
that because of a need for more MTD due to demand for more ATP than can be
supplied due to biological demands including senescence and the orderly
dismantling by mitophagy.
5. mtDNA repair
systems
Having set this out,
the
when through a poorly understood signal system, when the mtDNA is of high
quality the MTD undergoes reproductive process of fission or fusion (next
section), or if of low quality of orderly dismantling though mitophagy.
4. Fission and
fusion: As established, the stress from reactive
chemical both justifies their role in eukaryotes as part of the high-level of
MTD maintenance, for which there are three broad paths, repair, destruction,
and replacement. Fission is replacement,
it fills a gap created by the reduction in the number of MTD by mitophagy. Fusion
is a type of repair in which 2 MTDs
that are underperforming join together to form a larger MTD and in which
damaged parts are repaired and replaced.
Full fusion is a unique process of the MTD in Eukaryotes, but one which
commonly occurs in prokaryotes.[4] Partial fusion, such as DNA transfer has been
well documented among eukaryotes, including in primates, but I don’t know of
cell fusion, at least in mammals. For
example, the use of swine skin as a bandage in burn treatment, the genes from
the swine have been found years later in patients so treated. Moreover, gradually
the disadvantageous genes
are eliminated, while others spread to different tissues.
Fission and fusion are part of the fix. “Fusion enables the filtering
and re-use of
still viable mitochondrial components, and the removal of worn-out components,
thus to build better mitochondria.” [5] Fusion integrates the contents of moderately
damaged MTD. That both fission and
fusion like other systems have been implicated in CAWD, follows the pattern of
a general assault upon all systems[6]
The AMPK stimulates
the fission and fusion processes, while insulin inhibits that process. “The subsequent
identification of AMP-activated protein kinase (AMPK) and
its activation by exercise and fuel deprivation have led to studies of the
effects of AMPK on both IR and metabolic syndrome–related diseases. . . . In
addition to glucose transport, lipid and protein synthesis, and fuel
metabolism, AMPK regulates a wide array of other physiological events,
including cellular growth and proliferation, mitochondrial function and
biogenesis, and factors that have been linked to insulin resistance (IR),
including inflammation, oxidative and ER stress, and autophagy. AMPK plays a
central role in regulating
insulin sensitivity.”
5. Mitophagy: Mitophagy is a system for the dismantling of dysfunctional
MTD. While fission and fusion (described
below) are building processes; mitophagy is though destructive, essential
protective in that it disposes of mitochondria which leak reactive chemical and
operate inefficiently. During the period
when autophagy is turned on, repairs can occur for the MTD through fission and
fusion. Another process is mitophagy, a
subclass of autophagy. Mitophagy
is the dismantling,[7]
which occurs in the lysosomes in the cytosol.
MTD are short lived, compared to the cells they are found in. For example,
in the liver 1-2 day, heart 3-6
days, and brain and kidneys 24 days.[8]
Given the number of MTD in a cell and their short life, the orderly dismantling
conserves uses compounds and prevents the release of reactive chemicals.
“We
estimated the actual
liver mitochondrial half-life as only 1.83 days, and this decreased to 1.16 days
following 3 months of dietary
restriction [fasting of mice], supporting the hypothesis that this intervention
might promote mitochondrial turnover as a part of its beneficial effects.” [9] This is the modus operandi for why fasting
can reverse t2d and IR, since as shown in
MTDD plays a key role in developing those conditions. Replacing
underperforming MTD and thus lower ATP as well as a reduction in the leaking of
reactive chemical promotes turning down the PP, lowering serum glucose and thus
insulin, reducing DNL, and metabolizing excessive fat, increasing the
functionality of repair processes, and possibly most importantly metabolizing
fat in the pancreas and liver. The
diminished rate of replacement is pathogenic as it promotes fat accumulation in
organs, leaking of reactive and IR,
5. Sex hormone
protective: Early in 2018, I came to
the realization that the long list of conditions associated with the western
diet had as a starting point the reactive sugar fructose damaging mitochondrial
DNA. Subsequent investigation found that
the sex hormones testosterone, DHEA, estradiol and its associate progesterone
are mitochondrial protective re reactive chemicals, and this is the mechanism CC
to their long list of benefits. “Both steroids trigger a complex molecular mechanism that involves
crosstalk between the mitochondria, nucleus, and plasma membrane, and the
cytoskeleton plays a key role in these interactions. The result of this
signaling is mitochondrial protection, at Sept
2013.
“Our results
indicate that testosterone improves
cell survival and mitochondrial membrane potential and reduces nuclear
fragmentation and reactive oxygen species (ROS) generation. These effects were
accompanied by a positive regulation of neuroglobin, an oxygen-binding and
sensor protein, which may serve as a regulator of ROS and nitrogen reactive
species (NOS), . . . these findings
suggest that astroglia [star shaped glial cells in the brain] may mediate some
of the protective actions of testosterone in the brain upon pathological
conditions.” [10] and similar for cyto-protection
and cardiac recovery after MI.[11]
These sex hormones explain why with
their reduction among the elderly the age related conditions increase, and why
as supplements their many have such varied health benefits. Unfortunately, the
industry that profits from
illness has opposed their usage with success.
That the 4 named hormones
are protective is to be expected in that MTD have receptors for them,[12]
and that these hormone have been shown to lower the risk for a long list of
conditions (see http://healthfully.org/rc/id2.html
for HRT and http://healthfully.org/rc/id7.html for testosterone. Given
these benefits and the drop in their
level with menopause and andropause has caused me to conclude that this is
nature way of culling the elderly from the village and town, because the
elderly is neither a warrior or laborer.
At the healthfully on HRT, NIH knowingly used the worst HRT, which
contains equine estrogen was used with medroxyprogesterone--marketed as
Prempro. That progestin blocks several
of the major benefits of estrogen.
Another example of pharma and its lapdog the NIH maximizing illness,
while claim the opposite. I have been
taking testosterone since 2004 at 3 times the dose of Androgel from a
compounding pharmacy and I have been taking sublingually DHEA since 2002.
“The metabolic pathway of glycolysis
converts glucose to pyruvate by via a series of intermediate
metabolites. Each chemical modification (red box) is performed by a different
enzyme. Steps 1 and 3 consume ATP (blue) and steps 7 and 10 produce ATP
(yellow). Since steps 6-10 occur twice per glucose molecule, this leads to a
net production of ATP. in most organisms the glycolysis occurs in the cytosol.
Above is the Embden–Meyerhof–Parnas
pathway, the most common pathways.” https://en.wikipedia.org/wiki/Glycolysis
6. ATP
The dominant role for the MTD is the production of ATP. The pyruvate
produced by glycolysis are
actively transported across the inner mitochondrial membrane and into its
matrix where it is oxidized by and combined with coenzymes A to form CO2
acetyl-CoA and NADH.[13] The acetyl CoA is the primary substrate to
enter the Krebs cycle. “Glycolysis (pathway
above) is a sequence of ten-enzyme catalyzed
reactions. Most monosaccharides, such as fructose and galactose, can be converted
to one of these intermediates. The
intermediates may also be directly useful. For example, the intermediate dihydroxyacetone phosphate (DHAP) is a
source of the glycerol that combines with fatty acids to form fat. the
latter two are produced in the cytosol in the presence of
oxygen then transported to the MTD. Pyruvate is produced by glycolysis of
glucose. “If pyruvate is shunted off
toward lactic acid synthesis, cell respiration will be anaerobic. If pyruvate
is transported into the
mitochondria, then cell respiration will be aerobic [Krebs cycle].” [14] When oxygen is scarce metabolism shifts into
the cytosol for anaerobic fermentation.
“The production of ATP from glucose has approximately 13-fold higher
yield during aerobic respiration compared to fermentation,” supra. This
occurs the Krebs cycle, an
aerobic process that produces CO2 and
H2O as byproducts. About 30 ATPs are
produced per molecule of glucose” supra.
When consumed in
metabolic processes, it converts either to adenosine
diphosphate (ADP) or to adenosine
monophosphate (AMP). “Other processes regenerate ATP so that the
human body recycles its own body weight equivalent in ATP each day.[2] It is also a precursor to DNA and
RNA, and is used as a coenzyme.” [15] Need I say more?
Pyruvate [the
conjugate base of pyruvic acid] is
the intermediate in several metabolic pathways throughout the cell. Pyruvic
acid can be made from glucose through glycolysis, converted back to carbohydrates (such as glucose) via gluconeogenesis, or to fatty acids through a reaction with acetyl-CoA. It can also
be used
to construct the amino acid alanine and can be converted into ethanol or lactic
acid via fermentation. Pyruvic acid
[pyruvate] supplies energy to cells through
the citric
acid cycle (also known as the Krebs cycle) when oxygen is present
(aerobic
respiration), and alternatively ferments to
produce lactate when oxygen is lacking (lactic
acid fermentation).[16]
NADH TO NAD+
Reduction of pyruvate to lactate
One molecule of glucose breaks down into 2
of
pyruvate which then can directly enter the Krebs cycle, or be converted to
oxaloacetate by an anaplerotic reaction to replenish intermediate of the Krebs
cycle. Adding more of an intermediate
increases the amount of the other intermediates (citrate, iso-citrate,
alpha-ketoglutarate, succinate, fumarate, malate, and oxaloacetate) and thus
the amount of ATP produced. This
addition increases the capacity to metabolize acetyl-CoA in the Krebs
cycle.
Pyruvate metabolism Pyruvates are
produced
by glycolysis [the process whereby glucose is
converted to the 3 carbon pyruvate, a 10 enzyme-catalyzed reactions]. Pyruvate
is actively
transported across the inner mitochondrial membrane, and into the
matrix where they can either be oxidized and combined
with coenzyme
A to form CO2, acetyl-CoA, and NADH, or they can be carboxylated (by pyruvate
carboxylase) to form oxaloacetate. This latter
reaction fills up the amount of oxaloacetate in the citric acid [Krebs] cycle,
and is therefore an anaplerotic
reaction, increasing the cycle’s capacity to metabolize acetyl-CoA
when the tissue's energy needs (e.g. in muscle) are suddenly increased by activity. [anaplerotic reactions are chemical reactions that form
intermediates of a metabolic pathway—see steps below.] In the citric acid
cycle, all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate,
succinate, fumarate, malate, and oxaloacetate) are regenerated during each turn
of the cycle. Adding more of any of
these intermediates to the mitochondrion therefore means that the additional
amount is retained within the cycle, increasing all the other intermediates as
one is converted into the other. Hence,
the addition of any one of them to the cycle has an anaplerotic effect, and its
removal has a cataplerotic effect. These
anaplerotic and cataplerotic reactions will, during the course of the cycle,
increase or decrease the amount of oxaloacetate available to combine with
acetyl-CoA to form citric acid. This in
turn increases or decreases the rate of ATP production by the mitochondrion, and thus the
availability of ATP to the cell.
Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from
the beta-oxidation of fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the cycle, one molecule of
acetyl-CoA is consumed for every molecule of oxaloacetate present in the
mitochondrial matrix, and is never regenerated.
It is the oxidation of the acetate portion of acetyl-CoA that produces
CO2 and water. The
energy thus released is captured in the form of ATP. . . . Pyruvate molecules produced by glycolysis are actively transported across the
inner mitochondrial membrane, and into the matrix where they can either
be oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH,[14] or they can
be carboxylated (by pyruvate carboxylase) to form oxaloacetate. This latter reaction ”fills
up” the
amount of oxaloacetate in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle’s capacity to metabolize acetyl-CoA
when
the tissue's energy needs (e.g. in muscle) are
suddenly increased by activity”—Wiki mitochondria supra.
Beta Oxidation, the catabolism of fatty acids
Glycolysis the ten steps
https://en.wikipedia.org/wiki/Glycolysis; the 10th
step is pyruvate
Fat metabolism: In the cytosol of the cell (for example a muscle cell),
the glycerol will be converted to glyceraldehyde
3-phosphate, which is an intermediate in the glycolysis, to get further oxidized and produce energy. However, the
main steps of fatty acids catabolism occur in the mitochondria.[15] Long chain fatty acids (more than 14 carbon) need to
be
converted to Fatty
acyl-CoA in order to pass across the mitochondria membrane.[6] Fatty
acid catabolism begins in the cytoplasm of cells as Acyl-CoA
synthetase uses the energy from cleavage of an ATP to catalyze the
addition of Coenzyme
A to the fatty acid.[6] The resulting Acyl-CoA cross the mitochondria membrane and enter the process
of beta
oxidation. The main products of the beta oxidation pathway are Acetyl-CoA (which is used in the Citric
acid cycle to produce energy), NADH and FADH.[17]
In fatty-acid catabolism, the number of ATP produced
varies with length of the carbons chain.
fatty acids are converted
in the cytosol to acyl-CoA, which
then enters the mitochondria through a carnitine shuttle which is then
converted back to acyl-CoA located on the interior face of the inner MTD
membrane.[18] Beta oxidation of FA then occurs in the
mitochondrial matrix. Beta oxidation is
repeated until the fatty acid has been completely reduced to two carbons and
now the compound is known as acetyl-CoA.
The acetyl-CoA condenses with oxaloacetate to form citrate which enters
the Krebs cycle. The cycle produces 1
GDP and 11 ATP per each acetyl-CoA.
Note, the liver has the ability when glucose is very low to produce
glucose from acetyl-CoA for erythrocytes which lack MTD, and some types of
cells in the central nervous system.[19]
“The process converting ADP to ATP happens
so rapidly that in young healthy
person that it “equals his own body weight equivalent of ATP each day . . . . Mitochondria
comprise nearly 25% of the volume of a typical cell.”[20] There are other processes for producing ATP,
but this review is on the MTD. That ATP is widely conserved in nature is
indicative of its importance. Even
plants make and utilize ATP through their MTD.” [21] In plants, ATP is synthesized
in
the thylakoid membrane of the chloroplast. The
process is called photophosphorylation. The
"machinery" is similar to that in mitochondria except that light
energy is used to pump protons across a membrane to produce a proton-motive
force. ATP synthase then ensues exactly
as in oxidative phosphorylation. Some of the ATP produced in the
chloroplasts is consumed in the Calvin cycle, which produces triose sugars.” [22]
They are in 2:4 (fructose
through fructation causes MTDD)
Where is 7.
The vulnerable mtDNA and RNA 8. The vulnerable mtDNA criticized by
KOLs 9. What is causing MTDD
10. How fructose causes MTDD
[1] Chipuk, JE, L
Bouchier-Hayes, et al, May 2006, Mitochondrial outer membrane
permeabilization during apoptosis: the
innocent bystander scenario
[2] Dynein is a family of cytoskeletal motor
proteins that move along the microtubules in cells.
[3] Zhang, L, Y Yuan, et al, Aug 2015,
Reduced plasma taurine level in
Parkinson’s disease: association with
motor severity and levodopa treatment
[4]
The process of fusion for MTD is one more part of the evidence for the
prokaryotic origin of the MTD; a useful trait that has been preserved.
[5]
Griffith, Mitochondrial in health and disease,
P. 46.
[7] Koemer,
Guido, Galluzzi Lorenzo, et al, March 2008, To die or not to die that is the autophagic
question
[9] The
highlighted section is explicative for how fasting can reverse type 2 diabetes
through increasing the rate of replacement of MTDDs. Miwa,
Satomi, Conor
Lawless, et al Nov. 2008, Mitochondrial
turnover in liver is fast in vivo and
is accelerated by dietary restriction: application of a simple dynamic model
Various other processes are turned on, such as in increase in HGH, higher rate
of metabolism, and others. Elevated
physical and mental performance promotes survival when without food.
[10] Toro-Urrego, Nicolas, Luis Garcia-Segura,
et al June 2016, Testosterone Protects Mitochondrial
Function and Regulates Neuroglobin Expression in Astrocytic Cells Exposed to
Glucose Deprivation, Full in Frontiers in Aging Neuroscience
[11] Er, Fikret, Guido Michels, et al, Nov 2004, Testosterone Induces Cytoprotection by
Activating ATP-Sensitive K+ Channels in the Cardiac Mitochondrial Inner
Membrane
[12] Gavrilova-Jordan,
Larisa, Thomas Price, 2007, Actions of
steroids in mitochondria,FULL
The steroid functions in MTD with their rapid decline with menopause and
andropause adds strong support for the role of MTD in aging, and culling the
elderly from the village (3:6, 9).
[13]
Aijaz Wani, Molecular and biochemical understating
of mitochondrial diseases
also see 2:3:1
[14]
Griffiths, Ray, Mitochondria in Health and
Disease supra. P 33, part of a
series. Griffiths’ chapter 3, P 30-44, Energy Production starts with the sun, then an explanation on the
production of
reactive oxygen species leaked from the Krebs cycle., and related topics. It
has the imprint from years of
lecturing. The entire Part I, to page
127 is the best in print. Part II is on
MTD in diseases.
[19] The blood-brain barrier blocks long-chain
fatty acids (not medium and short), thus possible creating a need for
glucose.
[20] Wikipedia adenosine
triphosphate, Aug. 2018.
[21] Plant equivalent of mitochondria are the
chloroplasts, organelles that conduct photosynthesis to use sunlight to produce
ATP and NADPH while using oxygen from water.
“However, the mitochondria of many other
eukaryotes, including most plants, use the standard code. Many slight
variants have been discovered since, including various alternative
mitochondrial codes” wiki. Nov 2018, https://en.wikipedia.org/wiki/Mitochondrion#Function
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Enter supporting content here
On how daily excessive fructose damages the mitochondria and thus is the main
cause for the conditions associated with the Western diet--much, much, more the cause than insulin resistance, type-2
diabetes, and weight gain, all of which are caused by mitochondrial dysfunction, which starts first in the liver.
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