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3-1 Mitochondrdial structures and maintenance




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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.

https://upload.wikimedia.org/wikipedia/commons/thumb/e/e4/Mitochondria%2C_mammalian_lung_-_TEM_%282%29.jpg/220px-Mitochondria%2C_mammalian_lung_-_TEM_%282%29.jpg

Mitochondrion mini.svg

“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?

 

 

 https://upload.wikimedia.org/wikipedia/commons/thumb/1/18/Electron_microscopy_reveals_mitochondrial_DNA_in_discrete_foci.jpg/220px-Electron_microscopy_reveals_mitochondrial_DNA_in_discrete_foci.jpg

 

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.  

https://upload.wikimedia.org/wikipedia/commons/thumb/3/3e/Mitochondrial_DNA_en.svg/1280px-Mitochondrial_DNA_en.svg.png

By derivative work: Shanel (talk) Mitochondrial DNA de.svg: translation by Knopfkind; layout by jhc - Mitochondrial DNA de.svg, CC BY-SA 3.0,

 

An external file that holds a picture, illustration, etc.
Object name is cshperspect-DAM-012641_F1.jpg

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-CoA-2D colored.svg              Brenztraubensäure.svg

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] 

 

https://upload.wikimedia.org/wikipedia/commons/thumb/0/09/FluorescentCells.jpg/300px-FluorescentCells.jpg

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

[5] Supra 57

[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 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. 

[11] Wani. Supra 3.4. 

[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. 



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.  

 

 

A summary pathway diagram of glycolysis, showing the multi-step conversion of glucose to pyruvate. Each step in the pathway is catalysed by a unique enzyme.

“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]

Pyruvate wpmp.png Biochem reaction arrow reversible YYYY horiz med.svgLactic-acid-skeletal.svg 

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 CO2acetyl-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 CO2acetyl-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.   

 

[14] Breakdown of Fatty Acids by Beta Oxidation

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.

[6] Supra 48-50. 

[7]  Koemer, Guido, Galluzzi Lorenzo, et al, March 2008, To die or not to die that is the autophagic question

[8] Koemer Supra

[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. 

[18] Some authors refer to pyruvate, which is converted to acetyl-CoA by pyruvate dehydrogenase.  See for example under “Glycolysis” Wiki https://en.wikipedia.org/wiki/Adenosine_triphosphate Sept 2018.

[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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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 than insulin resistance, type-2 diabetes, and weight gain