1. Metabolism in the mitochondria

TWO DIAGRAMS OF THE KREBS CYCLE

Krebs cycle, Citric Acid Cycle https://en.wikipedia.org/wiki/Lipid_peroxidation

The electron transport chain in the mitochondrion is the site of oxidative phosphorylation in eukaryotes. The NADH and succinate generated in the citric acid cycle are oxidized, providing energy to power ATP synthase

Mitochondria matrix   https://en.wikipedia.org/wiki/Oxidative_phosphorylation

ATP Synthase

derived from X-ray crystallography, https://en.wikipedia.org/wiki/ATP_synthase

Note:   its size and complexity, each circle represents a molecule, mostly amino acids

ATP synthase generation from ADP

https://en.wikipedia.org/wiki/Electron_transport_chain

Essential for ETC and Krebs  explain

Table 4. Key nutrients required for proper mitochondrial function [9, 60]

Required for the TCA cycle (i) Iron, sulfur, thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin

B3), pantothenic acid (vitamin B5), cysteine, magnesium, manganese,

and lipoic acid.

(ii) Synthesis of heme for heme-dependent enzymes in the TCA cycle

require several nutrients, including iron, copper, zinc, riboflavin, and

pyridoxine (vitamin B6) [60].

(iii) Synthesis of L-carnitine requires ascorbic acid (vitamin C).

Required for PDH complex Riboflavin, niacin, thiamin, pantothenic acid, and lipoic acid

Required for ETC complexes Ubiquinone (CoQ10), riboflavin iron, sulfur, copper

Required for shuttling electrons between ETC complexes  Ubiquinone, copper, iron[1]

Mitochondrial functions are regulated by cellular needs such as the amount of oxygen, of cellular ATP, insulin signaling, etc.

From the cytosol:  Fatty acids are broken down into 2 carbon units which enter the Krebs cycle in the MTD before the first step between the citrate and the cis-aconitate; while carbs enter as pyruvate at the acetyl CoA –citrate point—see Krebs cycle graph above.  Each glucose is split and converted into 2-pyruvates.   (For the sake of simplicity I am skipping the minor source of ATP from the amino acids/proteins, which is about 10-15% of ATP produced for those on the high protein western diet, about double the average needed thanks to the influence of meat lobbies in the 50sm upon the USDA recommendations.) 

The Krebs cycle – also known as the tricarboxylic acid (TCA) and citric acid cycle (CAC) – is a series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA which is formed from bonding to the pyruvate which has been created by splitting of 6-carbon glucose into two, 3-carbon pyruvates.  Pyruvate can also be derived from other carbohydrates, fats, and amino acids.    The process consists of oxidative decarboxylation, a reaction in which a carboxylate group (COO ^- ) is removed.  Each reaction (and there are 3, reduces a NAD⁺ to NADH and forms a carbon dioxide (CO2).  The acetyl CoA is preserved while the pyruvate is catabolized into CO2.  The adenosine triphosphate (ATP) which has 3 phosphate groups from its reduced forms which have 2 phosphate adenosine diphosphate (ADP) or 1 (AMP) adenosine mono phosphate, which will in 2 steps gain the 2 phosphates it has lost through reactions that it supplied the energy for.  The process is circular meaning at the end citrate is recreated to continue the cycle, which runs at a rate sufficient to restore ADP and AMP to ATP.  If there is excels acetyl CoA then the process can be used to create free fatty acids (FFA), and when they are in excess or when insulin is high the FFA are converted to the storage for of triglycerides.  High serum glucose causes the rise in insulin which function to promote glucose metabolism and this entail the stoppage of fat metabolism.  In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions.  The cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD+ to NADH, and produces carbon dioxide as a waste byproduct.  The NADH generated by the citric acid cycle is fed into the oxidative phosphorylation (electron transport) pathway. The net result of these two closely linked pathways--glycolysis and Krebs--is the oxidation of nutrients to produce usable chemical energy in the form of ATP.[2]

Lipolysis is the removal of the glycerol molecule from the triglyceride in the cytosol to form free fatty acid.  It occurs in a 3 step process, removing one fatty acid, then the next, and then the last one.  The newly released fatty acids enter the blood-stream where they are taken up by mainly by myocytes and hepatocytes as needed, or recirculated back to the adipocytes.[3]  Intracellular triglycerides are stored in lipid droplets which are then phosphorylated as the first step.  Unlike triglycerides which are not water soluble and are transported within lipoproteins, FFA are blood soluble.  FFAs not taken up may be bonded to albumin, its major carrier, for transport to surrounding tissues as needed.  The glycerol by product of lipolysis also can enter the blood where it is mainly absorbed by the liver and kidneys.  Esterification is the process by which triglycerides are formed—the opposite of lipolysis.  It is the adding of the glycerol molecule to 3 fatty acids.  This is the storage form for fats, and also the transport form where it is packed inside of a VLDL for transport to area and ultimately cells that are receptive to the transport of fatty acids.   

Lipolysis predominantly occurs in adipose tissue.  It is used to mobilize stored energy during fasting or exercise. and is directly induced in adipocytes by glucagon, epinephrine,  epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.” [4]  Weight can only be loss through switching in the mitochondria from glucose metabolism to fat metabolism and this requires a low level of blood glucose and as a consequence a low level of insulin.  Eating small frequent meals with significant digestible carbs is a way of blocking fat metabolism—yet such is the dietary recommendation given by doctors and dieticians. American average eating 6.2 times a day.

Fasting state:  when not eating for an extended period of times, as when sleeping or skipping a meal, the cells switch to beta oxidation of fatty acids to produce the essential energy molecules, mainly ATP.  Beta oxidation results in the production of acetyl-CoA in the MTD which enters the Krebs cycle. 

Beta oxidation (fat metabolism):  is the “catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate  acetyl-CoA, which enters the citric acid cycle, and NADH and FADH₂, which are co-enzymes used in the electron transport chain. It is named as such because the beta carbon of the fatty acid undergoes oxidation to a carbonyl group. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes” [organelle involved in the catabolism of very long chain fatty acids, branch chain fatty acids, D-amino acids, polyamines and the reduction of hydrogen peroxide, also the biosynthesis of phospholipids among other functions].[5]  

Contrary to industries, the body prefers for energy source fats.  For example, the heart and brain preferentially metabolize ketone bodies which are derived from fats—possible because of the more reactive start. The body preferentially stores fat, with the typical lean women at about 23% by weight fat, and the man at 13%, while glucose is stores are typically under a half a pound.  The body prefers to burn fat.  Red blood cells which lack nuclei and therefore can’t make the proteins for the MTD, and nerve cells of the central nervous system don’t metabolize fatty acids, but instead rely upon glucose and ketone bodies (section below).  So during periods of starvation the liver will convert sufficient fat to glucose for those tissues and provide ketone bodies.  Moreover, “glycolysis . . . is not the ideal source of fuel—fatty acids are more of a stress through the release of ROS than beta oxidation, and thus those vital tissues favor beta oxidation with its ketone bodies—the heart and brain.  Overall, the burning of fatty acids is responsible for 60-70 percent of all of the energy our cells create [an average for the paleo peoples].” [6] Excess carbohydrates are converted for fatty acids which are stored as triglycerides, not as glycogen, which is stored only to maintain blood glucose level, and is used in times of extreme stress.  Carb packing prior to races has been replaced with keto adaptation.   Many endurance athletes have switched to a ketogenic diet (under 10% net carbs).   

Compared to a glucose converted to 2 pyruvates which produces 76 ATP molecules, “a 16 carbon fatty acid called palmitate yields 129 ATP molecules” (Lee Know, p. 67-68 supra).  The higher production of ATP is because of the reduced state of the carbon molecules in the fatty acids.  There are 2 ways the stores of fatty acids in adipose tissue are transported.  One is in the storage form of fat, triglycerides which are transported as need bound within a water soluble lipoprotein such as an LDL or a VLDL to tissues needing ATP and fat for building cell membranes.  The second form is as free fatty acids, usually bound to a small protein such as albumin.  Unlike glucose, fatty acids enter directly into the MTD.  For entrance 2 phosphate groups are attached.  Once inside the MTD, to enter the MTD matrix requires the carnitine shuttle.[7]   At this point beta-oxidation in the matrix occurs in a 4-step process of oxidation, hydration, oxidation, and then thiolysis cleaves off 2-carbons from the fatty acid and releases acetyl CoA.  Another CoA is required to cap the newly shortened molecule (supra 56).  Then the 4 step process is repeated until of the carbons in the fatty acid are tuned into acetyl CoA. 

Many PUFA have an odd number of carbons and several catabolic pathways exist for them.  With them the last product is the 3 carbon propionyl CoA.  “Each round of beta oxidation produces 14 ATP.” [8]  The C-17 margarate yields 100 ATPs— (7 X 14 + 2) the last 3 carbon steps yield just 2 ATPs. 

For PUFA the process is slower as the carnitine shuttle is slower and the catabolism is similar but requires 2 extra enzymes, enoyl CoA and 2-4 dienoyl reductase.  Beta oxidation also occurs in both the MTD and in the peroxisomes.  For very long-chained (C-24) fatty acids and branch chained fatty acids, it occurs in the peroxisomes only.  This is because these fatty acids are unable to use the carnitine shuttle into the MTD.  The catabolism in the peroxisome is similar to that in the MTD.   

Fatty acid catabolism produces ketone bodies:

1. Activation and membrane transport of free fatty acids by binding to coenzyme A.

2. Oxidation of the beta carbon to a carbonyl group.

3. Cleavage of two-carbon segments resulting in acetyl-CoA.

4. Oxidation of acetyl-CoA to carbon dioxide in the citric acid cycle.

5. Electron transfer from electron carriers to the electron transport chain in oxidative phosphorylation.” Wiki beta oxidation supra.

               Acetone               Acetoacetic acid           Beta-hydroxybutyric acid

Ketone bodies

Ketone Bodies:  are three water-soluble molecules (acetone acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone) containing the ketone group that are produced by the liver from fatty acids during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, prolonged intense exercise, alcoholism or in untreated (or inadequately treated) type 1 diabetes mellitus. These ketone bodies are readily picked up by the extra-hepatic tissues (tissues outside the liver) and converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy.  In the brain, ketone bodies are also used to make acetyl-CoA into long-chain fatty acids.[9] 

Ketones are oxidized in the MTD, generating acetyl CoA which fuel the Krebs cycle.  However, in the starvation mode muscles are not broken down until the fat store falls under 7%, thus one can go a long time without food and without muscle lose.  The seeming thinness and lost of muscle prior, is merely the loss of fat stores in muscle tissues and in adipose tissue.  In fact, for example the heavy weight lifter is not stronger than a thin one, just gives the appearance due to fat storage.  Extra weight for squats in competition has the advantage of aiding in balance, but offers no advantage for bench presses.  This mistake about when muscle burning occurs is accepted in the literature.[10]  

A little tidbit in Wiki on fatty acids about a process in the brain.  It hardly enlightens the reader in that articles.  The brain being one of the five highest energy consuming organs has energy and repair requirements which entails atypical needs compared to other organs.  The other 4 are liver, kidney, intestines, and heart.  To be more precise it is certain only certain very active cells in a number of organs (more than 5) such as the endothelia cells in the intestines.  The production of fat in the brain fills energy reserve requirements and for cellular repair and replacement.  I tell you this because KOLs paint a different picture about ketone bodies, fats, cholesterol, glucose, et al that causes cognitive dissonance.  Unfortunate, there is no Listerine that with one gargle will clear the brain of KOL grown plaque.  Perhaps a Greek prayer to the Muses: “Drink deeply from the well of knowledge” will help to clear the brain of the slime planted by the blue meanies.  “Are you bluish?” then pray to the Muses.[11] 

Ketones are continuous produced in the liver at a low rate, but when intracellular glucose is low the product is upregulated to meet ATP needs.  Ketogenesis occurs in the MTD matrix of hepatocytes.  Ketones are oxidized in the MTD, creating acetyl CoA , and thereby provides an alternate source for the Krebs cycle.  Acetyl CoA is the substrate of the synthesis pathway.  Acetyl CoA may be derived from beta-oxidation of fatty acids, catabolism of the ketogenic amino acids, or by oxidative decarboxylation of pyruvate.  Ketogenesis is upregulated during high rate of lipid catabolism and gluconeogenesis.   Since fats can’t cross the blood-brain barrier, during starvation the glucose and ketones supplied by liver supply the brain’s and erythrocytes[12] needs.  Because of the increased production of ROS from glucose metabolism and the high rate of metabolism, the myocardial myocytes prefer to metabolize ketones.  The liver produces ketone bodies, and all cell with a nuclei and convert them in one step to enter the Krebs cycle, all but the liver which lacks an essential coenzyme (beta-ketoacyl-CoA transferase (thiophorase).  Acetone in low concentrations is taken up by the liver and is converted to lactate.  In high concentrations acetone it is taken up by other cells and converted to pyruvate. 

There are 5 metabolic shift with starvation or ketogenic diet, which occur in about 5 days during starving according to the work of Prof. George Cahill done in the 1980s.  For example, in the brain at about 3^rd days it gets 25% of energy from ketone bodies, and 70% on the 4^th day.  Under normal conditions, the brain conserves fat for building and repairs.    

Oxidative phosphorylation (AMP converted to ADP, and ADP to ATP):  the metabolic pathway in which cells use enzymes to oxidized nutrients, thereby releasing energy which is used to produce adenosine triphosphate (ATP).  “In most eukaryotes, this takes place inside mitochondria.  During oxidative phosphorylation, electrons are transferred from electron donors to electron acceptors such as oxygen, in redox reaction.  These redox reactions release energy, which is used to form ATP. . . .  The amount of energy released by oxidative phosphorylation is high, compared with the amount produced by anaerobic fermentation.  Glycolysis produces only 2 ATP molecules, but somewhere between 30 and 36 ATPs are produced by the oxidative phosphorylation of the 10 NADH and 2 succinate molecules made by converting one molecule of glucose to carbon dioxide and water.” [13]   “Oxidative phosphorylation is used to refer to the formation of ATP [from ADP] from the energy released by oxidation of various substrates, especially the organic acids involve in the Krebs cycle” [14]  

Electron transport chain (ETC) In the mitochondria: “is a series of complexes that transfer electrons from electron donors to electron acceptors via redox (both reduction and oxidation occurring simultaneously) reactions, and couples this electron transfer with the transfer of protons (H⁺ ions) across a membrane. This creates an electrochemical proton gradient that drives the synthesis of adenosine triphosphate (ATP), a molecule that stores energy chemically in the form of highly strained bonds. The molecules of the chain include peptides, enzymes (which are proteins or protein complexes), and others. The final acceptor of electrons in the electron transport chain during aerobic respiration is molecular oxygen. . . . Each electron donor will pass electrons to a more electronegative   acceptor, which in turn donates these electrons to another acceptor, a process that continues down the series until electrons are passed to oxygen, the most electronegative and terminal electron acceptor in the chain. Passage of electrons between donor and acceptor releases energy, which is used to generate a proton gradient across the mitochondrial membrane by actively "pumping" protons into the intermembrane space, producing a thermodynamic state that has the potential to do work.” [15]  This potential to do work generated by the ETC is stored on the inner MTD membrane and is used to attach phosphates radicals to ADP and AMP to make ATP, a molecule that stores energy.   This process of attaching PO3 radicle is known as oxidative phosphorylation.  ATP synthase converts mechanical work into chemical energy by producing ATP. This process using the Krebs cycle produces approximately 17 times more ATP from glucose than the lactate fermentation process.    

There are several other systems using the same basic principle of redox including that which occur in anaerobic metabolism in bacteria some of which use sulfur compounds and of eukaryotes in fermentation in the cytosol, and a similar process in plants involving oxygen in CO2 in the process of photosynthesis in which sunlight provides the energy in the chloroplast which involves the conversion of oxygen to water and NADP⁺ to NADPH. 

superoxide

Superoxide:  The main source is from oxidative stress occurs from the premature electron leakage to oxygen to generate the very reactive superoxides.  The percentage of leakages depends upon the integrity of the membrane structure and other related factors to the electron transfer process. Thus with age and stress from reactive chemicals, that rate increases.  The reactive products of the leakage have the potential of damaging the MTD in a vicious cycle.  At some point the damage is beyond repairing, so the MTD in the cell signals for apoptosis.   This risk is sufficiently pathogenic as for there to be a system for neutralizing superoxides, appropriately named superoxide dimustase (SOD).  It converts superoxides into oxygen or hydrogen peroxide through the reduction of 2 types, copper-zinc or iron-manganese which are bound in the protein dismutase.  This defense is in nearly all cells exposed to oxygen including bacteria and higher plants.[16]  

1. Major Sugar Facts

Pyranose is a term for saccharides in a 6-member ring; furanose a 5-member ring.

Wikipedia:  https://en.wikipedia.org/wiki/Fructose#/media/File:Isomeric_forms_of_fructose.svg

          Glucose              Fructose

                Sucrose                                        Glucose        Fructose

Note that in the Fischer projection (right) that the ketone oxygen is on the 2^nd carbon for fructose and 1^st for glucose is the aldehyde form.  

Sucrose is a disaccharide of fructose and glucose. 

In the stomach sucrose is rapidly converted into its monosaccharides, the same for easily digestible starches which are split to form glucose.

Glycation is non-enzymatic bonding of glucose to electron donor, most often amino acid.  The term is also used to include other sugars, or the other sugar is named, fructation, ribosylation, [1]  etc.

Fructation—like glycation--is the random (non-enzymatic) bonding of fructose to amino acids or other targets (electron donors) such as PUFAs.

 Wild plants are low in the sucrose and the less common monosaccharides fructose, glucose, and sorbitol; and fruits are smaller and seasonal.  Note, sorbitol’s intestinal absorption is 17%.

“For thousands of years, humans consumed about 4-6 g of fructose each day, mainly as fruits and honey obtained from foraging and agricultural activity.”[2]

Selective breeding has greatly increased sugars in fruits and some vegetables.    

Over the past two centuries, per capita consumption of dietary fructose and sucrose has increased over 10 fold among the working class.  Fructose now accounts for ~10% of caloric intake (~20% sucrose), and over half the population consume more than the average.  The bodily repair systems can’t handle that load of fructation.           

In the cytosol, glucose is converted to pyruvate and then transport to the MTD for metabolism before fructose is utilized in the cytosol.  The delay increases the net total fructation to an average of at least 20 fold greater than glucose from its 10 fold. 

Fructose is 10 times more reactive than glucose.  But a net 20 times because its catabolism is delayed while glucose is catabolized.

Fructose is absorbed in the intestines and transported to the liver by the hepatic portal vein and there deposited.[3]

The liver does not absorb all the glucose only about 10% from the hepatic portal vein (depending on need), therefore the liver allows glucose to reach cells throughout the body for absorption and thus product of ATP.  However, nearly all of fructose is absorbed by the liver. 

On a diet of low protein and 40% of the calories from fats and 60% from carbohydrates which includes 10% of calories from fructose, there is remaining 50% calories from glucose; however, since on 10% is absorbed by the liver there is ½ the amount of glucose in the liver compared to fructose.  Thus the amount of glycation in the liver is 40 times more by fructose than glucose. 

On the western diet this amount of fructose is well above what the hepatic-cellular repair systems can fix, thus causing extensive cellular damage, of which the best publicized are IR in the liver, fatty liver, NAFLD, and MTDD in the liver.  Fructose in excess is a liver toxin.    

Fructose on an average does 4 times the amount of glycation compared to glucose though the amount of glucose in the diet is 5 fold greater.[4]  

Fructose is metabolized nearly exclusively in the liver (about 95%).[5]

Blood level of fructose is about 1/20^th the level following a soda (42 grams of sucrose or HFCS), and even less between meals.  

In the cytosol of the liver fructose is phosphorylated and then can undergo several metabolic pathways, depending on need. 

The polyol pathway in cells is turned on when glucose level is high in the cytosol.  Glucose by conversion in a 2 steps, first to sorbitol, then fructose.  The polyol pathway causes fructation in every cell of the body. 

Sorbitol is an enantiomer of glucose and thus like glucose is approximately 20 times less reactive than fructose.

The standard blood assay does not distinguish the different sugars that can attached to hemoglobin. 

Reactive oxygen species are generated by the further reaction that occur when fructose or glucose attaches to electron rich substrates. 

Much of the research fails to distinguish which sugar molecule attaches to a substrate, thus misleading assuming that the results apply only to glucose.  The same is repeated in the assay of HBA1c and fasting glucose.   

Fructose is converted glucose and then depending on need the glucose can be 1) metabolized in the krebs cycle, 2) be converted to glycogen by the fructokinase pathway,[6] or 3) palmitic  fatty acid by DNL. 

The 5 and 6 carbon sugars exist mainly in the form of a ring.  A small fraction of the time the ring opens up to form an enol compound 

The 6-carbon pyranose ring is the most stable.

The 5-member furanose ring is significantly less stable.

Fructose exists 70% in the pyranose 6-member ring, and about 22% in the furanose 5-member ring and 8% in the beta or open forms.  Glucose in solution exists almost exclusive in the pyranose ring.

Even at 1 percent in the open reactive form, it is sufficient to cause significant bonding to the amino acid lysine by fructose—see 2:4,8.

Glucose also forms the pyranose and furanose rings, but because the double bonded oxygen is on carbon 1 (not 2 of fructose), the percentage of time in the furanose and then open form Glucose exists only 0.5% of the time. 

High carbohydrate diet is lipogenic because insulin signals cells to stop metabolizing fats, store them as triglycerides, and metabolize only glucose. [7]

Poly and mon unsaturated fats are electron donors for glycation & ROS. 

        Lactose is a disaccharide of glucose and galactose.

       Of the 4 isomers of galactose, 2 form the furanose 5-member ring. 

       In the cytosol galactose is rapidly converted to glucose, thereby limiting its attachment to proteins.  

The organs with the highest rate of metabolism are the heart, liver kidney, and brain; they have the most MTD and are subjected to the highest rate of glycation and their MTD have the shortest half-life.

Oxidative phosphorylation is the adding of a phosphate group to AMP   converts it to ADP, and again converts ADP to ATP.   The energy for this process comes mainly from the catabolism of glucose and fatty acids. 

5. The sugars (Fructose made from glucose  )

          Glucose              Fructose

                Sucrose                                        Glucose        Fructose

Note that in the Fischer projection (far right) that the ketone oxygen is on the 2^nd carbon for fructose and 1^st for glucose. The open form of glucose in solution (and thus blood) is “less than 0.02%.  Not much time for glycation compared to fructose’s 8%.

Sucrose, a disaccharide consisting of glucose (left) and fructose (right above).  Note the 5-member ring of fructose, the angle of the oxygen member of the ring is under greater stress because of it angle than the oxygen in the 6-member glucose ring, and this entails that the frequency of fructose being in the open form (instead of ring) is significant greater.[8]  In this open form, fructose--to a greater extent than glucose--reacts with several amino acids on proteins in a process called either fructation (also called glycation), and a large number of other electron dense sites on molecules including unsaturated fats, DNA, RNA, and others; and if not directly by the reactive chemicals produced following the fructation which can bond to DNA, RNA, PUFA, and others (see 2:4,5 through 11). Various sources rate fructose as 7 to 10 more reactive than glucose, which is increased by its delayed metabolism.  Since 95% of dietary fructose[9] is metabolized in the liver in the cytosol, and being a reactive sugar, the byproducts of its fructation have a wide variety of targets including the MTD (see 2:4,5).  Because it is delay while glucose is metabolized first, fructose is at least a net 20 plus times more reactive than glucose.   Fructation and its reactive products explain why the high-fructose (sucrose) diet overwhelms cellular repair systems. 

The other common dietary form of glucose is in starches, a polymeric carbohydrate consisting of a large number of glucose with some glycositic bonds, which are bonds of chains of glucose to hydroxyls, thyioglycosides, selenglycosides, and some such as glycosylamines such as adenosine with adenine attached to the starch/glucose. 

Glucose (also called dextrose) is the most abundant monosaccharide, a subcategory of carbohydrate.  It is mainly made by plants and most algae during photosynthesis from H2O and CO2 in the D optical configuration.  Like galactose and fructose (and others similar sugars), glucose exist in the furanose 5-member ring (not shown above), and the 6 bond pyranose ring--see galactose below. D-glucose is one of 16 optical isomers of the aldohexose configurations. The ring forms exist in an alpha and beta form depending upon the rotation of the OH group on the 6^th carbon.  In aqueous solution the 99% of glucose is in the 6-member ring form (pyranose).   The furanose is in .025% and the open (reactive) form is negligible.  As a consequence it has the lowest ”tendency than other aldohexoses to react nonspecifically [random glycation] with other amine groups of proteins.” [10]  This advantage is causal for glucose being the most common of the aldohexoses.  All animals are capable of producing glucose as needed.  In humans there is about 18 grams of free glucose of which about 4 grams is in the blood (Wiki supra).  This low percentage of the furanose form and thus a lack of an open form entails that glucose is far less reactive than fructose which in aqueous solution in in the furanose form 22% of the time.  Though often drawn planar, the rings exist in the “chair” form of #3 above—the same for the 5-member ring but in the “envelope” form like cyclopentane.   (Note: if you haven’t guessed, I was an undergraduate chemistry major, and organic chemistry was by far may favorite class.)[11] 

          Glucose chains are partially broken down by amylase in the saliva[12] to cause bonding to T1R2 and T1R3 proteins on the tongue, which permits the identification of glucose containing foods, and explains why such foods are a major source of energy.  In cells glucose is phosphorylated which assures that it can’t defuse across membranes and thereby leave the cell or enter organelles including MTD.  In excess within cells the glucose can be broken down and converted to fatty acids or it can be converted in the PP to fructose.  In the liver glucose is use to restore the glycogen reserve for when glucose is needed.  The metabolic pathway for the production of glucose which occurs mostly during starvation beings with either 2 or 4 carbon molecules.  

Natta projection of glucose open chain

          For this paper the truly major difference is that glucose is in the open chain form 0.08% of the time[13]  This allows gives a much slower rate of glycation for glucose than fructose. And this gives rise to MTDD with its pathogenic consequences of excess fructose.  .    

Galactose is a sugar similar to glucose and is found with glucose in the disaccharide lactose.  It is rapidly converted (unlike fructose) to glucose mainly in the Leloir pathway.  Given its similarity to glucose, it is unlikely that galactose is a major contributor to CAWD.   

                                    Furanose ring                   Pyranose ring

Ribose “Relative abundance of different forms of ribose in solution: β-D-ribopyranose (59%), α-D-ribopyranose (20%), β-D-ribofuranose (13%), α-D-ribofuranose (7%) and open chain (0.1%). . . . The ribose β-D-ribofuranose forms part of the backbone of RNA. It is related to deoxyribose, which is found in DNA.   Phosphorylated derivatives of ribose such as ATP and NADH play central roles in   metabolism.  cAMP and cGMP, formed from ATP and GTP, serve as secondary messengers in some signalling pathways.”[14]  It is a 5-carbon sugar, and is even more reactive than fructose, and could synergistically contribute to MTDD.  There are some articles supporting its role.  “D-ribose in the AMP molecule reacts with proteins could be significant for those with advanced stages of insulin resistance.” [15]  “D-ribose is a pentose monosaccharide which has all the hydroxyl groups on the same side in the Fischer projection, and it forms a 5 member ring that in the open form reacts randomly with certain proteins and DNA in ways that alter pathogenic.” [16]    Because of d-ribose’s pentose ring it opens up more than the 6 member rings.  The natural 6 carbon hexose sugars form 5 carbon furanose ring and also the 6-carbon pyranose ring. From the 5 carbon ring these sugars will open into the open chain which then exposes the aldo or keto group which are electrophilic.  Fructose of those sugars has the greatest percentage of time in the open-chain form.  Further studies are required to see if ribose is a significant contributor to MTDD.   I have failed to find sufficient evidence, if it exists—to resolve that question.  Ribose bonds to amines to form nucleosides, and

Sorbitol an alcohol sugar (without an aldol group) is less reactive than glucose; some fruits contain sorbitol, and for those on a western diet, its main source is synthesis from glucose in the polyol pathway.  The claims as to its being pathogenic is based upon a putative accumulation in cells when the polyol pathway converts glucose to sorbitol, and then sorbitol to fructose.  I find this claim likely more KOL TS--See 2:6, where the putative evidence for sorbitol being pathogenic is presented, and my response to those claims.

Glycogen:  glycogen consists of chains of glucose molecules linked by glycosidic bonds between the C1 and C4.  Enzymes which degrade glycogen only operate on chain terminals. A core protein is surround by about 30,000 glucose molecules.  

Glycogen is stored in the liver and constitutes 10% of its mass,[17] about 100-to 120 gm.  It’s main function there is to act as a reserve to maintain the desired amount of blood glucose, about 4 grams.  During fasting/starvation this level supplies glucose to erythrocytes and certain nerve cells[18].  It is also stored in the muscles, but unlike the liver, muscles lack the enzyme for transport into the blood. Glycogen remains in the muscle tissue and acts as a reserve for when demand for glucose exceeds  the maximum that can be absorbed from the circulation.[19]  It constitutes 1-2% of muscle mass, and about 400 grams total for a 70 kg person.  Physical training, basal metabolic rate, and eating habits will affect those amounts. 

Glycogenesis is the process of glycogen synthesis, it is upregulated by insulin, and down regulated by epinephrine. 

Glycogenolysis: the breakdown of glycogen occurs in the cytoplasm—the lysosomes.   It is stimulated by glucagon and epinephrine.  It is the breakdown of glycogen to glucose-1-phosphate which is converted to glucose-6-phosphate, which often is shuttled to the MTD for glycolysis.  To preserve glycogen, glycogen phosphorylase can only shorten the chain of glycogen when it has five or more units of glucose. [20] 

Gluconeogenesis is a process where by various types of molecules may be degraded in order to provide substrates for making glucose; these include proteins from tissues during apoptosis, the glycerol from triacylglycerols, propionyl CoA (a product of beta oxidation of fatty acids), lactate which on anaerobic conditions can be converted back to pyruvate which is a substrate used in gluconeogenesis It occurs in the hepatocytes and in the renal cortex;[21] and it provides a during starvation and when on a ketogenic diet a way to stabilize serum glucose (supra P 31-1).  The process occurs in the cytosol.  

          Gluconeogenesis in mammals it is one of serval main mechanism used to maintain blood glucose for the erythrocytes which lacking MTD must obtain ATP from glycolysis of glucose to pyruvate, and from lactic acid fermentation (anaerobic) from the resulting pyruvate--both processes occur in the cytosol and without the consumption of the oxygen they are transporting.  Gluconeogenesis is restricted to the liver, kidney intestines, muscles, and astrocytes in the brain, though the precursors are not so restricted.  The liver preferentially uses lactate, glycerol, and glucogenic amino acids (especially alanine, while the kidney preferentially uses lactate, glutamine, and glycerol.  Under extreme conditions because of the erythrocytes, the production of glucose becomes essential. 

Plants make fruits sweet when their seeds are mature so as to promote their dissemination,  The sweetness signals that he fruit is safe to eat.  The production of fructose from glucose, given fructose’s greater sweetness entail a smaller amount of glucose is lost.  Given wild fruits low sugar content, the adverse consequence are miniscule compared to today’s selective bred sweeter fruits. 

1. FRUCTOSE AS POISON:  (depending on lifestyle and health)[22] 

   THE BASIC FLOW CHART for this poison:

Excess fructose (very reactive sugar) >>> 95% to Liver >>> in Cytosol >>> Fructation>>> Reactive oxygen species (ROS) >>> Damages MTD & mtDNA >>> Dysfunctional mitochondria >>> Slowed Krebs (metabolism) cycle >>> Less ATP per minute thus more cellular glucose  >>> Cells avoid excess glucose by down-regulating glucose transport -- Insulin resistance in liver  >>> Higher insulin signal increased fat storage as triglycerides >>> Higher serum glucose in all cells cause higher cellular glucose >>> Cells convert excess glucose to fructose in polyol pathway >>> Damage to MTD & mtDNA in those cells by fructation and their ROS >>> IR those tissues causes increased fat storage >>> Rate of fat and glucose metabolism slows (weight gain and fatty liver) >>> MTDD entails slowed conversion of ADP to ATP thus lower metabolism (more weight gain) >>>  With less ATP there is a slowing of cellular repair and defense systems >>> Increased risk for all the Conditions Associated with the Western Diet >>> Also insulin controls leptin a hormone which regulates hunger and metabolism >>> leptin resistance because of IR >>> Metabolism decreases and appetite increases >>> Dis-regulation of the mammalian weight regulatory system >>> Obesity >>> Insulin resistance increase until fatty pancreas and MTDD there causes type-2 diabetes >>> MTDD through underproduction of ATP causes all of CAWD!   

Most modern fruits have been selectively bred to have over 4 times the sugar of their natural cousins

Low sugar is why the Mediterranean, paleo diets and vegetarian diets are healthful—and would be more so if they all avoided added sugar and juices 

7,   On fructose

Structure:  It all starts with a structural difference, which makes fructose far more reactive that glucose.  Fructose 22% of the time is in a furanose ring, and that ring is open about 0.25 % of the time.  The difference is because, “furanose forms [of glucose] exists in negligible amounts. . . [thus] the linear form of glucose makes up less than 0.02% of the glucose molecule in water solution.” [23] The difference between fructose’s 0.25 and glucose’s 0.025 is12.5 fold longer for fructose in the chain form.  This comes is about in the middle of the 3 different measurement for fructose in the open chain form.  The 10 greater rate of fructation in vitro compared to glycation of glucose has a structural foundation.

An evolutionary prospective:  for plants whose evolutionary path for seed dissemination was through ingestion of its fruit, a message of safe to eat was used with the earliest flowering plants sometime between 160 and 120 million years ago.  This message was through a modification of glucose to the hexose fructose, which is twice as sweet.  Only a smaller amount is necessary for sweetness signal of safe for ingestion.  There was negative selective pressure to use glucose, which would attract insects (a poor vector in spreading seeds).  Thus fructose over and over again families and orders of plants evolved converting glucose to fructose.   Reptiles, then mammals, and birds that consume fruits evolved in their brains a link to the reward centers that promoted fruit ingestion—the origin of sugar addiction.  With low wild-fruit levels there wasn’t addiction.   But financial gains changed all that.   

Fructolysis:  “Though the metabolism of glucose through glycolysis uses many of the same enzymes and intermediate structures as those in fructation, the two sugars have very different metabolic fates in human metabolism.”[24]  The traditional view, all or nearly all the fructose is transported by the hepatic portal vein to the liver, while a March 2018 study using tagged carbon found that above a certain level (around 0.5 gm/kg per meal or 3 gm/day) the jejunum metabolized most of the fructose (see 2:3). “Fructose is transported from the intestines and about 95% is taken up by the hepatocytes, which then phosphorylate fructose at the 1 carbon site which is then further metabolized to glyceraldehyde 3-phosphate which then enters in the cytosol glycolysis or gluconeogenesis according to cellular energy status.” [25]  In other words, depending on bodily need fructose can be converted through fructolysis in cytosol into 2 3-carbon molecules, pyruvate and glycerol aldehyde 3 phosphate for transport into the mitochondria where it is metabolized; or it can be converted to glycogen in the hepatocyte cytosol.  As with glucose, fructose can result in the same end-products including lactate, and the in Krebs cycle CO2 and water.  Fructose is not directly converted to fat, but rather through with its conversion to acetyl CoA and then enter DNL to produce triglycerides.[26]  The term lipogenesis encompasses both fatty acids and triglyceride synthesis. The production of pathways are tightly regulated to fulfill cellular needs, thus since fructose is converted last after glucose, when there is cellular sufficient ATP and glycogen, it is converted in tatty acid, mainly the stable 18 carbon saturated palmitic acid, and often next into triglycerides.    

Fructose’s contribution to lipogenesis in the liver has been shown to be pathogenic, the cause for NAFLD.  Its higher conversion rate follows from the metabolism of glucose first; the then additional converted fructose if not needed for production of ATP is then shuttled into fatty acid production (DNL).  The other way which is not well covered by research is through the production of ROS from fructation.  I and a few others hold that NAFLD is a dual assault, that of the accumulation of fat and the damage by ROS (see 3:6). Fructose also can as a byproduct of its metabolism produce uric acid.   The condition of the rich, gout, was once attributed to meat consumption through the production of purine.  If this as the case than population which consume mostly meat would have the highest incidence.  However, population studies have established an association with the western diet, and in particular to sugar (Taubes 3, P. 241).  “Its [fructose] ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid, and another which serum uric acid rises acutely after the ingestion of fructose”[27]  The effects of fructose is as a slow poison when in long-term excess, glucose isn’t.

8,    Fructose is different than glucose:  A debate going back to at least 1900, if not before was on the need for fiber, and how sucrose differs from glucose.  The importance of fiber is still debated, but by the 1960s the case against sucrose was decisive.  For example the work of John Yudkin on rats had established major differences in comparing starch to sucrose:  “They have different proportions of subcutaneous fat and liver fat, a different distribution of the fatty acids in the fat, and a difference, sometimes considerable, in the activity of several of the enzymes concerned in metabolism of carbohydrate and fat. The mechanism which produces these effects are not known, but there are two relevant differences between sucrose and starch that may provide a clue.” [28] The rapid absorption of the monosaccharides and the blood fructose were the differences.  It was assumed that fructose was rapidly converted to glucose in the cell—this was false.  His work observed that feeding sucrose as a replacement for glucose in starch produces greater physiological effects referred to above.  This presumed rapid conversion was believe to occur for the other dietary sugar (xylose, mannose, galactose, et al.)  Yudkin went on to note that in “The poorer countries of Africa, Asia, and South America, the total amount of carbohydrates tends to be a little higher” than the UK. . . . This small amount of sucrose occurs almost entirely in fruits and vegetables, rather than in manufactured foods and drinks to which sucrose is added.[29]   Health consequences are noticed with western high sucrose diet: “The properties of sucrose provide evidence of its involvement in human disease. It is most obvious in regard to obesity, as is attested by the history of many obese patients. Much of the high consumption of sugar in Western countries is of items where it is combined with other calorigenic ingredients - flour, fat, cocoa - to make cakes and biscuits, chocolate, confectionery and ice cream. Mainly, people take these foods and sugary drinks in order to get the pleasure of palatability and not to satisfy hunger (Yudkin 1978). Moreover, the metabolic effects of sucrose tend towards greater fat storage than do those of starch.” [30] 

The science exposing fructose as the villain has in the 34 years since Yudkin’s article above. 

An excellent summary is found in Fat Chance (2012, p. 123-4) by Prof Robert Lustig, MD: 

“The 60 calories of glucose do the same 20-80 split, so 12 calories of glucose will enter the liver.  But, unlike with glucose, which can be metabolized by all organs, the liver is the primary site of fructose metabolism (although the kidney has the capacity to metabolize a few calories in rare cases).[31]  The whole 60 calories of fructose end up in the liver.  So the liver gets a 72-calorie dose, triple the amount as with glucose alone. 

1.  Triple the dose means the liver needs triple the energy to metabolize this combo versus glucose alone, depleting the liver cell of adenosine triphosphate. . . . ATP depletion leads to the generation of the waste product uric acid  . . .

2. The fructose does not go to glycogen.  It goes straight to the mitochondria[32].  Excess acetyl CoA is formed, exceeding the mitochondria’s ability to metabolize it. 

3. The excess acetyl-CoA leaves the mitochondria and gets metabolized into fat, which can promote heart disease (chapter 10).[33]

4. Fructose activates a liver enzyme, which is the bridge between liver metabolism and inflammation.  This inactivates a key messenger of insulin action, leading to liver insulin resistance. . . .

8.      The high insulin blocks leptin signaling giving the hypothalamus the false sense of  ‘starvation’ . . .

      10.     Fructose undergoes the Maillard reaction 7 times faster than glucose. . .” [34]

Another major difference is that fructose causes sugar addiction through stimulating activity in the nucleus accumbens.  A more complex cause is through the development of IR and thus leptin resistance.  Leptin stimulates in the brain appetite, and it also can lower metabolism when there is prolonged caloric deficit.  Thus it creates a feeling of the need to eat to feel better.  Fructose’s role in IR through MTDD is another difference from that of glucose.  Also the stimulation effect of sugar, and thus through reinforcement causes behavioral addictive behavior.  But I am getting ahead of the topics--see 3:3, 3:4.[35]

“Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid” [36]  And there are other ways such as through ROS.  Moreover, fructose is nearly invisible to glucose, its insulin index is 17 compared to glucose’s 100.  Insulin which signals the uptake of glucose and its metabolism when above a certain level; this regulatory function entails when glucose is elevated that it be metabolized before fructose. 

The quote below shows that fructose is not subject to gating, thus the transport to the liver when, for example, drinking a liter of soda over a couple of hours will result in levels of liver fructose well above safe levels.  An experiments on healthy volunteers (college students) in a metabolic ward in which 40% of calories came from sugar produced insulin resistance in 2 weeks, the same amount of sweetener using glucose (corn syrup) instead of sugar did not produce insulin resistance, and thus excess fructose was causal.[37]  There is an extensive body of research producing similar results with murines.  The lack of gating permits toxic damage to the liver, the starting point for IR (see 3:3) 

“The canonical pathway of glucose metabolism is glycolysis, which begins with phosphorylation of glucose on its 6-position [of the 6 carbons that make up backbone to which OH groups and one O are attached], followed by reversible isomerization to make fructose 6-phosphate (F6P).  In many microbes, fructose is phosphorylated on its 6-position and thereby follows nearly the same metabolic pathway as glucose.  In mammals, however, fructose phosphorylation occurs on the 1-position, not 6-position, catalyzed by the enzyme ketohexokinase (Khk) (Heinz et al., 1968.  The location of this initial phosphorylation is a pivotal difference, as fructose 1-phosphate (F1P) can be directly cleaved into three-carbon units, whereas F6P [of glucose] must be phosphorylated on its 1-position by phosphofructokinase, the most heavily regulated enzyme of glycolysis, before such cleavage.  Thus, fructose bypasses the gating step of glycolysis.  Moreover, its metabolism generates, in addition to the standard glycolytic intermediate dihydroxyacetone phosphate (DHAP), a non-phosphorylated three-carbon unit in the form of glyceraldehyde (Heinz et al., 1968).”[38]

The low insulin response is another way that makes fructose even more lipogenic because it bypasses hormonal regulations (insulin index is 17, glucose is 100), etc. 

“There are slight differences in glucose versus fructose metabolism because fructose results in trioses that lack phosphate thus need to be phosphorylated for mitochondrial oxidation. Hepatic metabolism of fructose favors lipogenesis because fructose metabolites contribute to triglyceride backbone structure. Furthermore, the ADP formed from ATP after phosphorylation of fructose on the 1-position can be further metabolized to uric acid, which utilizes nitric oxide, a key modulator of vascular function. Indeed, an association between fructose intake, uric acid, and triglyceride levels has been observed.  In addition to dietary fructose, intracellular glucose can be converted into fructose by the aldose reductase enzyme in the polyol pathway.  Aldose reductase and the polyol pathways play an important role in the development of diabetic complications.

Increased accumulation of intracellular reactive oxygen species is considered the final common mechanism that mediates hyperglycemia-induced intracellular biochemical changes and development of diabetic complications. Increased reactive oxygen species generation can cause increased cell stress and apoptosis and is shown to turn on the pleiotropic transcription factor NF-κB.”[39]

This lack of “gating” allows for a high level of fructose in the cytosol.  Being a reactive sugar, not surprisingly, its blood level is about 1/20^th that of glucose so as not to damage the endothelial cells[40] that form a barrier on the walls of arteries, veins, and capillaries and the organs.  “Blood levels of fructose are about 1/20^th that of glucose following a dose equivalent to a can of soda (adjusted for body weight).” [41]  A byproduct of fructose metabolism is uric acid, which is causal for gout—see 2:7 for its many health issues.  Other pathways of fructose involve DNL and that of lactate in the cytosol.  Another process “once liver glycogen is replenished [from glucose metabolism to make ATP and then conversion to the storage form glycogen] the intermediates of fructose metabolism are primarily directed towards triglyceride synthesis.”[42]  It is because of this that fructose is causal for NAFLD (fatty liver) with its liver inflammation, along with the release of reactive chemicals due to it 10 fold higher rate of glycation compared to glucose that excess fructose is a poison. 

Plants make fructose in their ripe fruit to promote the dissemination of seeds; the sweetness of fruit is to promote the eating of the safe, ripe fruit.  Only a small amount of fructose is need to promote dissemination of their seeds through eating its fruit. The several fold higher amount of fructose due to selective breeding, mostly as sucrose, is a symbiotic relationship benefiting only the plant and farmer’s profits, while harming people.

          When considering the tight-complex metabolic regulations of carbohydrate metabolism and that its systems and their regulation developed first in fish and reptiles, modified moderately by mammals, and later-near primate ancestors, and that none consumed large amounts of ethanol or fructose, it is no surprise that our current high consumption by some has pathogenic consequences. “Glucose converted to pyruvate and lactate are then used normally as energy to fuel cells all over the body”, [43] but not dietary fructose, and glucose catabolism comes first.   

“Under one percent of ingested fructose is directly converted to plasma triglyceride. 29% - 54% of fructose is converted in liver to glucose, and about quarter of fructose is converted to lactate. 15% - 18% is converted to glycogen” Wiki supra.  The 18% glycogen is applicable only when glycogen level has been depleted—sedentary lifestyle and frequent carbohydrate snacks and meal prevent glycogenolysis.  These figures don’t consider the great variation dependent upon situation.  However, the only major glich so far detected has been the high fructose diet.  Lifestyle, snacking, high carbohydrate, high fat, and high protein diets all have examples of LSP, and they don’t suffer until sugar is introduced CAWD (see 2:2).     

          Another source provides more information: “Hepatic metabolism of fructose favors lipogenesis because fructose metabolites contribute to triglyceride backbone structure. Furthermore, the ADP formed from ATP after phosphorylation of fructose on the 1-position can be further metabolized to uric acid, . . .  In addition to dietary fructose, intracellular glucose can be converted into fructose by the aldose reductase enzyme in the polyol pathway.  Aldose reductase and the polyol pathways play an important role in the development of diabetic complications.” [44] Contrary to food manufacturers fructose is not like glucose, and fructose’s; moreover, fructose’s pathogenic consequences are by pharma is attributed to glucose.  Pharma profits from tight management of glucose and the harm done by fructose.  Fortunately the message is getting out, mainly in Europe, Australia, and Canada; confirmation to which is found on the video page at http://healthfully.org/rh/id7.html.  The only significant source in the US is that of Prof. Lustig of the UC San Fransisco and its TV programming the UCTV network.  I have not been able to find mass coverage, though it once was carried by Direct TV.  There are possible some local cable companies that carry UCTV, but none of the national carriers.[45]    

As you shall see in the subsequent 2:3,11 and elsewhere, the overloading of systems designed to handle the reactive sugar by an unnatural amount of fructose is the main cause for MTDD and the comorbidities of CAWD.  All the common reactive reducing sugars are causes in an additive way, however in the last 2 centuries our consumption of sucrose, and thus fructose has increased 10 fold.  Fructose is the only reactive sugar absorbed by the intestines (jejunum) in a form that produces pathogenic amount of ROS for the HSPs.  Coupled with its production in the polyol pathway which is riding upon hepatic insulin resistance is causal for MTDD trough UTAP causes down regulation of the production of collagen, hyper-sensitivity to uric acid, cytotoxicity and other pathogenic consequences.  

9.     Industry being industries:  Unfortunately, it isn’t in the interest of industries to research MTDD--their golden goose--but the evidence is there, simply use scholar.google and a mountain of article come up including its pathogenic consequences which covers most of the conditions associated with the western diet as listed in 1:2.  Below are 3 samples, the first’s closing optimism in 2007 has not been fulfilled. 

Abstract

Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health, disease, and aging. A wide range of seemingly unrelated disorders, such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis, have underlying pathophysiological mechanisms in common, namely reactive oxygen species (ROS) production, the accumulation of mitochondrial DNA (mtDNA) damage, resulting in mitochondrial dysfunction. Antioxidant therapies hold promise for improving mitochondrial performance. Physicians seeking systematic treatments for their patients might consider testing urinary organic acids to determine how best to treat them. If in the next 50 years advances in mitochondrial treatments match the immense increase in knowledge about mitochondrial function that has occurred in the last 50 years, mitochondrial diseases and dysfunction will largely be a medical triumph.

Mitochondrial dysfunction and molecular pathways of disease Pieczenik, Steve, John Neutadt, et al, August 2007. 

          Too often in the literature the cart is put before the horse, I say this so that you focus on what is causing in every cell MTDD, and not the associated effects, like smoke from a fire.  There are many, many effects associated with MTDD.  The literature too often in a drug oriented workplace is looking for treatments of signs. But treating signs is Band-Aid-fix that often results in life-long medications.

Etiologic mechanisms underlying fatigue are not well understood; however, fatigue is a hallmark symptom of mitochondrial disease, making mitochondrial dysfunction a putative biological mechanism for fatigue. Therefore, this review examined studies that investigated the association of markers of mitochondrial dysfunction with fatigue and proposes possible research directions to enhance understanding of the role of mitochondrial dysfunction in fatigue. A thorough search using PubMed, Scopus, Web of Science, and Embase databases returned 1220 articles. . . .  Six common pathways were proposed: metabolism, energy production, protein transport, mitochondrial morphology, central nervous system dysfunction and post-viral infection. Coenzyme Q10 was the most commonly investigated mitochondrial enzyme. Low levels of Coenzyme Q10 were consistently associated with fatigue. Potential targets for further investigation were identified as well as gaps in the current literature.

Association of mitochondrial dysfunction and fatigue: A review of the literature, Filler, Kristin, Debra Lyon, et al, June 2014.  For example, the research on low CoQ10 is likely a response because of the reduced need for CoQ10 based on a feedback system; therefore, a supplement of CoQ10 is likely not to have significant impact on MTDD; and the same for protein transport.  Central nervous system dysfunction is because of MTDD, for which I have in section in separate chapters 5 major causes for cellular toxicity.