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Mitochondria
ATP
Krebs / Citric Acid Cycle
Inefficient Recycling of ADP back to ATP, and AMP Production
Recycling AMP?
Anaerobic Respiration
Reduced numbers of Mitochondria in each cell
Effect of Hydrogen Sulphide on the Mitochondria
Effect of excessive D-Lactate on the Mitochondria
Cytochrome c Oxidase enzymes partially inactivated by Mercury
Free Radical Damage
     Excessive Oxidative Damage to Mitochondrial Enzymes
     Excessive Oxidative Damage to MItochondrial DNA
     Peroxynitrite-induced NADH deficiency
Mitochondrial Membrane Integrity
     Factors affecting Mitochondrial Membrane Integrity
     Repairing oxidative damage to the Mitochondrial Membranes
     Clearing foreign/unwanted matter/waste from the mitochondrial membranes
Important Cofactors and Coenzymes in Mitochondrial Function
Supplemental ATP Replacement
     D-ribose
     Peak ATP
Relevant Tests

 
Mitochondria:

Energy production (metabolic function) in the body is reliant on mitochondria in the cells. These are small orgonelles that float around inside a cell, and each cell contains up to several thousand mitochondria depending on its function. The mitochondria are the body's furnaces, that are responsible for the production of energy inside each cell. They take in oxygen, sugar and ADP (effectively spent energy) and produce energy, carbon dioxide and ATP (the currency of energy). A compelx variety of processes and compounds are involved in this process.

http://en.wikipedia.org/wiki/Mitochondria

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellularRespiration.html

www.immunesupport.com/library/showarticle.cfm/id/8799

An e-book (pdf) by Joseph L. Evans, PhD, of Xymogen, entitled 'The Secret Life of Mitochondria', can be read at the link below.

www.xymogen.com/2008/xymo_mitobook.pdf

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ATP:

The mitochondria are responsible for producing Adenosine-5'-triphosphate (ATP). The molecule contains three phosphate groups.

www.biology-online.org/1/2_ATP.htm

http://en.wikipedia.org/wiki/Adenosine_triphosphate

ATP is a multifunctional nucleotide, it's main role being a coenzyme responsible for intracellular energy transfer. That is to say, during cellular respiration, the mitochondria inside each cell produce ATP, a coenzyme, which acts to distribute chemical energy inside of that cell for metabolism. The ATP moves out of the mitochondrial membrane and float around inside the cell in the cytoplasm until it is used up in a variety of processes, described below.

Energy is released when ATP (adenosine triphosphate) is converted to ADP (adenosine diphosphate). This occurs by breaking off a phosphate molecule from the ATP molecule, the action of which actually releases energy which can be absorbed by a protein or enzyme as part of a cellular activity. It drives virtually every biochemical reaction in the body and is in constant demand by the cells of the body.

www.trueorigin.org/atp.asp

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/Diffusion.html

ATP is consumed by various enzymes and many cellular processes. These include the active transport of nutrient ions such as Sodium (Na+) or Potassim (K+) against the concentration gradients at the cell membrane, e.g. enabling transport proteins to push K+ into the cell and push Na+ out of the cell; other uses include mechanical work (e.g. muscle contraction - for skeletal movement and heart muscle to circulate blood around the body), motility (ability for a cell to move or 'swim' using its flagella - the tail like structures that protrude from the cell walls), biosynthetic/chemical reactions (i.e. conversion of chemical compounds and creation of macro-molecules essential to life, e.g. conversion of amino acids from one form to another, creation of enzymes and coenzymes, etc.), act as a binary on/off control mechanism to cellular reactions by changing the shape of peptide chains (when energy is absorbed or released), and cell division.

Mitochondrial Transport Systems @ CliffNotes.com

The average person turns over approximately his or her own body weight in ATP each day. Studies show that a person of 68 produces approximately half the amount of ATP compared with a person of 39 years of age. An electron micrograph of a single mitochondrion showing the organised arrangement of the protein matrix and the inner mitochondrial membranes is shown above (Photo: U.S. Dept. of Health and Human Services/National Institutes of Health).

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Krebs / Citric Acid Cycle:

The main activity of the mitochondria is the recycling of ADP back to ATP, so that the ATP can again be used for energy release around the cell. The conversion of ADP back to ATP is achieved by a complex set of biochemical processes, which are part of the Krebs (citric acid) Cycle, and by the action of ATP Synthase enzymes. The Krebs Cycle, representing one form of aerobic metabolism, is pictured below.

http://en.wikipedia.org/wiki/Citric_acid_cycle

http://cellbio.utmb.edu/cellbio/mitochondria_1.htm

www.vrp.com/articles.aspx?ProdID=art868&zTYPE=2

'The citric acid cycle, also known as the tricarboxylic acid cycle (TCA cycle) or the Krebs cycle,...is a series of enzyme-catalysed chemical reactions of central importance in all living cells that use oxygen as part of cellular respiration. In eukaryotes, the citric acid cycle occurs in the matrix of the mitochondrion. The components and reactions of the citric acid cycle were established by seminal work from both Albert Szent-Gyšrgyi and Hans Krebs. In aerobic organisms, the citric acid cycle is part of a metabolic pathway involved in the chemical conversion of carbohydrates, fats and proteins into carbon dioxide and water to generate a form of usable energy. Other relevant reactions in the pathway include those in glycolysis and pyruvate oxidation before the citric acid cycle, and oxidative phosphorylation after it. In addition, it provides precursors for many compounds including some amino acids and is therefore functional even in cells performing fermentation.'

A summary of the Electron Transport Chain can be seen in the video below.



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

'An electron transport chain (ETC) couples a reaction between an electron donor (such as NADH) and an electron acceptor (such as O2) to the transfer of H+ ions across a membrane, through a set of mediating biochemical reactions. These H+ ions are used to produce adenosine triphosphate (ATP), the main energy intermediate in living organisms, as they move back across the membrane.'

The electron transport chain is a very finely balanced system and may be easily disrupted by a number of processes described below, deficiencies, as well as a 'confused' and 'unbalanced' body being bombarded with various types of unwanted supplements.

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Inefficient Recycling of ADP back to ATP, and AMP Production:

In CFS patients, one of the main causative factors is inefficiency in recycling ADP back to ATP again. This pathway is often the bottleneck in energy production in such individuals. If the cell is not efficient at recyling ADP to ATP, then the cell runs out of energy very quickly, which causes the symptoms of weakness and poor stamina. The cell must then go into a 'rest' period until more ATP can be manufactured/recycled (from ADP). At any one time, the cells in the heart muscle only have enough ATP in reserve for around 10 contractions. If a cell is pushed to produce energy when no ATP is available, then it will use the ADP instead, and convert this into AMP (adenosine monophosphate). AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine. AMP cannot however be recycled, which is why the body does not normally use ADP to produce energy from. Any ATP which is converted to AMP is considered to be 'spent'. So any ATP must be recycled from any ADP that remains, and the rest must be created from scratch using fresh raw ingredients. To create ATP from scratch, the body must first breaking down the various proteins, triglycerides, fatty acids and sugars into their constituent parts, and then the mitochondria must build up ATP from these components using its enzymes ATP Synthase (see the Krebs Cycle above).

http://en.wikipedia.org/wiki/Adenosine_monophosphate

'The ratio between ATP and AMP is used as a way for a cell to sense how much energy is available and control the metabolic pathways that produce and consume ATP. Apart from its roles in energy metabolism and signaling, ATP is also incorporated into nucleic acids by polymerases in the processes of DNA replication and transcription.'

www.cfids-cab.org/MESA/DrMyhill-373.pdf

The slow production of ATP by the body from scratch (when little or no ADP is available to convert) partly explains the delayed and prolonged fatigue that CFS patients experience after intensive activity, 'overdoing it' (more severe than their 'usual fatigue', i.e. a 'crash' or a 'flair') or even losing too much body heat (outside in the cold or at night with insufficient blankets). This is why CFS patients should try to pace themselves and take regular breaks and respect their limits so that they allow themselves a chance to regenerate ATP again rather than converting too much ADP to AMP, where they end up in the deficit part of the cycle (i.e. feeling much more fatigued than normal etc.)

This is further examined in the paper below, 'Chronic fatigue syndrome and mitochondrial dysfunction' (12 January 2009) by Sarah Myhill, Norman E. Booth, John McLaren-Howard.

http://www.ijcem.com/files/IJCEM812001.pdf

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Recycling AMP?

Although Dr Sarah Myhill states in the above paper 'Chronic fatigue syndrome and mitochondrial dysfunction' that AMP cannot be recycled, she makes the further assertion that a small amount of AMP can actually be recycled:

Dr Sarah Myhill's book 'Diagnosing and Treating Chronic Fatigue Syndrome (CFS)' 30th edition, May 2012:

http://www.drmyhill.co.uk/drmyhill/images/7/76/Cfs_book_27.pdf

Dr Sarah Myhill's article: 'CFS - The Central Cause: Mitochondrial Failure' (January 2009):

www.drmyhill.co.uk/article.cfm?id=381

'Problems arise when the system is stressed. If the CFS sufferer asks for energy faster than he can supply it, (and actually most CFS sufferers are doing this most of the time!) ATP is converted to ADP faster than it can be recycled. This means there is a build up of ADP. Some ADP is inevitably shunted into adenosine monophosphate (AMP -1 phosphate). But this creates a real problem, indeed a metabolic disaster, because AMP, largely speaking, cannot be recycled and is lost in urine.'

'And now for a bit of good news! You will have read (and will read again) that AMP cannot be recycled. Actually, AMP can be recycled, but it happens very slowly. For practical purposes for patients who are very fatigued, this recycling is so slow that it is clinically insignificant. Interestingly, the enzyme which facilitates this recycling ("cyclic AMP") is activated by caffeine! So the perfect pick-me-up for CFS sufferers could be a real black organic coffee with a teaspoon of D-ribose! Not too much or one can run into calcium problems.'

I have not heard the above assertion regarding the ability to recycle AMP in very limited quantities, however am keen to find further sources that arrive at the same conclusion. However, it should be noted that the amount of additional ATP that can be recovered or recycled by consuming caffeine is relatively small, and one may wish to offset this against the negative effects of caffeine and/or coffee consumption (i.e. acidic pH, toxicity, diuretic qualities.)

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Anaerobic Respiration:

Dr Sarah Myhill states in her article 'CFS - The Central Cause: Mitochondrial Failure' (January 2009) that anaerobic respiration is another mechanism used when insufficient ATP is available for requirements.

www.drmyhill.co.uk/article.cfm?id=381

'However there is another problem. If the body is very short of ATP, it can make a very small amount of ATP directly from glucose by converting it into lactic acid. This is exactly what many CFS sufferers do and indeed we know that CFS sufferers readily switch into anaerobic metabolism. However this results in two serious problems - lactic acid quickly builds up especially in muscles to cause pain, heaviness, aching and soreness ("lactic acid burn"), secondly no glucose is available in order to make D-ribose! So new ATP cannot be easily made when you are really run down. Recovery takes days! When mitochondria function well, as the person rests following exertion, lactic acid is quickly converted back to glucose (via-pyruvate) and the lactic burn disappears. But this is an energy requiring process! Glucose to lactic acid produces two molecules of ATP for the body to use, but the reverse process requires six molecules of ATP. If there is no ATP available, and this is of course what happens as mitochondria fail, then the lactic acid may persist for many minutes, or indeed hours causing great pain. (for the biochemists, this reverse process takes place in the liver and is called the Cori cycle).'

Anaerobic respiration is defined on Wikipedia at the link below.

http://en.wikipedia.org/wiki/Anaerobic_respiration

Lactic acid build up (and improper breathing - i.e. CO2 build up) can contribute to Acidosis as well as muscle ache and 'burn' as described above.

According to Genova Diagnostics:

'Lactic acid, or lactate,...is formed from pyruvate in anaerobic or oxygen starved (hypoxic) circumstances to allow for ongoing production of ATP in these anaerobic conditions. There are no known clinical problems associated with low lactic acid. Low levels are usually a result of reduced amounts of its precursor, pyruvic acid.'

Please see the Cardiac Insufficiency page for more information.

N.B. Please note for Dutch readers that this section and all subsequent sections on this page have been translated into Dutch by a patient of Paul van Meerendonk of Biologisch Medisch Centrum in Utrecht, on his/her personal web site, with some removal of references to my personal experiences. The web site has no actual connection to van Meerendonk (nor myself).

www.biologischmedischcentrumbmc.nl/adp-atp-efficiency.htm

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Reduced numbers of Mitochondria in each cell:

Another potential factor in explaining poor ATP availability is perhaps a lowered level of mitochondria in CFS patients or those with mitochondrial dysfunction in the first place. Mitochondria themselves have a very short life. In humans, it is estimated that they have a half life of 5-12 days (meaning half the mitochondria in the body will have 'died' after 5-12 days if no more were produced. In rat cardiac muscle, the half life is 18 days. If we were to assume the latter as a best case scenario, then the body would need to replace approximately 6% of its mitochondria every day. Mitochondria are recycled in the process called autophagy. This recycling of mitochondrial to produce new mitochondria requires energy, or ATP, which clearly if in deficit to start with, may be delayed or postponed, meaning that the resulting remaining functioning mitochondria may be somewhat less than it should be in a healthy organism. Fewer mitochondria means those that remain are put under more pressure to produce ATP and are thus depelted quicker than they would normally be. Most of this autophagy occurs during sleep when ATP demand is lowest, but ironically this is something that many CFS patients do not get enough of. This may be an important factor in explaining the low rate of mitochondrial regeneration (a catch 22 situation). Perhaps to some degree this is mitigated by having less mitochondria to recycle in the first place, so that an equilibrium is reached, somewhere below the amount that should be. How significant autophagy requirements are compared with cellular recycling in general (new cells) and muscle growth is not something I am an expert on, but indeed, all such functions seem to be impaired in CFS sufferers to varying degrees; exaccerbated by poor amino acid conversion.

'An Engineering Perspective on CFS' (7 Nov. 2008) - by Dave Whitlock

In the above article (discussed by myself on the Peroxynitrite page), Dave Whitlock argues that low basal NO levels may explain low levels of mitochondrial regeneration, resulting in lower numbers of mitochondria per cell than a normal, healthy person. NO (Nitric Oxide) is a major regulator of ATP levels. Low NO levels causes low ATP levels, which thus disables autophagy, preventing recycling of mitochondria. There is more peroxynitrite damage observed not because peroxynitrite levels are high and NO levels are higher, but because there is less recycling of mitochondria occuring (less autophagy) and hence less repair of peoxynitrite-damaged proteins and lipids. In other words, there is a resulting accumulation of peroxynitrite-damaged proteins. Because of low NO levels, there is less synchronisation between cells in terms of their energy output (in a muscle group or particular organ), meaning some are overloaded and some are underloaded. According to Whitlock, techniques do not exist to measure if adjacent cells are working 'in sync'. Whitlock proposes a number of methods of boosting NO levels (or more specifically NO donors) in the body to allow the body to produce more mitochondria, which include (in no particular order and not necessarily recommended by me as this is a THEORY) taking Nitroglycerine, L-arginine, Viagra, eating more green leafy vegetables, and meditation.

I believe that in many cases, the actual integrity of the mitochondrial membranes is more of issue than their actual number, which may or may not be normal. This is discussed below. However, it may be worthwhile in looking at all aspects of mitochondrial function to identify where the bottleneck(s) is.

Paul Cheney and Martin Pall argue the exact opposite (as discussed on the Nitric Oxide and Peroxynitrite page), that NO levels and Peroxynitrite levels in CFS patients tend to be higher than normal, rather than lower, on account of the enzymatic activities associated with over-immune system activation, on account of prolonged exposure to viri or bacterial infections etc., amongst other factors. Cheney proposes a numbe of methods of reducing one's NO production. As to who is correct, I am not certain, and it presumably depends on the exact individual in question as to what is going on on a specific biochemical level and where. Everyone however is probably in agreement that poor mitochondrial function is behind cardiac insufficiency.

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Effect of Hydrogen Sulphide on the Mitochondria:

As stated on the Bacterial Overgrowth page and above, Hydrogen Sulphide (H2S) is an endogenous toxin produced in the body by the action of bad bacteria (e.g. Prevotella) and fungi (such as Candida Albicans) fermenting sugar in the gastrointestinal tract. Elevated levels of H2S in the blood and tissues can result in mitochondrial dysfunction by their action on the Cytochrome C Oxidase enzyme which is involved in ATP production. Please see the Toxicity page for more information regarding H2S effects and treatment.

http://en.wikipedia.org/wiki/Hydrogen_sulfide

Hypothesis: Is ME/CFS caused by dysregulation of hydrogen sulfide metabolism? (2008) by Marian Dix Lemle

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Effect of excessive D-Lactate on the Mitochondria:

Streptococcus and Enterococcus bacteria ferment fibre to produce lactic acid. The two isomers of Lactic acid produced are L-Lactate and D-Lactate. Humans (and mammals in general) only produce L-lactate as part of anaerobic respiration and only possess the enzymes Lactate Dehydrogenase (LDH) for metabolising L-Lactate in any significant quantity. Mammals do not possess the D-Lactate Dehyrogenase enzyme in any significant quantity, and this is generally only found in plants and bacteria.

In humans, the two LDH enzymes act on L-Lactate to convert it into Pyruvate (and vice versa). One of these enzymes e.g. in Glycolysis in the NAD(P) dependent L-Lactate Dehydrogenase enzyme (EC.1.1.2.3). The other LDH enzyme is a Cytochrome c-enzyme found in the liver (EC.1.1.1.27). Mammals including humans however can metabolise D-Lactate using the D-alpha-hydroxy acid dehydrogenase enzyme found in the mitochondria (at 20% of the rate of a proper D-Lactate Dehydrogenase enzyme as found in plants).

http://en.wikipedia.org/wiki/Lactate_dehydrogenase

If excessive conmensal Streptococcus and Enterococcus fermentation in the GI tract occurs, then D-Lactate levels tend to rise in th body, and acidosis (a drop in blood pH) occurs - known as D-Lactic Acidosis. D-Lactate can accumulate in the mitochondria and inhibit their proper function. The body then has two main methods available to eliminate D-Lactate are renal excretion (i.e. whatever is in the fluid filtered off by the kidneys into urine) and via faeces (excreting the D-Lactate remaining in the stool) - which is not particularly efficient in clearing the D-Lactate, especially if it is being produced continually in the GI tract. Recent studies however have claimed to show that humans do actually possess the D-Lactate Dehydrogenase enzyme on the inner mitochondrial membrane. Studies from the 1920s showed that D-Lactate was poorly metabolised compared with L-Lactate, whereas studies from the 1980-90s found that D-Lactate was actually readily metabolised, although most academic and medical sources still quote the 1920s results as fact. The area is still hotly debated.

D-Lactic Acidosis is rare in general terms and usually only occurs in the case of short bowel syndrome in humans (malabsorption disorder caused by surgical removal of the small intestine) and children with gastroenteritis. It can of course occur in patients who have markedly poor digestion with a large proportion of undigested carbohydrate in the GI tract. In animals, it can occur through excessive grain consumption by ruminants (e.g. cattle, goat, sheep etc.) or in cases of diarrhea in calves.

www.cfids-cab.org/rc/Sheedy.pdf

http://jn.nutrition.org/cgi/content/full/135/7/1619

www.biolab.co.uk/docs/dlactate.pdf

http://www.drmyhill.co.uk/wiki/Fermentation_in_the_gut_and_CFS

Steptococcus and Enterococcus are types of lactic acid bacteria. There are many different species, some are probiotic, some are commensal and some are pathogenic. Probiotic strains include S.thermophilus, S.salivarius and S.faecium; and E.faecium and E.faecalis. The species most likely to be relevant in this instance are the commensal strains (i.e. imbalanced flora) that mke up the bulk of these species in the GI tract.

http://en.wikipedia.org/wiki/Streptococcus

http://en.wikipedia.org/wiki/Enterococcus

Other pathogenic bacteria besides Steptococcus and Enterococcus also produce D-lactate, although these are probably not so likely to be the cause in most cases of D-Lactic Acidemia:

http://jn.nutrition.org/cgi/content/full/135/7/1619

'Various pathogenic bacteria produce D-lactate, including Bacteroides fragilis, Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus. The use of D-lactate as a marker for infection was proposed in 1986.'

It is possible that a disproportionately large amount of probiotic lactic acid producing species such as Strepococcus and Enterococcus can be responsible for D-Lactic acidemia. It is more likely that the imbalanced S. and E. flora species would be responsible (in instances of elevated undigested carbohydrates in the GI tract) and that repopulation with the relevant required numbers of probiotic species, both lactic and non-lactic acid producing species, would help to correct the problem. Some recommendations do include abstaining from taking additional lactic acid producing probiotic bacteria, and only consuming non-lactic bacteria and bacteria that consume D-Lactate.

Please see the Bacterial page for this topic and related areas.

D-Lactate levels can be measured in a blood test. Please see the Tests page for more information.

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Cytochrome c Oxidase enzymes partially inactivated by Mercury:

Cytochrome c Oxidase enzymes are the last enzyme in the electron chain, found on the mitochondrial membrane and are involved in ATP production. They are based on the Heme protein, containing two Copper centres. If Mercury displaces one or more of these Copper molecules, it will impact the ability of this enzyme to function, this adversely impacting mitochondrial function. Please see the Effects of Toxicity page for more information.

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Free Radical Damage:

Peroxynitrite (ONOO-) is an rogue oxidant molecule formed when excessive Nitric Oxide is produced in the body and reacts with Superoxide. ONOO- forms a number of harmful radicals such as the Carbonate radical (CO3-) and the NO2 radical. The result can be a vicious circle of sustained elevated oxidative damage in the body, and of particular relevance here, oxidative damage to the mitochondria. There are tthree main effects of excessive Peroxynitrite-related oxidative damage in the body with regards to mitochondrial function. These are Active B3 (NADH) depletion (on account on DNA damage - discussed below), Inactivation of Iron-Sulphur protein-based mitochondrial enzymes and lipid peroxidation (mitochondrial membrane oxidation - discussed in the Mitochondrial Membrane Integrity section below.)

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Excessive oxidative damage to Mitochondrial Enzymes:

Excessive Peroxynitrite (ONOO-) and its related products (including NO) can inactivate iron-sulphur proteins. The most important of which arguably are those found in certain Mitochondrial enzymes that are part of the Krebs Cycle (Citric Acid Cycle), e.g. Aconitase enzyme. The damage to these enzymes (proteins) is irreversible and the only way their functionality can be restored is through resynthesis of these proteins. Damage to these proteins may result in a bottleneck in the Krebs Cycle and accumulations of both cis-aconitate and its precursor citrate. Succinate dehydrogenase (a.k.a. Succinate-coenyme Q reductase (SQR) or Complex II) is another example, and it participates in both the citric acid cycle and the electron transport chain.

Please see the Nitric Oxide and Peroyxnitrite Cycle page for more information on Peroxynitrite formation and damage.

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Excessive oxidative damage to Mitochondrial DNA:

In addition to excessive free radicals damaging the mitochondrial membranes, they may also cause damage to the actual mitochondrial DNA itself. Mitochondrial DNA is completely separate from nuclear DNA. Unlike Nuclear DNA, it is inherited solely from the mother in sexually reproducing organisms, e.g. humans. Mitochondrial DNA, because of its close proximity to the inner mitochondrial membrane's respiratory chain, a primary source of free radical production, and also their limited capacity for self-repair and self-protection, are particularly susceptible to free radical damage. General cell protection from damage by Superoxide is provided by intracellular Zinc:Copper SOD (Zn/Cu-SOD). Mitochondria are protected by Manganese-dependent SOD (Mn-SOD). Extracellular SOD (EC-SOD - another type of Zn/Cu SODase) protects the nitric oxide pathways that relax vascular smoother muscle tissue. For each form of SOD, genetic variations are known, and mutations and polymorphisms can occur during excessive oxidative stress placed on the DNA. DNA adducts (toxins that attach to DNA genes) can chemically block these genes however. Zinc, Copper and Manganese are extremely important elements for maintaining healthy SOD levels, and patients should ensure that these mineral levels are supplemented if they drop below their reference ranges.

http://en.wikipedia.org/wiki/Mitochondrial_DNA

http://ghr.nlm.nih.gov/chromosome=MT

In addition, free radicals can also be produced in excess by the liver. Liver function with regards to clearing undesired compounds from the blood involves a two step process. This is described in detail on the Inefficient Liver function page. The first step is Phase 1 Regulation, using the Cytochrome P450 enzymes, which are largely a set of oxidase reactions, producing a large number of free radicals. Sufficient antioxidant compounds and chemicals are required by the liver in order to keep these from causing too much damage within the liver and outside of the liver, these are both endogenously produced antioxidants and dietary sources of antioxidants. The second step of liver function is the Phase 2 Conjugation step, whereby molecules are added to the toxins in order to make them easier to remove from the body. These processes work in a perfect balance in a healthy liver. If antioxidant and conjugation steps are impaired, then a large number of free radicals will be produced which can cause oxidative damage within the liver and also spill out into the blood stream, flooding it with excessive free radicals.

The role of antioxidants such as Superoxide Dimutase and R-Lipoic Acid are discussed on the Cardiac and Nutritional pages.

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Peroxynitrite-induced NADH deficiency:

Several types of DNA damage can be inflicted including the nicking of of the backbone of DNA chains. These nicks stimulate the poly (ADP-ribose) polymerase enzyem, which uses Active Vitamin B3 (NAD) as a substrate. NADH is the reduced form of Active B3 that is involved in the electron transport chain in mitochondria. Therefore elevatd poly (ADP-ribose) polymerase enzyme production on account of the DNA damage caused by ONOO- can lead to a depletion of the pools of NADH/NAD that are normally used in mitochondrial function, thus heavily impacting ATP availability.

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Mitochondrial Membrane Integrity:

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Factors affecting Mitochondrial Membrane Integrity:

Any factors that affect the mitochondrial membrane can severely impact the body's ability to aerobically respire and force it to use anaerobic respiration more, or to convert ATP to AMP, to produce energy, include some of the following:

• Fatty Acid imbalances:
  
  Essential Fatty Acids (EFAs), namely Omega 3 and 6 fatty acids, are a key component of cellular membranes and brain tissue, and with an insufficient intake, or excessive intake of bad saturated fats, rancid (heated polyunsaturated) fats or trans fats, our cellular membranes may experience inflammation and a loss of permeability essential to cellular and mitochondrial functioning. For more information see the Nutritional page. If mitochondrial membranes are less permeable, it means that the requisite nutrients required to produce ATP are not available quickly enough, and so it has a knock-on effect in terms of ATP production in the cells of the body. The body is not able to produce energy as efficiently. Red blood cells are not able to oxygenate as efficiently either, nor to deliver their payload of oxygen to the cells of the body.



• Excessive free radical (oxidative) damage to the mitochondrial membrane:
  
  Free radicals damage the integrity of the mitochondrial membrane by attacking/oxidising the actual phospholipids that make up the majority of the mitochondrial membrane material. Free radicals are produced inside the mitochondria as a byproduct of energy production and respiration. The more energy you produce, the more free radicals you produce. The body has its own natural defence against such free radicals to prevent excessive free radical damage to the mitochondrial membranes. These are the antioxidant enzymes SOD and to a somewhat lesser extent Glutathione. Mitochondrial function is limited in a sense by the available of SOD as without it extensive mitochondrial damage would occur (with elevated respiration rates beyond the available SOD and glutathione that can be produced. However, if levels of the rogue oxidant peroxynitrite are elevated in the mitochondria, these may destroy the SOD enzymes, resulting in an increase in Sueroxide levels produced during respiration, resulting in more free radical damage to the mitochondrial membranes. Please see the Nitric Oxide and Peroyxnitrite Cycle page for more information on Peroxynitrite formation and damage.
  
  A deficiency in the production of either of these primary antioxidant enzymes can of course result in excessive free radical damage to the mitochondrial membranes and excessive perforation and leaking of powerful free radicals like Superoxide out of the mitochondria, causing additional knock on problems. Damaged mitochondrial membranes are sometimes referred to as causing 'energy leaks', although this is rather a gross simplification.
  
  The mitochondrial membranes are subject to wear and tear from the residual heat-induced damage from frequent discharge of its electric polarity.
  
  http://www.lef.org/prod_hp/abstracts/centrophenoxineabs.html#9
  
  Two indicators (or downstream products) of excessive (phospho)lipid peroxidation (and mitochondrial membrane damage) are the aldehyde derivates Malondialdehyde (MDA) and Crotonaldehyde, which can be found attached to damaged mitochondrial membranes. These factors are discussed in more detail in the next bullet point below.
  
  A third indicator of peroxidation of the mitochondrial membranes is F2-Alpha Isoprostane (a.k.a. 8-iso-PGF2 alpha). It is a downstream oxidation production of membrane oxidation, specifically the Omega 6 Essential Fatty Acid (EFA) component of the phospholipid matrix. Isoprostanes as prostaglandin-like compounds created from the free radical attack of esterified of the Omega 6 EFA known as Arachidonic Acid (ARA) inside the membrane phospholipid. ARA is particularly sensitive to peroxidation by free radicals. 8-iso-PGF2 alpha is of course a very different molecule to a prostaglandin which is a lipid compound produced enyzmatically by the body using cyclooxygenase (Cox1-2) from EFAs and has nothing to do with free radical attack on cell membranes. Isoprostanes in general are valuable markers in clinical biology as they are found in all biological fluids and tissues and are stable in vivo and ex vivo. There are 10 times more isoprostanes in atherosclerotic plaque compared with normal vascular tissue. They are also only dependent on their production (in this case free radical attack) rather than metabolism or excretion without intraindividual variability. There are many studies validating Isoprostanes as the most accurate and reliable indicator of oxidative stress in vitro and in vivo. F2-Alpha Isoprostane levels can be measured in one's urine and are a direct measurement of the extent of free radical oxidation of the mitochondrial membranes. Please see the Oxidative Stress Tests section on the Tests page for more information.



• Compounds clogging up the Mitochondrial Membranes:
  
  Toxins, waste products, partial detoxification products (failed detoxification attempts) or foreign/unwanted compounds cab clog up the mitochondrial membrane, in particular the translocator (TL) protein sites, thus reducing mitochondrial membrane permeability and ATP production. Mitochondria are the energy furnaces of the cells of the body, and it is essential for certain types of compounds, nutrients and minerals to be able to carried enzymatically in and out of the inner and outer membrane. If the mitochondrial membranes are clogged up, it can result in a bottleneck in the krebs cycle and thus a reduced capability to produce ATP, the energy currency of the cell. There should not be any such 'garbage' clogging up the mitochondrial membranes.
  
  Translocator Protein (TL) scavenges ADP from the cytoplasm and returns ATP from re-conversion with 'new' ATP from oxidative phosphorylation. TL can be blocked by zenobiotics and/or partial detoxification products.
  
  The presence of unwanted substances that can interfere with mitochondrial function contribute to a condition known as Neurotoxic Membrane Syndrome (a.k.a. Chronic Neurotoxic Syndrome). Please see the Inefficient Liver Function page for more information.
  
  An article 'The Detoxx System: Detoxification of Biotoxins in Chronic Neurotoxic Syndrome' [a.k.a. Neurotoxic Membrane Syndrome] by John Foster, M.D., Patricia Kane, Ph.D., Neal Speight, M.D. is shown at the link below.
  
  http://articles.mercola.com/sites/articles/archive/2003/08/09/detoxification-biotoxins.aspx
  
  Examples of unwanted compounds on the mitochondrial membrane could include heavy metals, PCBs, PBBs, pesticides, dichlorobenzene, foreign DNA/RNA (probably viral), lactic acid,, keto-acids, lipofuscin and the body's partial detoxification products including peptide complexes, glutathione conjugates and organic sulphate conjugates (the body's detoxification defence molecules bonded with toxins for removal from the body). This may in turn be a result of impaired liver function and/or excessive toxin build up in the body.
  
  Two indicators (or downstream products) of excessive (phospho)lipid peroxidation (and mitochondrial membrane damage), as discussed above, are the aldehyde derivates Malondialdehyde (MDA) and Crotonaldehyde. MDA is reactive and potentially mutagenic (changing one's DNA). Crotonaldehyde is a known irritant.
  
  According to John McLaren Howard of Acumen Laboratory, Aldehydes from lipid peroxidation (when it occurs) tend to accumulate in the mitochondrial membranes. Such aldehydes, usually in the form of malondialdehyde or crotonaldehyde, can block some translocator (TL) sites in the inner mitochondrial membranes. It is rare for them to accumulate to very high levels on the inner mitochondrial membranes but moderate or trace accumulation on TL sites does occur. The accumulation of these aldehydes on the mitochondrial membrane can impact oxidative phosphorylation (i.e. ATP production) and energy production significantly. In other words, their presence not only tells us that the mitochondrial membranes themselves have been oxidised/damaged (as above) but their presence on the mitochondrial membrane itself may also may be actively preventing proper mitochondrial function.
  
  However, according to John McLaren Howard, the body tends to clear MDA from the mitochondrial membranes, but if they are being produced as quickly as they are being removed, then they will remain on the mitocondrial membranes. If one stops or reduces the source of oxidative stress which resulted in the oxidation of the lipids and hence their production, then their levels will go down. The only exception to this is where MDA is adducted to the DNA (i.e. DNA Adducts) where it cannot be cleared very quickly.
  
  It is possible to have clogged up/blocked TL sites AND damaged mitochondrial membranes; or fairly in fact mitochondrial membranes that are very clogged up.
  
  Poor protein digestion can also result in peptide complexes (short chain proteins) attaching themselves to the mitochondrial membrane. In addition, poor immune function may result in cytokines attaching themselves to the mitochondrial membrane, and perhaps causing mitochondrial clumping (which in turn may disturb the function of the cytoskeleton within the cytoplasm of the cells). Cytokines are immune system messenger molecules (either up regulatory or down regulatory).
  
  Cytokines are defined by Wikipedia here.
  
  Such protein attachment to membranes does not normally affect translocator protein sites, but could affect ATP function in a more general way. More information on cell membrane congestion can be found in the identification, nutrition and toxicity pages. Cytoskeleton is defined by wikipedia below.
  
  http://en.wikipedia.org/wiki/Cytoskeleton



• Elevated Hydrogen Sulphide levels:
  
  Elevated H2S levels caused by the fermentation of sugar by bad bacteria and fungi in the digestive tract - H2S attaches to the mitochondrial enzyme Cytochrome C Oxidase and weakens oxidative phosphorylation and ATP production.



• Too low a pH at the membrane (e.g. too acidic):
  
  The Translocator (TL) Protein site on the inner mitochondrial membrane is extremely pH sensitive and can be affected by local or general acidosis, including the organic acid accumulation from over-dependence on anaerobic metabolism (the dominant form of metabolism where oxygen levels are too low).can affect the ability of the TL sites



• Elevated intracellular Calcium and reduced intracellular Magnesium:
  
  The efficiency of TL site can also be compromised by increased intracellular Calcium or reduced intracellular Magnesium. Enzymatic reactions are required to transport minerals in and out of the cells of the body, which require ATP. ATP shortages can have knock on effects as above which further exacerbate the problem.

Mitochondrial dysfuction may in turn affect hypothalamic/hormonal dysfunction, poor liver and kidney functioning, cardiac capability and digestive efficiency. Mitochondrial function will impact all the cells of the body and their normal function to some degree, impacting all the organs and glands (some more than others), and their ability also to produce enzymes and hormones as they should etc. Symptoms of mitochondrial disfunction may include a lack of physical energy, lack of mental energy and ability to concentrate ('brain fog'), tendency to crash and burn, muscle and joint weakness, cardiac weakness/insufficiency, digestive inefficiency, and perhaps even muscular control. The exact effects varies according to the individual.

Getting sufficient oxygen to the mitochondria is key to enabling proper mitochondrial function. Low blood and body oxygen levels are frequently associated with excessive fat, insufficient cardiovascular exercise, slightly lowered blood/bodily pH (excessive acid producing food consumption), fatty acid imbalances and/or poor cell membrane permeability.

A high intake of essential minerals and krebs cycle metabolites, and sufficient levels of these in the blood, does not necessarily correlate to sufficient levels of these at the mitochondrial membrane (e.g. on account of toxin congestion and of displaced zinc from zinc finger proteins for example on account of the presence of heavy metals.)

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Repairing oxidative damage to the Mitochondrial Membranes:

In order to repair the mitochondrial membranes, one must ingest or produce enough of the requisite Phospholipids and ingest sufficient Essential Fatty Acids. The problem that often occurs in CFS patients is that the body is unable to produce high volumes of Phospholipids on account of a blockage in the methylation pathway, which is dependent on the bio-availability of the correct amino acids as well as active forms of Folate and B-12. Thus, it is very important for those with damaged or leaking mitochondrial membranes to supplement sufficient Essential Fatty Acids (Omega 3 and 6) and also Phospholipids (especially Phosphatidyl Choline). This is discussed on the Nutritional page. Phospholipid Therapy is discussed in detail on the Detoxification page.

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Clearing foreign/unwanted matter/waste from the mitochondrial membranes:

Treatments for removing heavy metals and partial detoxification products from the mitochondrial membrane, for example clathration, chelation, LED and Phospholipid supplementation or injections (PLX), are examined on the Detoxification page.

Please note that heavy chelation may in the short term have a negative impact of mitochondrial function as more heavy metals are present in the blood, albeit usually bounded to a chelating agent, and detoxification requires glutathione, which is also needed as a protective measure to prevent oxidative damage during respiration (secondary to Superoxide Dismutase (SOD)), and if more is being used up for chelation, then less will be available for respiration. So a chelation programme must be offset against one's mitochondrial capability and levels of gluthatione production at any one moment in time.

Treatments for removing protein attachment (peptides from poor digestion or cytokines) to inter- and intra-cellular membranes include FIR saunas and PLX (Phosphatidyl Choline/Glutathione) injections, Phospholipid oral supplementation, as well as perhaps Zinc and Magnesium injections (in the case of cytokines). Phospholipid therapy is a type of detoxification protocol, to assist gallbladder function and to help clear the mitochondrial membrane TL sites of unwanted waste/toxin compounds, as well as protocol to repair mitochondrial membranes (as mentioned above), which is in a sense a type of nutritional therapy.

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Important Cofactors and Coenzymes in Mitochondrial Function:

There are therefore a number of goals when in comes to assisting a return to normal mitochondrial function in the body, with a positive knock on effect on many other systems of the body. As mentioned above, these are increasing the efficiency of ATP conversion and distribution (i.e. actual energy release), speeding up the rate of recycling of ADP back to ATP again (i.e. energy recovery times and energy reserve), and also providing the body with enough raw materials to produce new ATP (i.e. replenishing depleted energy reserves - having converted some of the ADP to non-recoverable AMP in lieu of any ATP being available).

A large number of different metabolites and co-factors are used by the body in the Krebs (citric acid) cycle, a series of chemical reactions that enable glucose to be used for energy production within the cells of the body. Some of these are discussed below.

• Krebs Cycle Organic Acids


• Citric acid
• (Isocitric acid)
• Alpha-Ketoglutaric acid (AKG) - the conversion from AKG to Succinic acid involves the reconversion of ADP to ATP
• Succinic acid
• Fumaric acid - oxidised form of Succinic acid
• Malic acid
• (Oxaloacetic acid)
• Pyruvate - precursor to Acetyl Coenzyme A, which combines with Oxaloacetic acid (above) to form Citric acid

Those organic acids that are not significant supplementally are shown above in brackets. There are a number of possible organic acids that may not be converting properly in the Krebs Cycle, as can be seen above.

High levels of Citric acid and Malic acid are available in fruits (e.g. apples - rich in both) and fermented foods (e.g. Kombucha - rich in Malic acid). Malic acid supplements are available in acid form (i.e. Malic acid) or salt form (e.g. Magnesium Malate); and in combination products such as Ultra Muscleze. Malic acid is frequently shown to be low in CFS sufferers (together with Magnesium).

Alpha-Ketoglutarate (AK) is the salt form of the acid Alpha-Ketoglutaric Acid (AKG). KA supplements are often found in the form of Potassium Magnesium Alpha-Ketaglutarate (K-Mag KG).

Another is Pyruvic acid which is produced from carbohydrates and is a precursor to Co-Enzyme A. Typically however, malic acid is most commonly deficient of all these acids.

• Magnesium - is particularly important in regulating and stabilising ATP, and is often displaced by the presence of heavy metals. With a deficiency of Magnesium, the ATP becomes over-regulated or inhibited, resulting in low energy levels. Magnesium helps to fire up various essential enzymatic reactions. Nutritional elements such as Magnesium, Zinc and Selenium have an important role in protecting the body from the effects of heavy metals, and those individuals with elevated heavy metal levels have a greater requirement for these nutrients (and a corresponding great need to detoxify the heavy metals from their bodies). Magnesium is best taken in Chelated form, e.g. Citrate or Glycinate, together with the amino acid Taurine to help carry it into the cells.


• Active B1 - Thiamine PyroPhosphate (TPP), a.k.a. Thiamine Diphosphate (TDP) or Cocarboxylase, is the biologically active form of Vitamin B1, Thiamine, and is used in the efficient burning carbohyrate and removing excess lactic acid (a cause of muscle ache).


• Active B2 - Riboflavin, Vitamin B2, is also involved in the Krebs Cycle, as a cofactor in Complex I and II. There are two active, coenzyme forms of B2, Flavin Mononucleotide (FMN) and Flavin Dinucleotide (FAD). FMN is the coenzyme form of B2 found in supplement form.


• Active B3 - A variant of Vitamin B3 (Niacin), known as Nicotinamide Adenine Dinucleotide plus high-energy Hydrogen, or NADH for short, is also involved in the Krebs cycle. Niacin can be obtained from protein but it is dependent on efficient protein digestion and amino acid conversion in the body. NADH and NAD are an essential part of the ATP to ADP conversion. Active B3 probably has most immediate noticeable effect on energy levels, but all B-vitamins are important to some degree in energy production. B3 levels can drop significantly if there is Peroxynitrite-related oxidative damage occurring in the body (to poly (ADP-ribose) polymerase enzyme DNA), having a knock on effect on the mitochondrial electron transport chain. Please see the Peroxynitrite page for more information.


• Vitamin B5 - Pantethene (a biologicaly active form of Vitamin B5) is involved in the synthesis of Coenzyme-A (CoA). CoA is important in energy metabolism for pyruvate to enter the tricarboxylic acid cycle(TCA cycle) as acetyl-CoA, and for alpha-ketoglutarate to be transformed to succinyl-CoA in the cycle.


• Active B6 - Pyridoxal-5-Phosphate the active form of Vitamin B6 can catalyze transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis. P-5-P is also a required coenzyme of the glycogen phosphorylase enzyme, that allows glycogenolysis to occur.


• Active B12 - The enyzme Methylmalonyl Coenzyme A mutase (MUT) requires vitamin B12 in the form Adenosylcobalamin (AdoB12). MUT is involved in carbohydrate metabolism, converting Methylmalonyl-CoA (MMI-CoA), the coenzyme A link form of methylmalonic acid (MMA), into Succinic-CoA (Su-CoA), the conenzyme A link form of succinic acid. It forms part of the Krebs cycle for the production of energy.


• Acetyl-L-Carnitine (ALC or ALCAR) - is an amino acid that and allows proper transport and burning of excess fat and prevents mitochondria from shutting down. It is the acetylated ester of the amino acid L-Carnitine. Carnitine helps to transport ATP and ADP across the mitochondrial membranes, and to transport activated ATP to where it is actually used. It is manufactured intracellularly in the body from the Essential Amino Acids L-lysine and L-methionine, by a process of methylation i.e. does not float around in the blood stream (and thus urine) - and hence is usually not included as a parameter in amino acid analyses.
  
  However the quantities manufactured endogenously are relatively low, especially if there is a bottleneck in the production of carnitine (i.e. impaired methylation, insufficient quantities or precursor(s), impaired enzymatic function, lack of availability of ATP for these enzymes, low levels of coenzymatic cofactors , etc.) Otherwise the body relies on external dietary sources of carnitine to maintain sufficient levels. External sources are limited to meat, i.e. other animal's cells. Vegetarians or vegans who do not supplement carnitine will not be ingesting any carnitine and will be relying solely on endogenously produced carnitine to enable them to fulfill their energy requirements. Dietary (meat) sources of L-Carnitine may also not cross the blood brain barrier efficiently in some individuals, or digestion and absorption may be impaired in those with digestive difficulties. A lack of carnitine, for any of the above reasons, may adversely affect the body's ability to produce energy on demand. In such cases, supplementation with Acetyl-L-Carnitine (and eating red meat if possible) will help.
  
  A powerful antioxidant and a mitochondrial cofactor (transporter of ATP). It helps to lower the mitochondrial phase transition (which leads to apoptotic cell death), thus playing a protective role in mitochondria. It also helps to transport fatty acids into the mitochondria. The inner mitochondrial membranes' cardiolipin are made up predominantly of fatty acids. (90+% Omega 6 fatty acids).
  
  www.renegadeneurologist.com/?s=acetyl-l-carnitine
  
  http://en.wikipedia.org/wiki/Carnitine
  
  http://en.wikipedia.org/wiki/Acetyl-l-Carnitine
  
  The properties of Carnitine in its different forms is vastly different, and only one type may be absorbable by an individual at any given time. L-Carnitine is notoriously difficult to cross the blood-brain barrier. The body may only be able to utilise one form of Carnitine most effectively at a given time, and throwing the wrong kinds at it or too many different kinds may not necessarily increase the efficiency or absorption, ability to cross the blood-brain barrier or utilisation.
  
  Acetyl-L-Carnitine is the form most widely recognised as being most appropriate and efficient. The Acetyl group allows it to more easily cross the blood-brain barrier, and the Acetyl group is broken off to be used to create Acetylcholine (the essential neurotransmitter), leaving the L-Carnitine to be utilised by the brain's cells. ALC also enahnces the release of dopamine from neurons and helps it bind to dopamine receptor sites. Acetyl-L-Carnitine has been noted to increase levels of neurite production (i.e. projections from the cell body of neurons) in the brain. For this reason, it is best to avoid taking ALC supplements in the evening, as it may interfere with one's ability to sleep. ALC is also a poweful antioxidant.
  
  Besides Acetyl-L-Carnitine described above, Carnitine is also found in alternative forms, such as:
  
  - L-Carnitine Fumarate - a blend of L-Carnitine and Fumaric acid, a Krebs cycle organic acid. The Biosint licensed forms are known as CarniShield and DuraCarn which are reputed to be highly bioavailable. It is used by a number of supplement manufacturers.
  
  - Acetyl L-Carnitine Arginate diHCl (ALCA) - this is Acetyl-L-Carnitine blended with the amino acid Arginine. This is reputed to be four times more effective in stimulating neurite production in the brain than Acetyl-L-Carnitine.
  
  - Acetyl L-Carnitine Taurinate HCl (a blend of Acetyl-L-Carnitine, Taurine and HCl).
  
  - Glycine Propionyl L-Carnitine (GPLC).
  
  Jarrow Formulas' CarnitAll 600 contains all of the above 4 forms. Jarrow states that the first three forms of Carnitine are for Cardiovascular function, whereas the GPLC is claimed to be a 'muscle-specific form of Carnitine that enhances endothelial function and promotes maximum muscular energetics'.
  
  Life Extension's product 'Optimized Carnitine with GlycoCarn' contains Acetyl-L-Carnitine HCl and Acetyl-L-Carnitine Arginate Di-HCl (trademark - ArginoCarn), and a patented form of GPLC called Glycine Propionyl L-Carnitine HCl, known as GlycoCarn. The product does not contain any L-Carnitine Fumarate however. GlycoCarn is also available (without the other forms of Carnitine) in the Life Extensions product Peak ATP, discussed below.
  
  I was muscle tested for different forms of Carnitine in April and June 2009, and neither GlycoCarn (GPLC HCl) nor L-Carnitine Fumarate were not wanted by the body, whereas (Jarrow Formulas) Acetyl-L-Carnitine was.

http://en.wikipedia.org/wiki/Carnitine


• L-Lysine - is the precursor to L-Carnitine, and is the amino acid found in all proteins and enzymes in the body. Lysine is metabolised to make Coenzyme A, a necessary fuel of the Krebs cycle for carbohydrate metabolism and energy production. Lysine is also used to make Collagen, the connective tissue in humans and other mammals. A deficiency in Lysine will have a serious impact on enzyme and protein production, as well as energy levels, and often results in weight loss. Determine whether you are actually deficient in Lysine as supplementing Lysine may well boost your Carnitine levels intracellularly more effectively than supplementing Carnitine as above.


• Lipoic Acid - is a cofactor in energy production, helping to regulate glucose metabolism. Lipoic Acid is active in all the tissues of the body and in its cellular compartments. Lipoic acid recycles both water and fat soluble antioxidant vitamins (e.g. vitamins C and E) and Coenzyme Q10, reducing them back to their non-oxidised original forms. Lipoic acid also improves sugar metabolism and energy production. It is a cofactor in the multienzyme complex that catalyzes the last stage of the process called glycolysis. Glycolysis is the first step in converting blood sugar (glucose), which is obtained from carbohydrates and proteins, into energy in a form that the body can use. This involves Magnesium, Active Vitamin B1 (TPP or TDP) and also Biotin, and so Lipoic Acid is best taken in conjunction with these other three supplements. Lipoic acid promotes the incorporation of cysteine into glutathione and combines synergistically with other antioxidants for greatly increased benefits. It is therefore frequently referred to as the ideal or universal antioxidant and free radical scavenger. It is also an excellent chelation agent. Please see the Detox page for more information.


• Coenzyme Q10 - and also Copper, Sulphur and Iron - are vital parts of the Electron Transport System (ETS) that harvest ATP energy from our daily food intake. Q10 helps to transport electrons from one molecule to another, hence allowing for energy production and transfer to take place. Beta blockers, tricyclic antidepressants and phenothiazines actually block CoQ10 production in the body and way worsen the situation. Coenzyme Q10 is naturally produced by the body by a process of methylation. If methylation is impaired in an individual, then Q10 levels may be quite low. Coenzyme Q10, aka Ubiquinone, is the most common form of supplemental Q10. For the non-vegetarians, heart is the most concentrated naturally occurring nutritional source of Q10. Coenzyme Q10 is defined on Wikepedia at the following link.

http://en.wikipedia.org/wiki/Coenzyme_Q10

CoQmax CF is a trademarked product by XYMOGEN. It is a proprietary, patent-pending, crystal-free form of CoQ10 that is reputed to offer very high levels of absorption and bioavailability. It utilises a proprietary monoglyceride carrier. Each capsule contains 50mg of CoQ10 (as ubiquinone). Clinical trials have shown it to be over 8 times more absorbable than powdered CoQ10 and more than twice as bioavailable as other oil-based or 'nano'-dispersed formulas. An example dosage in extreme cases might be 2 capsules, twice a day or more.

Another readily absorbable form of Ubiquinone (Q10) is Jarrow Formulas' Q-absorb Co-Q10. This uses a form of Q10 called Kaneka Q10 which is under licence from the Kaneka Corporation of Japan, and uses the 'ProSome' Formula. It comes in 100mg capsules. It is reputed to be absorbed 3-4 times better than ordinary chewable Co-Q10 tablets. The best elevation of blood plasma Q10 levels with this product have resulted in exercise being performed at the time of taking it, according to studies. Jarrow also offer other Ubiquinone products, such as Q-absorb Co-Q10 Plus and Q-absorb Co-Q10 Ultra. Both of these products contain the Citrus extract Limolene, which is reputed to help prevent crystallisation of Co-Q10 and thus aid absorption. The 'Plus' version contains 300mg of Limolene per capsule, in addition to 600mg Lecithin. Jarrow claims Q-Absorb Ultra has been clinically demonstrated in humans to raise plasma Co-Q10 levels by 500% (a six-fold increase over baseline Co-Q10 levels). Whether Limolene is used in CoQMax CF by Xymogen above is uncertain at this point in time. Limolene, it should be noted, is also an antimicrobial oil used to kill intestinal parasites (protozoa or nematodes).

Ubiquinol is a bio-activated (un-oxidised), trans-isomer form of Co-Enzyme Q10 (ubiquinone) and is reputed to be much more readily absorbed or utilised, in studies up to twice as effectively. It can be found in a number of Ubiquinol supplements and also in Premier Research Labs 'CoQ10-Quinol' product or Healthy Origins Ubiquinol. It is manufactured under license from the Kaneka Corporation in Japan, under the trademark 'Kaneka QH'.

In April and June 2009, I was muscle tested for various forms of CoQ10 (Ubiquinone), also including a Ubiquinol supplement, and CoQmax was the only brand/form of CoQ10 that was found to be agreeable to his body (at those times).

An alternative to Coenzyme Q10 is Idebenone. It is a synthetic alternative to Coenzyme Q10, an organic acid. It is reputed to have many of the same chemical properties to Coenzyme Q10. From my understanding, it is really an 'optional' supplement, to be taken in addition to Coenzyme Q10 rather than instead of it, or not at all. According to Dr Ward Dean MD, Idebenone does offer some unique benefits over CoQ10, including superior ability electron transport. In low cellular oxygen environments, Idebenone is more efficient at preventing free radical damage than CoQ10, whilst helping cells maintain relatively normal ATP levels (particularly useful to tissues that are rapidly damaged by insufficient tissue oxygenation such as the brain and the cardiac muscle - although are we talking about states where the patient is not breathing here? Rather than CFS?).

http://en.wikipedia.org/wiki/Idebenone


• Creatine - Creatine is a nitrogenous organic acid that helps to provide cells with energy until the Krebs cycle can start to produce energy. PhosphoCreatine is converted into ATP. It fills in the gap energetically between the 0.8s of energy (ATP) that cells have stored at any one time, and the 1.4 seconds it takes for the Krebs Cycle in the mitochondria to start producing more energy.
  
  http://en.wikipedia.org/wiki/Creatine
  
  By converting PhosphoCreatine into ATP during the initial stages of exercise, the body is able to provide energy before the body starts burn food to generate ATP. This can help to reduce the amount of ATP that is used up initially before more can be generated. Creatine helps to reduce lactic acid build up in the muscles and helps mitochondria to function efficiently at the start of a work out, and may also help with brain functioning.
  
  Unlike the Krebs Cycle nutrients, Creatine is not stored in the mitochondria, but is found locally in the cell. 95% of the body's Creatine is found in the skeletal muscles.
  
  Half of the Creatine in the body is derived from dietary sources, the other half is produced internally. Creatine is found in meat and fish, and vegetarians and vegans tend to have lower levels of Creatine unless they supplement it. Creatine tends to be denatured with heat in cooking. Creatine is manufactured by the body by a process of methylation, from the amino acids Arginine, Glycine and Methionine. However, if methylation is impaired, which it frequently is in patients with CFS and related conditions, and dietary sources are insufficient, then levels may be quite low. Those who are low in Creatine may benefit from taking Creatine Monohydrate or Creatine Ethyl Ester prior to a work out, or first thing in the morning. Bodybuilders are known to take creatine during high intensity weigh training workouts in order to perform addition reps at their maximum weight in order to build the maximum muscle mass in a session, and also to provide additional energy for intensive cardiovascular exercise (e.g. treadmills or jogging). Creatine is osmotically active and excessive supplementation, and in weight training applications, will result in increased water retention, especially in the muscles. This may result in a bloated or larger, ripped appearance, and may add as much as 1-2kg to one's normal weight. It has also been observed that regular creatine intake may encourage the liver to produce less creatine naturally, and so if supplemental creatine is then stopped, then the person may feel tired for a number of weeks before enzymatic creatine synthesis returns to normal to redress the balance. There are no known harmful effects from taking creatine, despite fears to the contrary. Creatine supplementation (and dosage recommendations) however should probably be based on ascertaining one's natural creatine levels and whether they require supplementation or not; and indeed whether the body reacts well to it using muscle testing, or other means, like any other form of supplementation.

www.pponline.co.uk/encyc/0164.htm


• N-Acetyl Cysteine (NAC) - is a powerful antioxidant and useful glutathione precursor, as has been discussed on the Nutritional page and Inefficiency Liver Function and Detox pages. It also promotes oxidative phosphorylation, key elements of the respiratory chain, mitochondrial membrane integrity and mitochondrial homeostasis, thereboy delaying apoptosis (Programmed Cell Death). L-Cysteine may also be supplemented instead, however the Acetyl group may make it more absorbable in the brain. Supplementing directly with Glutathione is also an alternative option. In addition, Superoxide Dismutase (SOD) enzyme production is probably even more important that Glutathione in terms of ability to assist in respiration, protecting against superoxide damage.


• Guanosine Triphosphate (GTP) - is a purine nucleotide is produced by a Krebs cycle enzyme in the process of producing ATP. It consists of a Guanosine molecule attached to a Ribose ring. Increasing one's purine intake (within limits as one does not want Gout) may assist increasing ATP levels.


• Copper, Zinc, Manganese and Iron - SOD enzymes are bound to a metal element, copper, zinc, manganese or iron, and therefore it is shrewd to maintain adequate levels of these mineral elements in one's diet or supplement regime (as mentioned above), and to ensure one's levels do not drop below normal (according to relevant test results).


• Chromium (III) - is a trace element that enhances the action of insulin (involved with carbohydrate, fat and protein metabolism). Chromium is a trace element and only small amounts are required. It should only be supplemented if levels are low, as excessive supplementation may lead to detrimental effects.

http://ods.od.nih.gov/factsheets/chromium.asp


• Vanadium - is believed to be involved with glucose metabolism (enhancing , Na/K transport, adrenal catecholamine metabolism (oxidation), and inhibiting cholesterol synthesis (lowering total and LDL (bad) cholesterol levels). Vanadium is a trace element and only small amounts are required. It should only be supplemented if levels are low, as excessive supplementation may lead to detrimental effects such as decreased energy production.

www.umm.edu/altmed/articles/vanadium-000330.htm

Some of these cofactors are summarised and discussed in the article below by Ward Dean MD, entitled 'Restoring Mitochondrial Function and Bio-Energetics'. The mitochondria inner/outer membrane diagram above is also found here.

http://www.vrp.com/articleprinter.aspx?a=912

As one can see, there are a large number of bio-chemical compounds involved in energy production in the body. There are many more that have not been discussed here, including various organic acids and hormones. Any number of these may be deficient in the body in a sufferer of CFS or related conditions, and are required in the correct quantities and correct relative ratios for optimum metabolic function. Knowing exactly what is required and in what quantity is critical, and it is recommended to consult with your naturopath to address this area, rather than simply take every expensive supplement that is all the rage on the internet, as this approach is unlikely to be completely effective. For example, you are unlikely to notice any benefit in taking high doses of Ubiquinol (CoQ10) if your levels of CoQ10 are actually satisfactory. The main effect will the antioxidant effect - and there are cheaper and more effective antioxidants - but mainly the effect on your wallet. Identifying what is actually in dire need by the body is therefore of paramount importance. It is tempting to simply take a long list of the above supplements expecting them to work, but one must consider what cofactors, minerals, vitamins and amino acids are actually deficient, and tackle those, rather than the arbitrary list above. Indeed, the actual problem may not be what you expect and may well be less obvious, relating to other krebs metabolites, dysbiosis, other amino acids being deficient, low hormone and neurotransmitter levels, amongst other things. A 'holistic' approach is therefore required to get to the bottom of why mitochondrial function is poor.

There are a number of combination mitochondrial formulas available by reputable suppliers, and many contain more than one of the cofactors and coenzymes listed above.

One can consider mitochondrial support and supplementation in two senses, for regular supplementation, usually twice or three times a day, and also ad hoc supplementation, when one's mitochondrial function is especially poor, i.e. dips during the day particularly when one has overdone things. There are various symptoms for this, which may vary from individual to individual, according to the exact mitochondrial and endocrine/neurotransmitter imbalance pattern. However, for 'emergency' or ad hoc supplementation, I have found personally that a combination of Acetyl-L-Carnitine (or whichever Carnitine works for you), Coenzyme Q10, and Active B3 help to relieve such symptoms most effectively. If cardiac symptoms have also arisen, then the above will also help to support more efficient energy production to the heart, but one should then also consider taking (additional) Hawthorn. This is described on the Cardiac Insufficiency page. If you are especially worn out in a mitochondrial sense, rather than sleep cycle sense, late in the evening, it may well be a good idea to take some extra ad hoc mitochondrial supplements so that the body can function properly, and thus allow you to fall asleep. Otherwise you may find your biochemistry is too chaotic to promote the correct neurotransmitter production pathways for sleep. Try experimenting if this is something that affects you to see what works best for you.

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Supplemental ATP Replacement:

There are two methods of replacing lost ATP or to supplement the slow regeneration of ADP and AMP. This involves either consumption of a precursor to ATP, i.e. the sugar D-ribose, or to take micro-encapsulated ATP in the form of Peak ATP. These are discussed below.

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D-ribose:

D-ribose is an aldopentose, a monosaccharide (a sugar), a component part of DNA, RNA and ATP. ATP is made up of three main components, adenosine, and amino acid, three phosphate molecules, and D-ribose. It is believed that supplementation with D-ribose ensures that it is 'exclusively' directed by the body to produce more ATP, i.e. when ADP has been converted into AMP and cannot be recycled. Some patients have reported an energy boost followed by a sudden 'crash' in energy levels, which might suggest that it is being metabolised to some extent as a sugar, rather than a building material for ATP. Paul Cheney believes that in a small number of patients it seems to be converted to glucose and metabolised by both the patient and his bad bacteria (resulting in increased wind); ana also in a small number of patients, D-ribose is reputed to be metabolised anaerobically resulting in a build up of lactic acid in the body. However, the most common experience is of some ATP production benefit overall, according to Cheney. D-ribose is promoted by a number of other specialists in the field for CFS, ME and Fibromyalgia sufferers.

http://en.wikipedia.org/wiki/Ribose

'D-ribose has also been used to reduce fatigue in fibromyalgia and chronic fatigue syndrome. A 2006 study [by Teitelbaum, Johnson and St Cyr] concluded that D-ribose (5 g three times a day) was effective in the treatment of FM and CFS. 66% of the 41 participants found the supplement helpful and it produced improvement in all the areas tested: energy, sleep, mental clarity, pain intensity and well-being. The study was not placebo controlled, however.'

www.ncbi.nlm.nih.gov/pubmed/17109576

www.endfatigue.com/tools-support/D-ribose.html

http://www.ei-resource.org/articles/chronic-fatigue-syndrome-articles/d%11ribose-treatment-of-chronic-fatigue-syndrome

I took 3 teaspoons of D-Ribose per day and over a period of a few months in the first quarter of 2009, beneficial effects were seen to have disappeared and it greatly contributed to the return of my bad bacteria and yeast. So not particularly successful. If one has been recommended D-ribose by one's practitioner, and/or has tested positively for it kinesiologically, then one should start out at a low dosage. If no beneficial effects are noticed in the short term, or when no more beneficial effects are noticed from taking it, one would be wise to desist from taking it, for the above reasons, as it may be causing more harm than good. Although it is widely hyped by some specialists in CFS and related disorders, I have only come across one person who experienced noticeably beneficial effects from taking it, of a small handful, the others simply noticed only a slight or no improvement.

Bioenergy Life Science are the manufacturers of 'BIOENERGY RIBOSE', the D-Ribose used by the most popular and highest quality supplement suppliers. Former known as Valen Labs, they launched the product in 2000, and subsequently changed their company name to Bioenergy Life Science in October 2006. 'BIOENERGY RIBOSE' is available capsule or powder form, but it makes more sense to take it in powder form, a teaspooon, in a small glass of water, for example, a couple of times a day. Bioenergy Life Science sell 'BIOENERGY RIBOSE' in their own branded product, Corvalen, which is also available as Corvalen M (with additional Magnesium and Malate). They also sell it under licence to other brands, and examples of other 100% 'BIOENERGY RIBOSE' D-ribose products include: Doctor's Best Best D-Ribose, Jarrow Formulas Ribose Muscle Edge, NOW Sports D-Ribose Powder and LifeExtension D-Ribose Powder. As all the above 'BIOENERGY RIBOSE' powder products are exactly the same, it may make most sense to buy the most cost effective brand, which is currently Doctor's Best (if purchased in/from the USA).

www.bioenergy.com

www.bioenergy.com/store/Main.aspx?html=ds&topic=b

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Peak ATP:

An additional way to support sufficient availability of ATP is to actually consume an ATP supplement, i.e. one that actually contains ATP, to directly replace that which is not there when it needs to be in the body's cells. This is more of an emergency or short term measure than a medium or long term strategy to an ATP deficit and mitochondrial dysfunction. One really should be looking to address the actual core reasons for mitochondrial dysfunction, and indeed ATP availability may only be part of the problem as can be seen above (i.e. ATP transport etc.) I have tried such a product, called 'Peak ATP'. Peak ATP is a form of enterically coated ATP (Adenosine 5'-Triphosphate Disodium) which is said not to be destroyed one's the stomach acid and is absorbed in the small intestine, and that which is absorbed in the blood stream can be directly be utilised by the body's cells as a readily available source of ATP (in lieu of the body's own sufficient production of fresh ATP and recyclying of ADP back to ATP). The efficiency of Peak ATP may also be dependent on one's digestive efficiency. Peak ATP is a trademarked product which is sold under licence by Solgar, Life Extension and MRM. It is also marketed under other brand names, such as Active ATP (MRM brand name). Other Mitochondrial supplements exist containing ATP, but it may be debated as to whether it is enterically coated or not and thus not simply destroyed in the stomach. I have tried the ATP products of all three manufacturers.

- Life Extension's PEAK ATP with GlycoCarn. Each tablet contains 100mg of Peak ATP and 500mg of GlycoCarn Glycine, a trademarked form of Propionyl-L-Carnitine Hydrochloride.

- Solgar PEAK ATP; or Solgar PEAK ATP with CoQ-10. The former product is cheaper than the latter. Both contain 125mg of PEAK ATP.

- MRM Biosorb Active ATP2. MRM BioSorb Active ATP2 is in chewable tablet form, and appears to be the most cost effective form of Peak ATP (Solgar's being 2nd cheapest). It contains 125mg of PEAK ATP and also contains 200mg of B-Alanine Peptide per tablet. It may not be suitable for those who have too high Beta-Alanine levels already, or if taken too regularly. It is quite a pleasant product to chew whereas the other two above if chewed are quite vile tasting and leaving a large blob of Magnesium Stearate (almost like chewing gun) afterwards, which is probably better spat out.

The Peak ATP web site can be seen below for further information regarding specifications and ATP related-research (although not specific to Peak ATP).

www.peakatp.com

Peak ATP seems to have made the most difference initially in terms of increased energy levels. I felt a huge rush, and warm sense of well being that lasted several hours after taking it. This sensation died down after a few days of taking it, and after a week, I felt that the product when taken, made a slight difference to my energy levels, but that sense of euphoria was nowhere to be felt, or ever so slightly, depending on a number of internal factors that may have come into play at the moment of taking it. Much larger doses were required to gain at least some of the initial effect back again. However, I felt it did provide more of an instant noticeable effect than taking D-ribose. The supplement works best when chewed in the mouth rather than swallowed, and hence absorbed more quickly, although this was a little disgusting! To what extent is the body getting adapting to the supplement and compensating by producing less ATP itself? And to what extent is the body simply getting used to it and largely learning to ignore it? One could argue that taking in replacement ATP would require much larger quantities in any case to have any effect, taking into account that the average person turns over his own body weight in ATP per day. How much would be enough? Perhaps this could be applied to some extent to ATP precursors like D-Ribose. This doesn't however explain the very positive initial effects I had with Peak ATP. It is also worth considering that taking ATP precursors or replacements is better whilst one still has energy rather than after one has 'burnt out' and used up all one's ATP and converted much of one's ADP to AMP. i.e. as a preventative measure to 'stop you rolling off the top of the hill' rather than trying to recover from a place 'at the bottom of the hill'. I first took it at a time when (according to blood/urine tests) my levels of cofactors and coenzymes were sufficient/borderline, and when I was already supplementing a wide range of other cofactors and coenzymes (perhaps gratuitously). To identify the best way of boosting your mitochondrial function in the short term requires laboratory testing and a skilled practitioner.

As I found out, it is easy to become dependent on Peak ATP, however, it is easy to keep increasing the dosages to maintain the same effect. Peak ATP by its nature seems to provide a quick 'fix', but is also followed an hour or two later by a low (predisposing one to taking some more), whereas without taking Peak ATP one may feel a more consistent level of energy. Taking Peak ATP does seem to shift the nature of one's mitochondrial function to some degree, not necessarily for the better. As stated above, however, it is useful in cases where one's mitochondrial function is so poor that one is experiencing chest pains (i.e. of a cardiac nature) or extreme shortness of breath or energy that is preventing one from sleeping. It can be useful to take also when one is having a particularly exhausting day, to keep one going, as a temporary measure. But like many crutches, one can become used to taking it regularly, and it may temporarily prevent the long term progress and recovery of one's natural mitochondrial function.

One particular negative thing that can be said about Peak ATP (which equally applies to D-ribose above) is that, apart from not really addressing the problems associated with mitochondrial function such as electron transfer and ATP transport, it does seem to potentially contribute to dysbiosis. I found that over a few months of taking both D-ribose and Peak ATP (the latter in very large quantities, perhaps because I was not taking much Acetyl-L-Carnitine or Coenzyme Q10), my dysbiosis which I had previously rectified came back with a vengeance, in particular, bad bacteria and yeast. One could assume that because Peak ATP is swallowed in tablet form, or even when chewed, a significant amount makes its way down to the colon, where it can directly fuel the bad bacteria (together with other nutrients in the stool that they require to feed). In addition, there may well be a significant amount of bad bacteria and fungus in the bloodstream and tissues, and this may also be directly assisted by taking peak ATP. The ATP the body naturally creates should be floating around the bloodstream of course, but the majority should remain within the cells where it is created. Taking a form of supplemental ATP means most of this floats around in the blood or digestive tract before it is actually absorbed by cells, so it is more likely to potentially result in dysbiosis. This is not such an issue if one is taking small amounts, but if large amounts are taken, then one should consider the consequences and indeed the reason why one needs to take this much, as it points to a severe problem in other areas of mitochondrial function, e.g. ATP transport, or electron transfer, B vitamin deficiency, krebs cycle cofactor bottlenecks, or mitochondrial membrane integrity, which if addressed would probably provide more benefit than the ultra-high dosages of Peak ATP.

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Relevant Tests:

A urine test such as the Metabolic Analysis Profile by Genova Diagnostics, for example, would highlight which exact metabolites or co-factors are out of balance. Blood tests, for example, a Mitochondrial Membrane - Translocator Protein Study and ATP Profile by Acumen, would highlight the health of the mitochondrial membrane and the level of ADP to ATP efficiency. Please see the links page for contact details of these and other laboratories. In addition, a therapy working on the body's energetic (qi) system may help. Such therapies are outlined on the energetic therapies page.

Please see the digestive disorders page for information about improper conversion of amino acids. And please see the hormonal deficiencies page for information about metabolic rate and basal temperature measurement.

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