In simple terms, the Krebs’ cycle metabolizes acetyl coenzyme A into citric acid and then runs through a complex series of biological oxidations, producing free hydrogen ions. A net of two molecules of ATP is created at this stage in the Krebs’ cycle. The hydrogen ions then enter a biochemical chain, known as oxidative phosphorylation, which is a highly efficient aerobic energy generator. Oxidative phosphorylation generates 36 molecules of ATP during a sequence of steps that combine hydrogen electrons to molecular oxygen to form water. Therefore, each molecule of citric acid that rotates through the Krebs’ cycle, generates 38 molecules of ATP for tissue fuel. (1)
Krebs’ Cycle Acids
Alpha-ketoglutaric Acid, Malic Acid, Fumaric Acid, Succinic Acid, Citric Acid, Pyruvic Acid, Pantothenic Acid
These acids are intermediate compounds that are found in the Krebs’ cycle and are necessary to generate cellular energy for tissue fuel. Supplementing these essential Krebs’ cycle acids in the presence of nutrient cofactors can enable a partially completed Krebs’ cycle to go to completion. They can prevent and remove the harmful byproducts that are generated from abnormal energy production in the mitochondria. And they can stimulate a high yield of ATP from the mitochondria for tissue energy.
Supplementing these Krebs’ cycle fuel sources may be advisable for different purposes. They can help correct certain metabolic disorders that result from abnormal mitochondria energy production. They can provide an ergogenic edge in athletic performance by generating muscle energy, increasing aerobic capacity and preventing fatigue. They may be even more helpful for improving athletic performance when used in conjunction with alkalizers that buffer lactic acid build-up in muscle tissue and improve tissue oxygenation.
Alpha-ketoglutaric Acid (AKG)
Alpha-ketoglutaric acid plays a vital role in the Krebs’ cycle production of energy. As a precursor of the amino acid, glutamic acid, AKG stabilizes blood glucose levels during exercise. Alpha-ketoglutaric acid benefits the athlete by supporting protein synthesis, allowing for longer, more intense workouts, and by promoting healthy nitrogen balance.
Studies of patients given supplemental alpha-keto-glutarate following surgery found a nitrogen-sparing effect and a reduction in loss of lean body mass. Alpha-ketoglutaric acid helps reduce ammonium levels that may interfere with exercise performance. Studies have demonstrated that ammonia formed in the muscle, kidney and brain combines with alpha-ketoglutarate and L-glutamate to reduce ammonia toxicity. (31-33), (16-18)
Malic acid acts as a catalyst in the Krebs’ cycle to increase energy production from the burning of pyruvic acid. Malic acid also aids in exercise recovery by counteracting the buildup of lactic acid. Supplementation of malic acid has been reported to be beneficial in Chronic Fatigue Syndrome by reducing symptoms of persistent fatigue, muscular myalgia and arthritic-like pains.
Fumaric acid is the trans-isomer of malic acid that enters the citric acid cycle. It’s a byproduct at certain stages in the arginine-urea cycle and purine biosynthesis. In healthy individuals, fumaric acid is formed in the skin from exposure to sunlight. A deficiency of fumaric acid leads to the accumulation of metabolic half-products that may be responsible for causing the skin lesions of psoriasis. Sufferers of psoriasis have a biochemical defect in which they do not produce enough fumaric acid, requiring prolonged exposure to the sun. Administration of fumaric acid to individuals suffering from psoriasis has caused a gradual elimination of the symptoms. (40-47), (25-32)
Succinic acid, like other Krebs’ cycle intermediates, is an entry
pathway for other metabolites into the cycle and is involved in a variety of
important biological actions. In addition to its enzyme activity, it combines
with protein to rebuild muscle fiber and nerve endings, and helps fight
infection. Individuals with Chronic Fatigue Syndrome have shown low levels of
succinic acid in their urine.
Several amino acids are metabolized into succinic acid, providing a source of anaerobic and aerobic energy. Amino acids that are metabolized into succinic acid have been shown to be important in supplying the heart with fuel for myocardium contractions under low oxygen conditions. The amino acid GABA can either be oxidized to succinic acid for cellular energy production, or reduced to GHB, depending on the metabolic needs of the body. (48-50), (33-35)
Citric acid, a natural organic acid present to some extent in all plant and animal tissues, occupies a pivotal location in the Krebs’ cycle. After proteins, fats, carbohydrates and amino acids have been oxidized into acetyl coenzyme A, the acetic acid subunit of acetyl CoA is combined with oxaloacetate to form a molecule of citrate. The acetyl coenzyme A acts as a transporter of acetic acid from one enzyme to another.
First isolated by the German biochemist, Karl Wilhelm Steele in 1784, today citric acid is widely respected for relieving conditions of fatigue, poor digestion, cold and flu infections, asthma, hypertension and cholesterol deposits in blood vessels.
Pyruvic acid is a three-carbon ketoacid produced in the end stages of glycolysis. In the mitochondria, pyruvic acid is either reduced to lactate in the cytoplasm, or oxidized to acetyl CoA.
Research has shown that taking pyruvate (the salt of pyruvic acid) can increase muscle endurance and promote fat loss. Pyruvic acid also appears to increase the amount of glucose that enters muscle cells from the circulating blood. This ability of pyruvic acid leads to increases in immediate available energy, as well as increasing stored muscle glycogen levels for future energy. Research has shown that pyruvic acid increases muscle endurance and improves cardiac efficiency.
In one study pyruvic acid was found to increase glucose extraction by almost 300% and muscle glycogen by 50% after one hour of exercise. The researchers found that arm endurance increased by 150% and leg endurance by 60%. Another study conducted at the University of Pittsburgh School of Medicine found that pyruvic acid produced a significant amount of weight loss and fat loss in obese women on a low calorie liquid diet. Two potential mechanisms by which pyruvic acid enhances both fat and weight loss are through increasing both resting metabolic rate and fat utilization. (51-56), (36-41)
Vitamin B5 is required for the synthesis of coenzyme A. Supplementation of panthenine (pantothenate bound to cysteamine) has been shown to reduce elevated blood lipids in humans. It is postulated that this action is due to the accelerated synthesis of coenzyme A. It has also produced an anti-arrhythmic effect in animal hearts by increasing ATP synthesis. A study of elite distance runners who were given two grams of pantothenic acid daily for two weeks found a 17% reduction in lactic acid buildup and a seven percent reduction in oxygen consumption during prolonged, strenuous exercise. (57-61), (42-46)
The Krebs’ cycle is an eloquent and essential system designed to generate large amounts of cellular energy required for life. Disruption of the Krebs’ cycle, whether caused by deficiencies in energy substrates, acquired or inherited disease states, or physical stress, leads to an inhibition of normal energy production and contributes to a wide range of metabolic disturbances and symptoms.
The use of supplemental Krebs’ cycle acids and anti-fatigue buffers can assist in the management of mitochondrial energy substrates and increase cellular energy production. Such a nutritional approach can be of benefit to athletes, anyone who is aging, as well as those suffering from metabolic disturbances caused by inherited mitochondrial diseases or acquired diseases, such as Alzheimer’s disease and Chronic Fatigue Syndrome (CFS).
When glutathione goes too low in the muscle
cells, the levels of oxidizing free radicals rise, and these react with parts
of the "machinery" in the little powerplants, lowering their output
of ATP. This involves what is called the Krebs cycle and the respiratory chain.
So the muscle cells then experience an energy crisis, and that's what causes
the fatigue. Over time, because of the lack of enough glutathione, more
problems accumulate in the mitochondria, including toxins, viral DNA, and
mineral imbalances. These have been observed in the ATP Profiles and Translocator
Protein test panels offered by Acumen Lab in the UK.
There are explanations that flow from this basic mechanism for other aspects of CFS. I haven't figured out explanations for all of the aspects of CFS, but I do think I understand a large number of them in some detail, and I've been able to explain enough of them that I believe this mechanism will account for the rest as well, if we can figure out the underlying biochemistry. My 2007 IACFS conference poster paper presented outlines of many of these explanations.
The involvement of infections by bacteria, viruses and fungi appears to have two aspects in CFS. First, as mentioned above, infectious agents can act as one of the stressors that initially bring down the level of glutathione and produce the onset of isolated cases of CFS in people who are genetically susceptible. I suspect that the clusters or epidemic occurrences of CFS (such as at Incline Village in the mid-80s) were caused by particularly virulent infectious agents, such as powerful viruses, and the genetic factor is less important in these cases.
Second, when a person's glutathione, methylation cycle, and folate cycle are not operating normally because of the vicious circle described above, the immune system does not function properly. In this case, viruses and bacteria that reside inside our cells and that are always in the body in their dormant, resting states are able to reactivate and produce infections, which the immune system is not able to totally put down. This accounts for the observation that most of the viral and intracellular bacterial infections seen in CFS patients are caused by pathogens that most of the population is carrying around in their dormant states.
Rich Van Konyenburg