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Metabolic Consequences

WARBURG EFFECT
The predominant symptom in chronic fatigue is the prolonged or intermittent extreme tiredness present in these patients. This extreme fatigue is accompanied by the Warburg effect, which refers to the fact that virus-infected cells produce energy, mainly in the cytosol, through a process of anaerobic glycolysis even under adequate oxygen conditions.

The expression of an oncogene of EBV (expressed during many forms of latency) LMP-1, would induce the expression of HK2 (hexokinase 2). Hexokinase 2 is an enzyme that limits the speed of glycolysis which, thanks to its activation, would lead to an increase in glycolysis and therefore lactate production. In addition, it is able to increase cell survival by inhibiting apoptosis by binding to the external mitochondrial membrane, interacting with the voltage-dependent ion channel (VDAC) to block the release of cytochrome C and thus caspase-dependent apoptosis 9.1

However, the use of glycolysis as the main metabolic pathway for glucose requires an increase in extracellular glucose uptake (increased expression on the surface of GLUT1 )2,3  to match the higher metabolic rate. In order to boost glucose uptake, recent studies on the behaviour of cancer cells have shown the emergence of a mechanism by which these cells can increase ATP consumption, thus leading to a decrease in ATP reserves as a consequence. During this process glucose is incorporated into biosynthesis pathways (lipid biosynthesis pathways and protein glycosylation) and is not intended for ATP production. Both in cancer and in cells with latent infection, there is a metabolism that is not adapted to support the production of ATP, but for consumption. It should be noted that one of the symptoms that has traditionally been associated with a tumour process is the constitutional syndrome, so the feeling of lack of energy is a common symptom in both pathologies.

In order to alter glucose metabolism, the cell needs the signalling pathway of phosphoinositol 3-kinase (PI3K), which is activated in many types of cancer and it has been seen that in cells with latent EBV infection, both LMP1 and LMP2A can activate PI3K4,5. Among its functions is the regulation of cell growth and survival.  AKT serine/threonine kinase, an important PI3K effector, promotes glucose uptake and increases the activity of glycolytic enzymes.

The most important mechanism triggered by AKT signaling is the increased Warburg effect. The activation of Akt promotes the glycosylation of proteins in the endoplasmic reticulum, which elevates the consumption of ATP and uninhibits an enzyme that limits the speed of glycolysis, which would have to be inhibited by a high proportion of the ATP/AMP quotient and thus is not, abnormally increasing the glycolysis process. This exaggerated increase in glycolysis causes the systems to be saturated in such a way that the cell uses both to obtain ATP, both the aerobic and the anaerobic pathways.

Under normal aerobic conditions, the pyruvate generated by glycolysis is transported to the mitochondria, where it is converted to acetyl-CoA by the pyruvate dehydrogenase complex (PDH). Under anaerobic conditions, when mitochondrial respiration is inhibited, pyruvate accumulates in the cytosol, leading to increased production and cellular excretion of lactate.

PDH activity is controlled by PDK kinases that inhibit the activity of the enzyme PDH by phosphorylation and phosphatases that catalyze dephosphorylation. Significant increases in inhibitory kinases PDK1, PDK2, and PDK46 have been seen in CFS, while PDK3 remained unchanged. These enzymes are found, among other places, in skeletal muscle, heart, and brain. The activations of PDKs are directly regulated through increased levels of ATP, NADH and acetyl-coA. Instead it is inhibited by ADP, NAD+, CoA-SH and pyruvate.

The sudden initial increase in pyruvate by glycolysis results in the inactivation of PDK and therefore allows PDH to perform its function and begin the Krebs cycle in the mitochondrial chain to generate ATP.  However, the speed of the Krebs cycle is limited, so the rest of the pyruvate is consumed anaerobically by increasing lactate levels. So far the cell is using both pathways for the production of ATP. The lactate generated can be used by muscle cells to use it as fuel or by the liver through the Cori cycle to generate new glucose.

However, the increase of lactate at the cytosolic level of the infected cells would activate the HIF1A protein, whose function in active state is to inhibit ATPsynthetase, i.e. it interrupts the production of ATP by the mitochondrial oxidative pathway. Although the electron transport chain is inhibited by the HIF1 protein, the cell can continue to generate intermediates of the Krebs cycle because the other enzymes are not inhibited.  Consequently, there is an increase of citrate in the mitochondria with expulsion to the cytosol to generate acetyl coA and that this is integrated into the biosynthesis pathways of fatty acids. At the same time, the pyruvate accumulated in the cytosol is consumed as lactate for the generation of ATP, since it is the fastest way to obtain energy and the only one in this case because the transport chain is inhibited. When there is an accumulation of acetyl coA (by fatty acid synthesis) in the cytosol, PDH via PDK would be inhibited and pyruvate would begin to accumulate. Again the elevated pyruvate would activate this pathway and begin the process. There has been an increase in PDKs in CFS patients, so this could be the explanation.

In order to follow a continuous glycolysis process it is necessary to constantly replenish NAD, this can be replaced by aerobic or anaerobic, in this case it would be anaerobic, because we have already said that aerobic has been inhibited, therefore, NAD is achieved by converting pyruvate to lactate by lactate dehydrogenase as NADH is consumed during glycolysis.

When mitochondrial electron transport decreases for any reason there are fewer oxygen molecules that are converted to water (H2O) by the enzyme cytochrome c oxidase. If the capillary delivery of oxygen to the cell is not modified, the concentration of dissolved oxygen rises in the cell. This activates dozens of enzymes that are kinetically regulated by the availability of dissolved oxygen and can act as oxygen sensors. One of these enzymes is NADPH oxidase (Nox4 gene)7  which increases levels of hydrogen peroxide (H2O2) to neutralize excess oxygen (O2). The reaction would be:

NAD(P)H + 2O2 -> NAD(P)+ + 2O2– +H+

It should also be noted that the enzyme NADPH oxidase which catalyzes the oxidation reaction of NADPH to NADP, uses as cofactors calcium, FAD and the heme group and in Naviux studies on metabolites in SFC a reduction of FAD has been shown.

This O2– is used by the SOD (superoxide dismutase) to form H202 that would go towards the peroxisoma and later would be neutralized by the catalase to H20. But the catalase has its speed limited so the rest of H202 has to be used by another route, so that glutathione, which is normally in its reduced form (GSH) is oxidized to GSSG by the enzyme glutathione peroxidase.

2 Glutatión (GSH) + H2O2 ⇌ Glutatión disulfuro(GSSG) + 2 H2O. 

La ruta de las pentosas fosfato está regulada por la concentración de NADP en citosol. The sudden increase of NADP by NADPH oxidase in response to excess oxygen, generates the start of the phosphate pentosas route. When NADPH accumulates along with the production of elevated levels of acetyl coA as a result of increased glucose uptake, both provide a stimulus for fatty acid synthesis.

ROLE OF PEROXISOMES
Peroxisomes play a key role in both the production and neutralization of reactive oxygen species (ROS) along with lipid metabolism. Peroxisomes generate significant amounts of hydrogen peroxide through the action of various peroxisomal oxidases (e.g. their acyl-CoA reductase oxidases). However, peroxisomes also contain multiple antioxidant enzymes such as catalase, SOD, glutathione peroxidase, epoxy hydrolase, peroxyrdoxine I… which contribute to the regulation of intracellular ROS levels and therefore to oxidative stress.8

It has been shown that latent infection with HVSK (VHH8) leads to increased proliferation of peroxisomes. They found that the metabolism of lipids (especially very long chain fatty acids) in the peroxisome was necessary for survival from latent infection with this herpesvirus.9

This proliferation of peroxisomes is induced by PPAR γ (gamma receptor activated by peroxisome proliferating factor). PPAR is activated both in cancer cells and in latent herpesvirus infections where it promotes an increase in the oxidation of fatty acids in peroxisomes.10,11 In a study on prostate cancer, it was shown that peroxisomal over-activation occurred in cancer cells with an increase in the peroxisomal b-oxidation of branched-chain fatty acids.12

All this indicates that peroxisomes have a role in the survival of cancer cells or latent infections. The peroxyxomal beta-oxidation produced in these cells would serve to consume part of the long chain fatty acids harmful to them and thus provide as a more acetyl product CoA to be used again by the cell in the synthesis of fatty acids. During this process energy is not produced in the form of ATP, but dissipated in the form of heat.

In the peroxisome during the beta-oxidation of fatty acids is formedFADH2 which reduces the oxygen to H20 to reuse the FAD in order to follow the beta-oxidation.  This harmful H202 is reduced in a second step through the peroxisome catalases where H20 and ½ O2 would be formed.

In addition, recent studies have shown reduced levels of CoQ10, a decrease in mitochondrial membrane potential (so there is no mitochondrial ATP production), an increase in mitochondrial superoxide levels, and an increase in lipid peroxidation levels in mononuclear cells in the blood of fibromyalgia patients.13

FORMATION OF FREE RADICALS
The hydroxyl -OH radical has a very short half-life (1 nanosecond) which allows it to act only at the site of its formation or in its proximity. It can react on the structure of DNA. The biological damage would be the chain reaction known as lipid peroxidation or lipoperoxidation.  When this radical is generated near biological membranes, it can attack the fatty acids of the phospholipids, which are preferably polyunsaturated acids such as arachidonic acid. A chain reaction is formed in which an OH can cause hundreds of fatty acid molecules to become lipohydroperoxides, the accumulation of which disorganises the membrane function and can even destroy it.14

The formation of the hydroxyl radical depends on a reaction catalysed by ions of transition metals (iron and copper) with iron ions being the promoters of free radicals. This is called the Fenton reaction where the ferrous ion reacts with hydrogen peroxide giving rise to the formation of the hydroxyl radical which is very reactive and interacts rapidly with DNA, proteins and lipids.14

Fe2+ + H2O2 à Fe3++ ·OH+OH– (Fenton Reaction)

The cell receives iron from the blood as a ferric ion attached to transferrin. The complex formed by transferin and iron is captured by specific receptors on the cell surface and internalized by endocytosis.

The acidic medium of the endosome releases the ferric ion of transferrin which can be incorporated into some proteins or stored as ferritin. While the transferrin-receptor complex is recycled to the cell surface. The ferric ion, in addition to being released from the transferrin, can also be mobilized from the ferritin, constituting the pool of iron not bound to proteins necessary for oxidative damage and which can be removed from circulation by ferric ion chelators, such as desferroxamine.  The ferric ion reacts with superoxide.14

Fe3+ + O2.-  -> Fe2+ + O2

These two reactions together are known as the Haber-Weiss reaction. The net result of both is thus represented:

O2.- + H2O2  -> ·OH + OH– + O2

All reactions that generate O2.- due to the reaction of the SOD also form H202. Having continuous flow of O2 – it can react with hydrogen peroxide to generate ·OH is why it is so important the action of antioxidants.14

ANTIOXIDANT MECHANISMS: ENZYMES AND VITAMINS
The primary antioxidant enzymes are superoxide dismutase (SOD), catalase (CAT) present in peroxisomes and glutathione peroxidase (GSH-Px). SOD catalyzes the enzymatic conversion ofO2– to H202. CAT removesH202 (hydrogen peroxide). GSH-Px complements the activity of catalase in the metabolization of H202, being predominantly located in the cytoplasm. This enzyme has two forms, one that requires selenium for its activity and uses hydrogen peroxide as a substrate, and another that does not require selenium and catalyzes the degradation of organic peroxides, especially lipoperoxides. The reduction of these peroxides is coupled to the oxidation of the reduced glutathione (GSH), generating oxidized glutathione (GSSG). The mechanism of regeneration of GSH from GSSG, is performed by the action of the enzyme glutathione reductase that requires for its activity the coenzyme NADPH. The provision of NADPH is carried out by glucose metabolism through the pentosas cycle.14

Reduced glutathione is also important for maintaining a reduced pool of ascorbic acid (vitamin C) used to suppress free radicals. Peroxides can also be eliminated, albeit to a lesser extent, by the action of the enzyme glutathione S-transferase, since glutathione conjugated compounds are metabolically inactive, being excreted. When there is a deficit of GSH-Px the activity of glutathione-S-transferase increases as a possible compensatory mechanism.14

Vitamin E is one of the most important antioxidants, especially the alpha-tocopherol form, present in cell membranes and LDL (low-density lipoprotein). Its importance lies in the fact that it is able to prevent the peroxidation of polyunsaturated fatty acids by the presence in its structure of a group -OH (alpha-tocopherol-OH) whose hydrogen is easily separable from the molecule.

During peroxidation, peroxyl and alcoxyl radicals are generated, which are preferably combined with alpha-tocopherol rather than with the adjacent fatty acid, ending the chain reaction. The alpha-tocopherol-O- (radical tocopherol) that forms, is very little reactive, being unable to attack the side chains of adjacent fatty acids. It can migrate to the membrane surface and be converted back to alpha-tocopherol by means of a reaction with ascorbic acid. It is likely that the reduced glutathione is also involved in the regeneration of alpha-tocopherol from its radical. On the other hand, vitamin C is a good eliminator of oxidants such asH2O2, O2.- y ·OH. It is a water-soluble vitamin so it is found in cytosol and extracellular fluids where it is oxidized by various oxidants to dehydroascorbate that protects lipid particles and membranes from potential oxidation. Dehydroascorbate is again reduced to ascorbate in a reaction involving reduced glutathione.14 In addition, the reduced form of coenzyme Q10, ubiquinol, is very effective as a lipid peroxyl radical scavenger and can also function as a regenerator of vitamin E oxidized.15 Uric acid can also eliminate free radicals, being a stabilizer of ascorbate. Glucose and pyruvate can also eliminate ·OH radicals, and according to some studies, coenzyme NADPH and carnitine can also reduce oxidative stress.14 In this way we could constitute as markers of marked oxidative stress a decrease in vitamin C, vitamin E, Q10 and serum carnitine.  In fact, in HIV a decrease in carnitine levels16 and a possible therapeutic route associating retrovirals with carnitine have been visualized, obtaining better CD4 counts.

ROLE OF CYSTEINE AND GLUTAMINE
Low levels of cysteine and glutamine have been found in patients with sepsis, major surgery, liver cancer, Crohn’s disease, ulcerative colitis and chronic fatigue syndrome. Both in sepsis, major surgery, HIV … can be observed a high production of urea with negative nitrogen balance, low levels of cysteine and glutamine, with elevated levels of glutamate and loss of skeletal muscle mass. This also occurs in high-performance athletes. Studies show abnormally low levels of glutamine in high-performance athletes, high levels of urea production, impaired immune functions, and an increased incidence of opportunistic infections.17

While weight loss in starvation affects virtually all organs including heart, spleen, and liver, cachexia present in cancer and sepsis has been shown to primarily affect skeletal muscle tissue to save on heart, spleen, and liver.

Given the high glucose consumption in the cells with Warburg effect blood glucose is decreased. This is a stimulus for glucagon and the liver begins to perform glycogenolysis and gluconeogenesis from lactate, amino acids such as alanine and glutamine present in muscles and from glycerol, resulting from triglycerides of adipose tissue.

Triglycerides in adipose tissue are degraded by a lipase to fatty acids and glycerol. The fatty acids have to be transported by the albumin and the glycerol goes to the liver to perform gluconeogenesis. The glycerol is phosphorylates and oxidizes to dihydroxyacetone phosphate and isomerized to glyceraldehyde 3 phosphate, intermediary of the gluconeogenic pathway.  The fatty acid in the cytosol is activated by acyl-CoA synthetase + ATP and is formed acyl-CoA and AMP. Small fatty acids can pass into the mitochondria directly, but long ones need carnitine. The acyl group is transferred to the carnitine formane acylcarnitine (catalyzed by carnitine acyltransferase I) which is in the mitochondrial outer membrane. Acylcarnitine transfers the acyl to a coA in a reaction catalyzed by carnitine acyltransferase II and the translocase returns the carnitine to the cytosolic by exchanging it for another acyl-Carnitine. Betaoxidation occurs in the mitochondria and this ATP is used for gluconeogenesis.

The muscle can degrade proteins to get fuel. The NH4 groups coming from its degradation, thanks to aminotransferases are transformed into glutamate. Glutamate transfers its amino group to pyruvate, from glycolysis, to form alanine and restore alpha-ketoglutarate thanks to alanine aminotransferase. The formation of alanine serves to transport non-toxic amino groups in blood to the liver, this is the so-called glucose-alanine cycle.

Another option for the transport of amino groups would be the formation of glutamine from glutamate by glutamine synthetase. Both glutamine (this part glutamine could be captured by infected or cancerous cells to replace the intermediates of their Krebs cycle) and alanine pass into the bloodstream until they are captured by the liver. Once alanine enters the liver it passes its amino group to an alpha-ketogluterate by alanine aminotransferase, to form pyruvate and glutamate. This pyruvate in the liver is used to produce glucose (gluconeogenesis).

In mitochondria, the enzyme glutamate dehydrogenase releases ammonia and alpha ketoglutarate (used in the citric acid/gluconeogenesis cycle) from glutamate. Ammonia would pass into the urea cycle.

Glutamine would be degraded to glutamate by glutaminase in hepatocyte mitochondria, releasing ammonia that would go into the urea cycle as well.

This may explain why CFS patients with high severity have high levels of glutamate and urea production along with low levels of glutamine and destruction of muscle mass.

The decrease in cysteine levels could be justified by the high oxidative stress of the infected cells, as this amino acid is the speed-limiter for generating glutathione. As the production of ROS is increased in cells with warburg effect, the formation of glutathione is constantly needed. A specific transporter (Xc) is needed to introduce the plasma into the cell.18,19Considering the low cystine content inside the cells, the physiological direction of this exchange consists in the exit of glutamate to favour the entry of cystine, which is rapidly reduced to cysteine. This increase of glutamate at serum level could be reused in the liver, exchanged again for cysteine and used for the formation of NAG (n-acetyl glutamate) from glutamate and coA by NAG synthase. NAG is an essential cofactor for the activation of carbamoyl phosphate synthase and therefore of hepatic ureagenesis. At the same time the infected cells capture glutamine to restore the glutamate lost in the exchange.

KETONE BODIES
Acetyl-CoA formed in the oxidation of fatty acids only enters the citric acid cycle if the degradation of fats and carbohydrates is adequately balanced. Entry into the acetyl-CoA cycle depends on the availability of oxalacetate, which will be diminished if there are no carbohydrates or these are not used properly (if there is not enough pyruvate generated by glycolysis, oxalacetate cannot be generated by pyruvate carboxylase). In situations of starvation or diabetes, oxalacetate is consumed in glucose formation (gluconeogenesis) and therefore is not available to condense with acetyl-CoA. Under these conditions excess acetyl-CoA is diverted to form acetate and D-3-hydroxybutyrate. Acetate and 3-hydroxybutyrate are normal fuels in aerobic metabolism. The brain adapts in fasting conditions or diabetes to the use of acetacetate as fuel. In prolonged fasting, acetate can provide up to 75% of the brain’s energy needs.

During prolonged fasting or in this case due to the consumption of glucose by the infected cells, there is a change in the use of fuels. Tissues use less glucose than during a short fast and predominantly use fuels derived from the metabolization of adipose tissue TAGs (i.e. fatty acids and ketone bodies). As a result, blood glucose does not drop dramatically and CFS patients experience cachexia with loss of muscle mass and fat.

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