Oxaloacetate CFS Potential Mechanisms of Action

Oxaloacetate CFS

Potential Mechanisms of Action

Metabolic changes seen in ME/CFS

Various metabolic mechanisms are turned on by damage to the body, and these ongoing metabolic changes can cause lasting fatigue if they are not reprogrammed back to the original normal metabolic state. Naviaux et al. suggests that these changes are characteristic of the “Dauer” state due to the “cell danger response”. [1] One such metabolic change is the increase in glycolysis in the cytoplasm of the cell. This shift in metabolism was first described by Otto Warburg in the 1930’s and has been named the “Warburg Effect”. Warburg described the metabolic energy shift in relation to cancer cells, and indeed, almost all cancers exhibit this change in energy metabolism. Otto Warburg thought that once the cell changed to this different energy production method, it could not change back into a normal cell. This energy pathway change can lead to pathological fatigue.[2]

The Warburg Effect is not only present in cancer cells but is seen in adaptive immune cells of myeloid and lymphoid lineage, characterized by a shift to aerobic glycolysis. [3]The Warburg Effect is present in the replication of viruses such as MERS-CoV and SARS-CoV-2. [4]Clinical work in ME/CFS patients shows this change to Warburg Effect metabolism, thus generating most of the energy currency, ATP, from non-mitochondrial sources.[5]

Another metabolic change seen in fatigued patients is the decrease in the NAD + /NADH in the cytoplasm.[6] NAD + levels in the cell act as a signaling molecule to drive certain metabolic states. In humans, NAD + levels decrease with muscle use. As an example of this, Graham et. al (1978) found that muscle NAD + levels are decreased with exercise at 65% and 100% of maximal oxygen uptake (V̇o2 max), and although increased muscle water accounted for ∼73% of this decrease, NAD + levels were still reduced when assessed on a dry weight basis.[7] NADH levels also increase,[8] which further drives down the NAD + /NADH ratio. In contrast with normal patients, Sweetman et. al. (2020) calculated that NADH levels are higher in peripheral blood mononuclear cells in patients with ME/CFS.[9]

Yet another metabolic change that takes place in response to cellular stress/damage is the translocation of the protein complex NF-kB from the cytoplasm to the nuclear compartment. While this response is critical for keeping us healthy, in some persons the response does not shut-off, such as in COVID-19 patients with Long-Haul symptoms, and the energy of the cell is continually tied up in immune response.[10] This inflammation pathway change to a chronic state can lead to on-going fatigue and is seen in the diseases that have fatigue as a common determinant.[11-13]

Mitochondria are organelles that produce most of the energy during normal cell function. Increased energy demands to fight infection and repair tissues can increase the production of reactive oxygen species (ROS) within the mitochondria, damaging mitochondrial function. Mitochondrial malfunction is implicated in ME/CFS patients.[14]

Another metabolic change that takes place in response to cellular stress/damage is reduced activation of the AMPK protein, and a resulting reduction in glucose uptake by tissues. This is seen directly in cells from ME/CFS patients.[15] Reductions in the glucose fuel available to power the cell can be a direct source of fatigue.

Fisicaro et al. identify that ME/CFS patients and Long COVID patients share neuropathophysiological changes that enhance the production of damaging reactive oxygen species, probably from the host response to the initial infection [16] (Table 1).

Metabolic change Effect on ME/CFS patient Normalization by oxaloacetate
Warburg Effect Increased lactate production Reduction in lactate production via inhibition of lactate dehydrogenase in the cytosol
Decrease in NAD+/NADH ratio Increase ROS production Reset of NAD+/NADH ratio and quenching of ROS by antioxidant Oxaloacetate
Increased NF-kB movement to nucleus Activation of chronic inflammation Reset of inflammation pathway to normal by Lowering NF-kB translocation to nucleus
Mitochondrial damage Reduced ability to process glucose Increased number of mitochondria to produce energy via PGC1-alpha increase
Reduced AMPK activation Reduced cellular glucose uptake Increase in glucose uptake via AMPK activation and more glucose fuel available for the patient
Increased neurological ROS production Damage from free radicals Oxaloacetate is a highly effective antioxidant

These six changes in metabolism seen in ME/CFS patients are different from what is seen in normal controls with physiological fatigue.

Normalization of Metabolism by Oxaloacetate

Aberrant energy production via increased glycolysis in the “Warburg Effect”

Cells from persons with ME/CFS show aberrant energy production, wherein more energy is produced within the cytoplasm via increased glycolysis and fermentation.[5] Oxaloacetate has been shown to reverse this trend in human cancer cells, reducing both glycolysis and the formation of lactate.[17] The “Warburg Effect” refers to a form of modified cellular metabolism, which tend to use specialized fermentation of pyruvate to lactate in the cytoplasm over the aerobic respiration pathway that burns pyruvate in the mitochondria that is used by most cells in the body under non-pathological conditions. Chronic Fatigue Syndrome patients have been shown to have activated this alternative energy pathway, increasing the amount of energy that is produced by glycolysis in the cytosol that continues after their pathological incident has passed.[5,18]

Cells from patients with fatigue show significantly lower NAD + /NADH ratio levels

Oxaloacetate increases the NAD + /NADH ratio in animal models [19, 20] which would push this ratio in ME/CFS patients towards normalization. When oxaloacetate enters the cell, it can react to the metabolite “malate” in the cytoplasm via the action of the ubiquitous enzyme malate dehydrogenase. As part of this reaction, NADH is turned into NAD + , boosting the NAD + /NADH ratio. Krebs measured the change in the NAD + /NADH ratio with supplemental oxaloacetate as a 900% increase within 2 min.[21]

NF-kB inflammation reduction

Cells from persons with ME/CFS show increased activation of NF-kB leading to persistently elevated levels of inflammatory proteins.[13] This inflammation pathway change can lead to on-going fatigue and is seen in the diseases that have fatigue as a common determinant.[11-13] Oxaloacetate has been shown to reduce the activation of NF-kB by up to 70% in animal models.[19] The reduction in NF-kB overactivation may lead to significant reductions in chronic inflammation and fatigue.

Mitochondrial damage is prevalent in fatigued patients [22]

In normal cells, the mitochondria are the “powerplants” of the cells. Oxaloacetate upregulates PGC-1alpha, which in turn activates mitochondrial biogenesis, leading to increased mitochondrial density.[23] Having more powerplants to burn glucose, and replace defective mitochondria, may be a major factor in reducing fatigue.

AMPK activation reduction

Cells from persons with disabling fatigue show an impaired AMPK activation, and impaired stimulation of glucose uptake.[15,24] AMPK is an energy sensing protein, which is activated during energy shortages in normal cells. Failure to activate AMPK will result in a reduction in glucose uptake by tissues. The reduced fuel available to the cell can be a direct source of fatigue. Oxaloacetate has been shown to increase glucose uptake in trials with diabetic patients and Alzheimer’s patients [25, 26] providing a mechanism to increase the amount of fuel available for cellular functions.

ROS reduction

Oxaloacetate is a powerful antioxidant, reducing both thiobarbituric acid and hydrogen peroxide in the brain.[27,28] Oxaloacetate also protects mitochondrial DNA from damage from agents such as Kainic acid.[29]

These six metabolic changes in ME/CFS and other fatigue patients may be the driving force of fatigue. Normalization of these metabolic changes by oxaloacetate may restore a non-fatigue state.

References

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