Based on the author’s clinical experience with patients in fatiguing states and the available science, the following paper outlines an approach to supporting cellular and mitochondrial function in patients with fatigue. The goal is to present both an evidence- and practice-based format for restoring cellular health.

It should be noted that many whole person therapies crucial to the treatment of fatigue, while not discussed in this review are assumed to be known and practiced concurrently. These include but are not limited to endocrine support, immune and infectious therapies, sleep hygiene and therapies, digestive support and diet therapy as well as many others.

Basis of the Disorders

Much has been published regarding the potential causes of fatigue. Most clinicians agree these causes to be multifactorial and patient specific. Potential partial causes or aggravations of fatigue states include hippocampal dysfunction,¹ neurotransmitter imbalance and autoimmunity,^2,3 lifestyle and physical activity deficits,⁴ oxidative stress and mitochondrial dysfunction,^5-14 methyl cycle defects,¹⁵ seasonal affective disorder,¹⁶ anemia,¹⁷ and many others.

In this review I will focus on cell health and the recovery of the internal and external cellular balance and function in service of fatigue recovery. This has been clinically the most efficacious therapy approach (when the above multifactorial issues have been assessed) regardless of the cause of the fatigue. I will focus on the support of oxidation-reduction (ReDox) reactions and mitochondrial health. I always attempt to work with ReDox first and then mitochondrial health; with improved mitochondrial health, the cell can start to operate faster, dump toxins and put stress on the ReDox system overall. I have seen this be a potential cause for poor reactions to mitochondrial therapies (even when it appears that mitochondrial therapies are most needed). In a fragile patient I may work on ReDox for one to four weeks before mitochondrial therapies. In more robust/higher vitality patients, I will address these two areas concurrently but still may start slower on the mitochondrial aspects of therapy.

ReDox Balance and Support Naturally Occurring in the Human

The overall ReDox state is governed by the interplay between fat-soluble (cell and mitochondrial membranes, lipid molecules such as cholesterol etc.) and water-soluble (plasma, cytosol, mitochondrial) compartments. The base of ReDox balance is tocopherols, balanced omega fats and triglyceride molecules (phosphatidyl choline, serine etc.) for lipid membranes and glutathione and ascorbate activity for the water-soluble compartments. Of note, in support of the idea of ReDox therapies before mitochondrial therapies, overall extracellular and cytosolic ReDox supports mitochondrial ReDox and stability.

Once the lipid membrane substrates (omega fats and triglycerides mentioned above) are in place and balanced, the overall ReDox state can be maintained by ascorbate, glutathione, and the tocopherols. Omega oils, arachadonate (or precursors) and triglycerides (such as phosphatidylcholine) and its relatives should be targeted first in the diet for ReDox system balance. Then supplemental additions can be added, using the variable dose strategy at the end of the article.

Glutathione can be administered parenterally or as an oral liposome as well as supported by lipoic acid, l-glutamine and N-acetyl-cysteine as precursors. Additionally, the cycling and support of glutathione requires specific nutrients, without which glutathione activity decreases. These include magnesium, selenium, zinc, and vitamins B-2, B-3 and B-5.^18-24

Rationale for Specific Mitochondrial Therapies

Oxidative phosphorylation is the process in which ATP is formed as a result of the transfer of electrons from NADH or FADH 2 to O2 by a series of electron carriers. In the more global nutrient substrate sense, NADH and FADH2 may be formed in glycolysis, fatty acid oxidation, and the citric acid cycle. When these substrates donate electrons to the process, they reduce molecular oxygen to water, a large amount of free energy is liberated, which can be used to generate ATP. This process, which takes place in mitochondria, is the major source of ATP production.²⁵

Consider the use of carnitine first as the fat substrates from food that provide the highest energy (via beta-oxidation) use carnitine transport. Carnitines are involved in mitochondrial transport of fatty acids and are of critical importance for maintaining normal mitochondrial function.²⁶ Supplementation of an antioxidant, acetyl-L-carnitine, completely or partially restored modulated gene expression levels in mitochondrial complex I, IV and V. It further reduced mitochondrial apoptosis and oxidative damage in an animal model.²⁷

Coenzyme Q10 (CoQ10) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant.²⁸ Electrons are carried from NADH-Q oxidoreductase by the reduced form of CoQ (also known as ubiquinone). Ubiquinone also carries electrons from FADH2.²⁹

Iron is also necessary. Ortancil et.al include a statement that significantly correlates with the author’s clinical experience with fatigue in general as well as fibromyalgia (FMS) “Our study implicates a possible association between FMS and decreased ferritin level, even for ferritin in normal ranges.”¹⁷ Most commonly, oral repletion of iron stores via diet and supplement interventions is preferred. In the author’s experience, in those with the other mentioned comorbidities and low ferritin of over five years duration injectable iron may be required. Clinical experience and the study by Ortancil indicate that a ferritin level over 40 (and ideally 50-75) is required to replete the mitochondrial iron reserves as well as hematologic requirements. All primary targets of iron stores (mitochondrial,²⁵ neurochemical and hematologic) contribute significantly when iron stores are low.

Regarding iron supplementation, if used appropriately, parenteral forms can raise ferritin and iron status faster than any oral repletion can, and clinically are associated with faster positive outcomes in low ferritin patients. Use caution with oral iron repletion in patients with active GI infections and significant dysbiosis.

The amino acid proline is an often overlooked mitochondrial component. It is actually similar to the crucial role CoQ-10 has. Although there are many papers on proline in mitochondria, an animal study by Hancock et.al outlines proline’s crucial role:

Proline dehydrogenase/oxidase (PRODH/POX) is a mitochondrial protein critical to multiple stress pathways. Because of the roles of PRODH/POX in signaling, and its shared localization to the mitochondrial inner membrane with the electron transport chain (ETC)…Our results suggest a potential regulatory loop between PRODH/POX and succinate in regulation of mitochondrial respiration.³⁰

Mitochondrial Effectors

The ionic mitochondrial cofactors calcium, magnesium, potassium, zinc, copper and chromium are well known in basic science data. They are of note, as all ionic cofactors are, in that they typically complete a cofactor with a paired inorganic portion (typically a B vitamin).

With the high affinity of mitochondria for many mineral (metal) and chemical substances, it is no surprise that the mitochondria are a trap for many toxic influences as well.

Many heavy metals affect mitochondrial function. Cadmium is actually one of the most potent mitochondrial poisons known. In a human cell model Mao et.al describes the mechanism:

We found that Cd could directly increase in permeability and decrease in membrane potential of mitochondria, even resulted in mitochondrial swelling, and that Cd could inhibit the activities of ATPase, lactate dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), enhanced the levels of reactive oxygen species (ROS) and lipid peroxidation (LPO).³¹

Many chemicals can slow or block mitochondrial function via direct or indirect inhibition of oxidative phosphorylation. These include barbituric acid, many phenols, ethanol, and a number of pesticides to name a few.

The Lipoic Acid-Based Thiols

Alpha lipoic acid (ALA) is a thiol and as such is known in basic science to support levels of glutathione in the liver and other tissues. In experimental models,^32,33 ALA has been shown to be helpful in pushing the redox balance in a positive direction via modulation of inflammatory cytokines such as tumor necrosis factor and NF-kappa-b. Other data provide multiple other mechanisms for ALA in mitochondrial function.^34,35

Lipoic acid mineral complex (LAMC), known as the proprietary formula “Poly MVA” in North America, has shown to be helpful in cell repair, mitochondrial repair and radioprotection.^36-39 Like ALA, LAMC does take time to work so most patients are advised that either therapy (like all others) may need to be continued for a number of months for a positive effect to be noted.

Of specific note in mitochondrial support and repair, a paper by Sudheesh et.al showed mitochondrial support and repair in the most mitochondrial dense tissue, the myocardium:

The formulation significantly (p < 0.05) enhanced the activity of CAT and GPx compared to the aged control. The level of GSH was also significantly improved and the level of lipid peroxidation was decreased significantly (p < 0.05) by POLY-MVA. The results indicate that POLY-MVA is effective to protect the age linked decline of myocardial mitochondrial antioxidant status. The findings suggest the use of this formulation against myocardial aging.⁴⁰

Therapeutic Strategies and Examples

Variable dosing strategy. A model using intake and supplement dosing, equivalent to need, includes lower supplemental dosing when in a healthy and preventive state, progressively elevated doses for a time in repletion or disease states, and lower maintenance doses when balance is restored. The pattern the author uses clinically is a “test dose” (to assess the sensitivity of the patient to the agent) followed by an escalating therapeutic dose (used for the duration of the active repair process) followed by either discontinuation of the agent or the use of a maintenance dose to augment diet. In the doses below the range from low to high reflects this three-tiered process. [Agents with an asterisk (*) are used only if clinically indicated, and doses are expressed as total daily intake, which may be in divided doses. As supplements vary in dose, these are approximate total oral doses.] For IV/parenteral therapy doses please see the Townsend Letter article I authored November 2014.⁴¹

ReDox Support

• Omega-3 oils* 500 IU to 3000 IU, dosed with food
• Phosphatidyl choline 500 to 3000 mg, dosed with food
• Mixed tocopherols 200 IU to 400 IU
  • (Or a tocopherol/tocotrienol combination 40 IU-100 mg to 120 IU-300 mg)

• Vitamin C 1000 to 4000 mg
• Liposomal glutathione 200 to 800 mg
  • (Or ALA 300 to 600 mg)

Mitochondrial Support

• Consider metal and chemical toxicity especially in recalcitrant cases
  • Curcumin 100 to 1000 mg per day can help both metals and chemicals leave the mitochondria.^42-44
  • Consider heavy metal testing and treatment.

• Acetyl-l-carnitine 500 to 2500 mg
  • L-Carnitine 2000 to 4000 mg

• NADH Lozenge ([25mg] / CoQ-10 [50mg]) *I use Seeking Health lozenges 1 to 4 daily
• A B-complex with riboflavin-5-phosphate content of 25 to 150 mg
• A multi-mineral supplement
• Proline (or a multi-amino supplement with this level) 500 to 2000 mg
• PolyMVA 5 mL to 30 mL
• Iron only if indicated as mentioned above. If using an oral product, I prefer one of the “hematinic complexes” available from many supplement companies.

Treatment time can vary greatly due to many factors. These include the comorbidities mentioned at the beginning of this paper, length of illness, status of digestive tract and others. In my experience for most fatigued patients a range of three months to two years may be required depending on these factors.

References

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6. Ibid.

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