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Can Mitochondrial Cofactors Alleviate Fatigue?

Can Mitochondrial Cofactors Alleviate Fatigue?

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The link between targeted nutrients and energy production

Fatigue can be a drain on one’s life, and many people suffer from it on a daily basis. Fatigue is often described by patients as a lack of energy, mental or physical tiredness, diminished endurance, and the need for prolonged recovery after physical activity.[1],[2]

Of course, fatigue is common after a bout of strenuous exercise, and in people who don’t get enough sleep. This type of fatigue usually resolves after sufficient rest.[3]

However, fatigue that goes on for a long time is not normal. Persistent fatigue can result from nutrient deficiencies, stress, inflammation, menopause, and other hormonal changes.[1],[4] If you often feel tired, despite getting a full night’s sleep, it may be time to consider the cause.

Fatigue is a byproduct of nearly every disease process, including viral and bacterial infections.[5],[6] For example, Lyme disease – an infection caused by a tick bite – is notorious for its association with fatigue, along with joint and muscle pain.[7],[8]

Fortunately, scientists are beginning to get a handle on fatigue by studying mitochondria, the energy powerhouses within cells.[9] The mitochondria are responsible for producing adenosine triphosphate (ATP), a molecule that contains high-energy bonds for use in biochemical reactions throughout the body.[1]

The production of ATP requires many different enzymes and cofactors, including Coenzyme Q10, NADH, L-carnitine, pyridoxal phosphate and magnesium.[2],[9]

While all these nutrients can be found in food, their levels in tissues tend to decline as energy demands go up. Growing evidence suggests that supplementation with one or more of these nutrients may help boost mitochondrial efficiency and reduce fatigue.

The link between mitochondrial function and chronic fatigue

Supplementation can increase ATP levels, reduce fatigue, and even improve one’s overall quality of life.

Much of the evidence comes from studies of chronic fatigue syndrome (CFS), a condition characterized by severe fatigue lasting longer than six months that is not relieved by sleep.[10],[11] The symptoms of CFS also include pain, mental fogginess, and insomnia. The clinical diagnosis of CFS can be made only if other disease processes have been ruled out.[12]

A biochemical evaluation of 138 patients with CFS revealed that the subjects all had measurable dysfunctions in one or more mitochondrial pathways.[13] Additional studies have shown that patients with CFS have deficient ATP production.[9],[14],[15] As a result, cells from CFS patients are unable to fulfill their cellular energy needs, especially during periods of high metabolic demand such as exercise.[16]

Since the mitochondria depend on multiple vitamins, minerals and antioxidants to operate these pathways, researchers have begun looking at mitochondrial nutrients to evaluate their effects on energy production.[16],[17]

A variety of studies have indicated that supplementation can increase ATP levels, reduce fatigue and even improve one’s overall quality of life. Very interesting results have been obtained with Coenzyme Q10, NADH, L-carnitine, magnesium, and pyridoxal phosphate (vitamin B6), as discussed below.

Coenzyme Q10  

People suffering from fatigue are often found to have low serum CoQ10 levels.

Coenzyme Q10 (CoQ10) has bioenergetic and antioxidant properties that keep the mitochondria running smoothly.[18],[19] CoQ10 is also known by its scientific names: ubiquinone, ubidecarenone, or ubiquinol.

The main function of CoQ10 is to transfer electrons along the mitochondrial electron transport chain, culminating in the formation of ATP. Because of its essential role, CoQ10 deficiencies impair energy production in the heart, muscles, and brain.[19],[20],[21]

In the general population, CoQ10 deficiencies can occur as a result of environmental toxins, poor diet, oxidative stress (which depletes CoQ10), exercise, infections, and the aging process.[18],[22],[23],[24],[25] CoQ10 deficiency is also a secondary effect of cholesterol-lowering statin drugs.[26],[27]

People suffering from fatigue are often found to have low serum CoQ10 levels.[2],[16],[28],[29],[30] Clinical studies suggest that CoQ10 supplementation may ameliorate fatigue associated with CFS, multiple sclerosis, and fibromyalgia.[31],[32],[33] In healthy adults, CoQ10 has been shown to alleviate exercise-induced fatigue and improve physical performance.[34],[35],[36],[37]

Supplemental CoQ10 may also be helpful for adults suffering from work-related fatigue.[38] In a randomized, double-blind, placebo-controlled trial, nurses with significant work-related fatigue were randomly assigned to either 200 mg CoQ10 daily or a placebo.[38] After four weeks of daily supplementation, a significant improvement in fatigue and sleep quality was found in the CoQ10 group as compared to the placebo group.

Nicotinamide adenine dinucleotide (NADH)

NADH and CoQ10, along with a membrane lipid formulation, significantly reduced fatigue in chronic Lyme disease patients.

Nicotinamide adenine dinucleotide (NADH) is a bioactive derivative of niacin (vitamin B3). Within the mitochondria, NADH serves an electron carrier for the ultimate production of ATP.[39],[40] It also serves as a cofactor for enzymes that recycle CoQ10, helping to keep CoQ10 in its active (ubiquinol) form.[41],[42] Cellular levels of both nicotinamide adenine dinucleotide and CoQ10 decline with age.[43],[44]

Individuals with CFS often have low NADH levels.[45],[46] In studies of identical twins, where one of the twin pair was diagnosed with CFS and the other was not, the metabolism of NADH was closely associated with the development of fatigue.[47]

In several clinical studies, individuals with CFS were asked to rate the extent to which fatigue had interfered with certain aspects of their day-to-day functioning.[48],[49],[50] Those who took NADH (20 mg per day) along with CoQ10 (200 mg per day) reported improvements in physical functioning and mental clarity after eight weeks. The supplemented groups were found to have higher levels of ATP in their blood cells,[48] and reported significantly less fatigue as compared to the placebo groups.[48],[49],[50]

Mitochondrial dysfunction has also been seen in individuals with Lyme disease.[51] In a pilot study, supplementation with NADH and CoQ10, along with a membrane lipid formulation, significantly reduced intractable fatigue in chronic Lyme disease patients.[52]


Individuals receiving carnitine reported greater subjective energy levels compared to placebo groups.

Acetyl-L-carnitine is a short-chain ester of L-carnitine, an amino acid derivative that is naturally produced in the body and is also found in food. Various conditions may increase the body’s carnitine needs, leading to a shortfall in this nutrient.[53]

Carnitine is indispensable for energy production, since it enables activated fatty acids to enter the mitochondria where they are broken down to form ATP.[54],[55],[56] Low carnitine levels impair the transport of fatty acids into the mitochondria, thereby reducing energy production.[51],[57] In some groups of Lyme disease patients experiencing fatigue and inflammation, acyl carnitine levels were only one-third of healthy control levels.[58]

In individuals with CFS, low blood and tissue carnitine levels often correlate with the presence of fatigue.[59],[60],[61],[62] Studies suggest that carnitine supplementation may improve exercise performance in healthy adults,[63] and it may alleviate fatigue in patients with CFS and other chronic conditions.[64],[65],[66],[67],[68],[69]

Mitochondrial dysfunction is a major contributor to age-related muscle decline and fatigue.[70],[71] Fortunately, carnitine supplementation may be helpful for older adults with fatigue and/or frailty.[61],[72] Individuals receiving carnitine reported greater subjective energy levels compared to placebo groups.


An adequate supply of PLP is particularly important for muscle health and repair.

Pyridoxal-5-phosphate (PLP) is a bioactive form of vitamin B6, a B-vitamin that serves as a cofactor for numerous biosynthetic enzymes.[73] PLP is critical for the synthesis of heme, the oxygen-binding component of hemoglobin, which supplies oxygen to every tissue in the body.[74]

An adequate supply of PLP is particularly important for muscle health and repair.[75],[76] PLP is needed for the synthesis of carnosine, a naturally occurring intramuscular dipeptide that is thought to attenuate fatigue during high-intensity exercise.[77],[78],[79]

A study of patients with CFS found that levels of a PLP-dependent enzyme (AST) were only 60% of normal, suggesting an association between low vitamin B6 status and fatigue.[80] Reduced levels of thiamine (vitamin B1)- and riboflavin (vitamin B2)-dependent enzymes were also seen, but to a lesser extent.

In older people, fatigue can make it difficult to carry out everyday chores, let alone exercise.[81] A 2021 study of older adults found that higher intakes of vitamin B6 were associated with a better ability to rise out of a chair (a standard test of muscle strength and frailty).[82] Also, greater B6 intakes were associated with improved handgrip strength in older adults with low physical activity levels.[82]

Marginal vitamin B6 deficiencies are also associated with depression in women, suggesting that higher intakes of vitamin B6 may help women achieve a more positive mood.[83],[84]


Various studies have shown a positive association between magnesium status and muscle performance.

Magnesium is an essential mineral with many functions. It stabilizes mitochondrial membranes and serves as a cofactor for enzymes involved in ATP production.[85],[86] Importantly, magnesium plays a pivotal role in the activity of F1Fo-ATP synthase, the enzyme that produces the bulk of cellular ATP.[87],[88]

A significant decline in serum magnesium concentrations has been seen in patients with CFS, multiple sclerosis, bacterial and viral infections, and many acute and chronic diseases.[89],[90],[91],[92],[93],[94]

Patients with CFS who were supplemented with magnesium reported enhanced energy levels, a better emotional state, and less pain.[95] Additionally, magnesium supplementation may alleviate muscle fatigue during exercise.[96],[97],[98] Various studies have shown a positive association between magnesium status and muscle performance, including measures such as grip strength, lower-leg power, and jumping performance.[97],[99]

In healthy elderly women, daily magnesium supplementation for twelve weeks improved hand grip strength and other indices of muscle health.[100],[101]

Magnesium also assists in the activation of vitamin D, which is important for muscle strength and function.[102],[103] Supplemental magnesium and vitamin D may help reduce the risk of frailty as we age.[104],[105] (Note: To keep muscles strong during aging it’s also important to get enough dietary protein and physical activity!)

Summing up

If you suffer from fatigue, be sure to consult a qualified health professional to rule out any underlying condition that might be causing the problem. Individuals who find that fatigue is interfering with their daily activities may want to consider supplementation with mitochondrial cofactors to see if they will help. Studies suggest that Coenzyme Q10, NADH, L-carnitine, pyridoxal phosphate and magnesium can improve mitochondrial function and reduce fatigue in many cases.

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