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Mitochondrial Dysfunctionand Chronic Disease: Treatment With Natural Supplements
Garth L.Nicolson, PhD
Loss of function in mitochondria,the key organelle responsible for cellular energy production, can result in theexcess fatigue and other symptoms that are common complaints in almost everychronic disease. At the molecular level, a reduction in mitochondrial functionoccurs as a result of the following changes: (1) a loss of maintenance of the electricaland chemical transmembrane potential of the inner mitochondrial membrane, (2)alterations in the function of the electron transport chain, or (3) a reductionin the transport of critical metabolites into mitochondria. In turn, thesechanges result in a reduced efficiency of oxidative phosphorylation and areduction in production of adenosine-5'-triphosphate (ATP). Several componentsof this system require routine replacement, and this need can be facilitatedwith natural supplements. Clinical trials have shown the utility of using oralreplacement supplements, such as L-carnitine, alpha-lipoic acid (a-lipoic acid [1,2-dithiolane-3-pentanoicacid]), coenzyme Q10 (CoQ10 [ubiquinone]), NADH (reduced nicotinamide adeninedinucleotide), membrane phospholipids, and other supplements. Combinations ofthese supplements can reduce significantly the fatigue and other symptomsassociated with chronic disease and can naturally restore mitochondrialfunction, even in long-term patients with intractable fatigue.
Garth L.Nicolson, PhD, is founder, president, and research professor in theDepartment of Molecular Pathology, The Institute for Molecular Medicine,Huntington Beach, California.
Corresponding author: Garth L. Nicolson, PhD
E-mail address: email@example.com
Mitochondrial dysfunction, characterized by a loss of efficiencyin the electron transport chain and reductions in the synthesis of high-energymolecules, such as adenosine-5'-triphosphate (ATP), is a characteristic ofaging, and essentially, of all chronic diseases.1-4 These diseasesinclude neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’sdisease, Huntington’s disease, amyotrophic lateral sclerosis, and Friedreich’sataxia1,2,4,5; cardiovascular diseases, such as atherosclerosis andother heart and vascular conditions6,7; diabetes and metabolicsyndrome8-10; autoimmune diseases, such as multiple sclerosis,systemic lupus erythematosus, and type 1 diabetes11-14;neurobehavioral and psychiatric diseases, such as autism spectrum disorders,schizophrenia, and bipolar and mood disorders14-16; gastrointestinaldisorders17,18; fatiguing illnesses, such as chronic fatiguesyndrome and Gulf War illnesses19-21; musculoskeletal diseases, suchas fibromyalgia and skeletal muscle hypertrophy/atrophy22-24; cancer25,26;and chronic infections.27,28
It is well known among researchers thatmitochondrial genetic or primary mitochondrial disorders contribute tomitochondrial dysfunction as well as secondary or acquired degenerativedisorders.29 This review will concentrate on nongenetic or acquiredmechanisms that could explain mitochondrial dysfunction and their replacementtreatment with natural supplements and combinations of natural supplements,including vitamins, minerals, enzyme cofactors, antioxidants, metabolites,transporters, membrane-type phospholipids, and other natural supplements.
Mitochondrial dysfunction arises from an inadequate numberof mitochondria, an inability to provide necessary substrates to mitochondria, or a dysfunction in their electron transport andATP-synthesis machinery. The number and functional status of mitochondria in acell can be changed by (1) fusion of partially dysfunctional mitochondria andmixing of their undamaged components to improve overall function, (2) thegeneration of entirely new mitochondria(fission), and (3) the removal and complete degradation of dysfunctionalmitochondria (mitophagy).30 These events are controlled by complexcellular processes that sense the deterioration of mitochondria, such as thedepolarization of mitochondrial membranes or the activation ofcertain transcription pathways.31,32
The ability of cells to produce almost all high-energymolecules like ATP is directly related to the ability of mitochondria to (1)convert the energy of metabolites to NADH (reduced nicotinamide adeninedinucleotide) and (2) transfer electrons from NADH to the electron transportchain and eventually to molecular oxygen while pumping s protons from themitochondrial matrix across the inner mitochondrial membrane to the intermembranespace. This process creates a transmembrane proton gradient (?p) and an electrochemicalgradient (?Ym) across the mitochondrial innermembrane.33,34 The transmembrane potential created by the protongradient then uses ATP synthase to flow protons back across the innermitochondrial membrane and employs the energy from this process to driveadenosine phosphorylation of diphosphate (ADP) to ATP.33-35
A consequence of the electron transport process is theproduction of reactive oxygen species (ROS), highly reactive free radicals thatare produced as a by-product of oxidative phosphorylation. The main sources ofROS and the related reactive nitrogen species (RNS) are mitochondria, and thesefree radicals can damage cellular lipids, proteins, and DNA.36-38 However,some mechanisms can neutralize ROS/RNS; dismutase enzymes and antioxidants cancontrol excess amounts of ROS/RNS.39,40 In addition to creation ofROS/RNS, the electron transport process can induce uncoupling proteins,resulting in a controlled leak of protons back across the proton gradient ofthe inner mitochondrial membrane into the mitochondrial matrix.33,34 This leak results in reduced ATP production while it still consumes excessoxygen.40
In the presence of a controlled proton leak, excess oxygenconsumption and the resulting ROS production can result in inappropriate damageto mitochondrial membrane lipids,38,39 such as the veryROS/RNS-sensitive cardiolipin, an inner mitochondrial phospholipid.41 Oxidative damage to the cardiolipin and other membrane phospholipids in theinner mitochondrial membrane can result inincreased proton and ion leakage back across the inner membrane into themitochondrial matrix and partial loss of the electrochemical gradient.Cardiolipin is also an important component of the electron transport chain,providing stability for the cytochrome/enzyme complexes in the innermitochondrial membrane.41 Once adverselydamaged by ROS/RNS, oxidized cardiolipin instigates loss of electron-transportfunction.42
Cellular antioxidant defenses usually maintain ROS/RNSlevels at concentrations that prevent excess oxidation of cellular molecules.43-45 Cellular antioxidant defenses that are endogenous are mediated by glutathioneperoxidase, catalase, and superoxide dismutase, among other enzymes.45,46 Also, some dietary antioxidants with a low molecular weight can affectantioxidant status.47,48 Some of these dietary antioxidants havebeen used as natural preventive agents to shift the excess concentrations ofoxidative molecules down to physiological levels that can be maintained byendogenous antioxidant systems.49
MITOCHONDRIALDYSFUNCTION AND FATIGUE
Mitochondrial dysfunction is directly related to excessfatigue. Fatigue is considered a multidimensional sensation that is perceived tobe a loss of overall energy and an inability to perform even simple taskswithout exertion.50,51 Although mild fatigue can be caused by anumber of conditions, including depression and other psychological conditions,moderate to severe fatigue involves cellular energy systems.50,51 Atthe cellular level, moderate to severe fatigue is related to loss ofmitochondrial function and diminished production of ATP.51-53 Intractable fatigue lasting more than 6 months that is not reversed by sleep(chronic fatigue) is the most common complaint of patients seeking generalmedical care.50,54 Chronic fatigue is also an important secondarycondition in many clinical diagnoses, often preceding patients’ primarydiagnoses.54,55
As a result of aging and chronic diseases, oxidative damageto mitochondrial membranes impairs mitochondrial function.56-58 Asan example, individuals with chronic fatigue syndrome present with evidence ofoxidative damage to DNA and lipids,58,59 such as oxidized bloodmarkers60 and oxidized membrane lipids,61 that isindicative of excess oxidative stress. These individuals also have sustained,elevated levels of peroxynitrite due to excess nitric oxide, which can alsoresult in lipid peroxidation and loss of mitochondrial function as well aschanges in cytokine levels that exert a positive feedback on nitric oxideproduction.62
NATURALSUPPLEMENTS AND MITOCHONDRIAL DYSFUNCTION
A number of natural supplements have been used to treatnonpsychological fatigue and mitochondrial dysfunction.29,51,63 Thesesupplements include those containing vitamins, minerals, antioxidants,metabolites, enzyme inhibitors and cofactors, mitochondrial transporters,herbs, and membrane phospholipids (Table 1).29 Although severalnatural supplements have been used to reduce fatigue, few are considered trulyeffective.64 This article will discuss some of the most promisingsupplements and conclude with combinations of specific supplements that havebeen used to treat intractable chronic fatigue and improve mitochondrial function.
Table1. An Incomplete List of Ingredients/Agents That Medical Practitioners Have Used or Suggested for Treatment of Mitochondrial Dysfunctiona
Abbreviations: NADH = reducednicotinamide adenine dinucleotide; CoQ10 = coenzymeQ10 (ubiquinone); a-lipoic acid = alpha-lipoicacid.
aModified from Kerr.29
Alpha-lipoic acid (a-lipoic acid [1,2-dithiolane-3-pentanoicacid]) is a potent antioxidant, transition metal-ion chelator, redoxtranscription regulator, and anti-inflammatory agent.65 It acts as acritical cofactor in mitochondrial, a-ketoacid dehydrogenases, and thus, it is important in mitochondrial,oxidative-decarboxylation reactions.66,67 Clinically, a-lipoic acid has been used as an oralsupplement in the treatment of complications associated with diabetes mellitus,and according to a review by Shay et al,67 it has been shown tobring about improvements in various diabetes-associated neuropathies,inflammation, and vascular health. In model cellular systems, these effectshave been attributed mainly to a-lipoicacid having signal-transduction effects on gene regulation and on glucoseuptake and metabolism as well as its antioxidant effects.68
As a result of aging and in many chronic diseases, certainsphingolipids—especially ceramides, and in particular, short-chainceramides—accumulate in mitochondria due to hydrolysis of sphingomyelin bysphingomyelinase, and eventually, this accumulation retards electron transportactivity.69,70 Ceramide accumulation in mitochondria is especiallydamaging to cardiac tissue. In aging rodents, a-lipoicacid has been used to lower ceramide levels in vascular endothelial cells ofcardiac muscle through inhibition of sphingomyelinase activity, resulting inrestoration of mitochondrial glutathione levels and increasing electron transportfunction.71
As mentioned above, in diabetes a-lipoic acid has been used extensively to reduce diabeticcomplications, such as sensorimotor polyneuropathies.72 One 4-year,blinded study demonstrated that some neuropathic impairments improved significantlyon a-lipoic acid (but not nerveconduction attributes), showing the antioxidant’s clinical utility and thesafety of long-term treatment with a-lipoicacid for diabetic patients.73
Given as an oral supplement, a-lipoicacid is rarely present in tissues above micromolar levels; thus, it is unlikelyto be directly involved as an important primary cellular antioxidant.67 However, its ability to increase cellular glutathione levels is an importantantioxidant property, and this increase is accomplished by regulatingglutathione synthesis and thus ameliorating oxidative stress.74 Thisantioxidant can affect the regulation of the nuclear transcription factor NF-kB, and thus, it can cause widespreadtranscriptional effects, resulting in the attenuation of production of freeradicals and cytotoxic cytokines.75
As a transition metal chelater, a-lipoic acid can remove excess copper, iron, and other metalsthat are involved in chronic diseases, such as hemochromatosis, end-stage renalfailure, and Alzheimer’s and Parkinson’s diseases, and it is a potential therapeutic agent for prevention ormitigation of heavy metal poisoning.65 It also improves cognitivefunction as well as mitochondrial function, suggesting a link between oxidativedamage to mitochondria and cognition.76 The use of a-lipoic acid for chronic fatigue has not yetbeen studied in controlled clinical trials, but its widespread use as a safesupplement (usually 200-600 mg/d)67 to support mitochondrialfunction and reduce oxidative stress has justified its incorporation intovarious supplement mixtures.67,73,75
L-carnitine (3-hydroxy-4-N-trimethylaminobutyrate) is a naturallyoccurring fatty acid transporter found in all species of mammals. It isdirectly involved in the transport of fatty acids into the mitochondrial matrixfor subsequent b-oxidation, but it alsofunctions in removal of excess acyl groups from the body and in the modulationof intracellular coenzyme A (CoA) homeostatasis.77,78 Because of itsimportance in fatty acid oxidation and CoA and acyl-CoA homeostatasis,L-carnitine is usually maintained within relatively narrow concentrationlimits; thus, dietary supplementation is important to maintain optionalL-carnitine concentrations within cells.78 Indeed, L-carnitinedeficiency disorders are associated with reduced mitochondrial function,insulin resistance, and coronary artery disease.79-81
The important role of L-carnitine in mitochondrialmetabolism has spurred the use of L-carnitine supplements to potentiallyimprove physical performance.82 The rationale is that increasedreliance on fat as the principle substrate for energy production during extremeexercise should reduce the need for carbohydrates and delay the depletion ofcarbohydrate stores and that these changes should increase overall energyproduction and reduce exercise-induced fatigue. Transport of fatty acids intomitochondria also requires increased levels of L-carnitine, and thus, indicatesa need for dietary supplementation of L-carnitine. However, studies have shownthat increasing oral L-carnitine supplementation, even for 2 to 3 weeks priorto extreme exercise, did not increase carnitine content in skeletal muscle.Therefore, it is unlikely that this supplementation alters muscle metabolismduring extreme exercise.83,84
L-carnitine supplementation has been successfully used inclinical disorders that are characterized by low concentrations of L-carnitineor impaired fatty acid oxidation, such as diabetes, sepsis, renal disease, andcardiomyopathy.77 For example, in a small study of 18 individualswith congestive heart failure and 12 placebo controls, propionyl-L-carnitinesupplementation resulted in increased peak heart rate (mean of 12%), exercisecapacity (mean of 21%), and peak oxygen consumption (mean of 45%) in thetreatment group.85
An important antiaging use of L-carnitine has been toincrease the rate of mitochondrial, oxidative phosphorylation that naturallydeclines as a result of aging. This decline impairs energy production while itincreases production of ROS/RNS. Feeding old rats acetyl-L-carnitine was found to reverse age-related decreases in L-carnitinelevels while it increased fatty acid metabolism. It also reversed theage-related decline in cellular glutathione levels and improved the complex IVactivity of muscle mitochondria.86
Although dietary supplementation with L-carnitine and itsvarious derivatives appears to be safe (doses up to 2 g/d)87 and potentially useful in increasing mitochondrial function, researchers havenot performed the necessary multiple clinical trials to show its effectivenessin most age-related chronic illnesses (other than diabetes and cardiovasculardiseases). One exception was a randomized, controlled clinical trial on 70centenarians who were treated with L-carnitine for 6 months. These participantswere generally found to have muscle weakness, decreasing mental health,impaired mobility, and poor endurance. By the end of the study, the treatedgroup showed significant improvements in physical fatigue, mental fatigue, andfatigue severity. They also showed reductions in total fat mass, increasedmuscle mass, and an increased capacity for physical and cognitive activitythrough reduced fatigue and improved cognitive function.88 Other trials on alcoholism, hepatic encephalopathy, coronaryheart diseases, Peyronie’s disease, cerebral ischemia, and infertilityindicated that administration of L-carnitine can have positive effects on signsand symptoms of these conditions.87
Coenzyme Q10 (CoQ10 [ubiquinone]) is a key cofactor andcomponent of the mitochondrial electron transport chain and one of the mostwidely used natural supplements.29,89 It is also a strongantioxidant in its reduced form, and it can affect the expression of certaingenes involved in cell signaling, metabolism, and transport.89,90 However, the main role of CoQ10 is its involvement in the transfer of electronsalong the multiple complexes of the mitochondrial electron transport chain.89,91 Clinically, it has been used in doses up to 1200 mg per day, but most studies usedlower doses.89
Because CoQ10 is an important component of the mitochondrialoxidative phosphorylation system, its supplementation in individuals withreduced levels should result in increased energy production and reducedfatigue.89,91 A systematic review of theeffects of CoQ10 in physical exercise, hypertension, and heart failure byRosenfeldt et al92 revealed that sixout of 11 published studies showed modest improvements in exercise capacity inthe participants given dietary CoQ10. In eight of the studies, which examinedthe effects of CoQ10 on hypertension, a mean decrease occurred in bloodpressure: systolic, a mean decline of 16 mm Hg; and diastolic, a mean declineof 10 mm Hg. In the review, nine randomized trials that examined the use ofCoQ10 in participants with heart failure showed nonsignificant trends towardincreased injection fraction and reduced mortality. Rosenfeldt et al92 performed their own 3-month, randomized, placebo-controlled trial on theeffects of oral CoQ10 in 35 patients with heart failure and found thatparticipants in the CoQ10 arm, but not in the control arm, showed significantimprovements in symptoms.92 The study also showed a trend towardimprovements in mean exercise times.92
The effects of administration of oral CoQ10 during physicalexercise have also been examined. In a blinded, cross-over trial, 17 healthyparticipants received CoQ10 or a placebo for 8 days, and their performance wasthen evaluated twice at fixed workloads on a bicycle ergometer for 2 hours,with a 4-hour rest between the tests.93 The participants on CoQ10were able to achieve higher work outputs and had less fatigue sensations, andtheir need for a recovery period was alleviated compared to the placebo group.92
Clinically, CoQ10 has been used to reduce symptoms andprogression in various neurodegenerative diseases.89,91 In studiesusing Alzheimer’s disease models, CoQ10 administration significantly delayedbrain atrophy and typical b-amyloid-plaquepathology.94,95 In a randomized, placebo-controlled, 16-weekclinical trial on 98 Alzheimer’s participants who took an oral mixture ofCoQ10, vitamins C and E, and a-lipoicacid, the test arm showed significant reductions in oxidative-stress markersbut did not show significant changes in cerebrospinal fluid (CSF) markersrelated to b-amyloid or tau pathology.96
In Parkinson’s disease, individuals generally show increasedoxidized-to-total CoQ10 ratios as well as significant increases in markers ofoxidative damage in the CSF, which can bepartially reversed with CoQ10 administration.97 In individuals withearly Huntington’s disease, the Huntington Study Group’s trial showed thatCoQ10 administration for 30 months slowed the usual decline in total functionalcapacity, but the differences did not reach statistical significance.98 Finally, in a multicenter, placebo-controlled, phase II trial with amyotrophiclateral-sclerosis patients, CoQ10 did not significantly modify functionaldecline over a 9-month period,99 and Mathews et al100 didnot find CoQ10 plus several vitamins to be effective in individuals withgenetic mitochondrial diseases.
NADH functions as a cellular redox cofactor in over 200cellular redox reactions and as substrate for certain enzymes.101,102 Humans universally require NADH, and itsdeficiency results in pellagra, which is characterized by dermatitis, diarrhea,dementia, and eventually death.101 In the mitochondria, NADHdelivers electrons from metabolite hydrolysis to the electron transport chain,but in its reduced form, it can also act as a strong antioxidant. The usualroute of dietary supplementation has historically been via NADH precursors,such as niacin, nicotinic acid, or nicotinamide, but recently, microcarriershave been used to stabilize oral NADH so that it can be directly ingested insmall doses and absorbed in the gastrointestinal system. This supplementationturns out to be more effective than large oral doses of NADH, as in somestudies that used up to 50 mg/kg/day. At that size of dose, the NADH is proneto oxidation and degradation, and such supplementation is generally consideredto be ineffective.103
In neurodegenerative diseases, oxidative damage isextensive,1,2 and various mitochondrial antioxidants have been usedto treat disease and delay progression.1-6,29 In Alzheimer’sdisease, one study showed that stabilized oral NADH could improve cognitivefunctioning and dementia103; however, another clinical trial showedno evidence of improvements in cognition or dementia using oral NADH.104 In a controlled trial with 26 Alzheimer’s participants who were givenstabilized NADH or placebo for 6 months, Dermin et al found that that the testgroup had significantly better performance scores than the placebo group inverbal fluency and visual construction and showed a trend toward increasedperformance on abstract verbal reasoning.105 However, the studyprovided no evidence of better performance for measures of attention or memoryor on scores of dementia severity.
Stabilized, oral NADH has also been used to ameliorate thesymptoms of Parkinson’s disease. In a preliminary, open-label clinical trial,Birkmayer et al examined the effects of IV and oral NADH in over 800individuals with Parkinson’s disease.106 They found that 19.3% ofparticipants showed a 30% to 50% decrease in disability; 58.8% had moderate(10%-30%) improvement; and 21.8% did not respond to the therapy (P < .01). Younger patients with a shorterduration of disease had a much better chance of responding and showing moresignificant improvements than older patients or patients with a longer durationof disease. The oral form was comparable to IV NADH in its effects.106 When they repeated this type of trial, however, Dizdar et aldid not find statistically significant improvements in Parkinson’s diseaserating scores in participants treated with NADH, and differences were also notfound in CSF clinical markers associated with Parkinson’s disease severity.107
Stabilized, oral NADH has also been used to reduce symptomsin patients with chronic fatigue. One such study on individuals with chronicfatigue syndrome was designed to treat participants with stabilized, oral NADHor placebo for 4 weeks in a cross-over trial.108 Of theseparticipants, 8 of 26 (30.7%) responded positively to the microencapsulatedNADH compared with 2 of 26 (8%) in the placebo arm (P < .05).108 Clearly an effectoccurred but only in a subset of participants in the trial; thus, these resultswere not considered significant by others.109 A clinical trial thatcompared oral, stabilized NADH to psychological/nutritional therapy for 31individuals with chronic fatigue syndrome, revealed that stabilized NADH alonereduced fatigue in the first 4 months of a 12-month trial. After the first 4months, however, symptom scores were similar in the two arms of the trial.110 In another study, stabilized NADH was given orally for 2 months to treatindividuals with chronic fatigue syndrome.111 This treatmentresulted in decreases in anxiety and in maximum heart rate after a stress testbut found few or no differences in the functional impact on fatigue, quality oflife, sleep quality, exercise capacity, or functional reserve.111 Thus stabilized NADH alone has shown mixed results in various diseases anddisorders, and not every patient responded to the oral, stabilized supplement.
The dietary replacement of mitochondrial membranephospholipids (lipid replacement therapy [LRT]) using food-derived molecules toremove damaged, mainly oxidized, membrane lipids in mitochondria and othercellular organelles has proved very effective at increasing mitochondrialfunction and reducing fatigue.10,20,51,52 To some degree,antioxidant supplements can reduce ROS/RNS levels and prevent some oxidation ofmitochondrial membrane phospholipids, but antioxidants alone cannot repair thedamage already done to cells, and in particular, to cells’ mitochondrial innermembranes.26,52,112
The use of oral membranephospholipids plus antioxidants in doses ranging from 500 to 2000 mg per day has been effective in the treatment of certainclinical conditions, such as chronic fatigue and fatiguing illnesses.52,64,112,113,114 LRT results in the actual replacementof damaged membrane phospholipids with undamaged (unoxidized) lipids to ensureproper function of cellular and especially mitochondrial membranes.
Oral membrane phospholipids can increase mitochondrialfunction and decrease fatigue in chronic fatigue syndrome, fibromyalgiasyndrome, and other fatiguing conditions, including natural aging (Table 2).For example, a mixture of membrane phospholipids and vitamins (Propax with NTFactor) was used by Ellithorpe et al114 ina study on aging individuals with severe chronic fatigue and was found toreduce their fatigue by 40.5% in 8 weeks. In these studies, fatigue wasmonitored using the Piper Fatigue Scale (PFS) to measure clinical fatigue andquality of life.55 In a subsequent cross-over study, the effects ofmembrane phospholipids on fatigue and mitochondrial function in patients withmoderate-to-severe, chronic fatigue was initiated.52 Oraladministration of NT Factor for 12 weeks resulted in a 35.5% reduction infatigue and 26.8% increase in mitochondrial function, whereas after a 12-weekwashout period, fatigue increased and mitochondrial function decreased backtoward control levels.52 Similar findings on fatigue reduction wereobserved in individuals with chronic fatigue syndrome and fibromyalgia syndromewho were given oral membrane phospholipids (NT Factor).113 Using anew formulation of NT Factor plus vitamins, minerals, and other supplements inindividuals with moderate chronic fatigue resulted in a 36.8% reduction infatigue within 1 week (Table 2).115
Table 2. Oral Membrane Phospholipid Supplementation and Fatigue in Chronically IllPatientsa
Abbreviations: Avg = average.
aModified from Nicolson andSettineri.51
bP < .001 compared to no supplement.
cP < .000 compared to no supplement.
COMBINATIONORAL SUPPLEMENT TO REDUCE FATIGUE
In a 2-month trial of the treatment of long-term intractablefatigue in patients with a variety of diagnoses, the author and severalcolleagues combined membrane phospholipids (2000 mg/d), CoQ10 (35 mg/d),microencapsulated NADH (35 mg/d), L-carnitine (160 mg/d), a-ketoglutaric acid (180 mg/d), and othernutrients into an oral supplement (ATP Fuel) to treat fatigue and mitochondrialdysfunction.116,117 The 58 participants in this trial hadmoderate-to-severe, intractable fatigue for an average of >17 years and hadbeen to an average of >15 practitioners without resolution of their fatigue.The study included 30 individuals with chronic fatigue syndrome; 17 withchronic Lyme disease; 16 with otherfatiguing illnesses, including fibromyalgia syndrome and Gulf War illness; 4with autoimmune disease, including rheumatoid arthritis; 2 with cancer; and 2with diabetes. These patients had tried many drugs and supplements (average>35) to reduce their fatigue without success.
Participants in this trial took the combination LRTsupplement (ATP Fuel) for 8 weeks, and fatigue was scored using the PiperFatigue Scale (PFS).116 The PFS is a validated instrument thatmeasures four dimensions of subjective fatigue: behavioral/severity,affective/meaning, sensory, and cognitive/mood.55 The study used theinstrument to calculate the four subscale or dimensional scores and the totalfatigue scores. Participants had initial, total, mean PFS fatiguescores of 7.51 ± 0.29, and after 8 weeks of supplements,the mean scores improved to 5.21 ± 0.28, or a 30.7% reduction in fatigue (t test, P < .0001 and Wilcoxon signed rank, P < .0001).116
PFS fatigue scores can be further dissected into foursubcategories: (1) the behavior/severity subcategory, which deals with completingtasks, socializing, and engaging in sexual and other activities and withintensity or degree of fatigue; (2) the affective/meaning subcategory, whichdetermines whether an individual finds the fatigue/tiredness to be pleasant orunpleasant, agreeable or disagreeable, protective or destructive, and normal orabnormal; (3) the sensory subcategory, which determines whether an individualfeels strong or weak, awake or sleepy, refreshed or tired, and energetic orunenergetic; and (4) the cognitive/mood subcategory, which assesses whether anindividual feels relaxed or tense, exhilarated or depressed, and able or unableto concentrate, remember, and think clearly. In the study being discussed inthis section, all of these subcategories showed significant reductions by theend of the 8-week trial (P < .0001), indicating that significant improvements occurred for allsubcategories of fatigue. For example, a 30.7% reduction (P < .0001) in severity/behavior of fatigueoccurred, indicating a significant reduction in the intensity of fatigue and asignificant increase in the ability to complete tasks, socialize, and engage insexual and other activities. Also, a 28.0% improvement (P < .0001) occurred in mood and cognitiveability, such as the ability to concentrate, remember, and think clearly.116
Regression Analysis of Fatigue Data
To determine the trends in fatigue reduction as the resultof participants’ use of the combination LRT supplement (membrane phospholipids,CoQ10, NADH, L-carnitine, a-ketoglutaricacid, and other ingredients) over the time of the trial, the author andcolleagues conducted regression analyses of the data to determine if resultswere (1) consistent, (2) occurred with a high degree of confidence, and (3)could predict further reductions in fatigue.116 The regressionanalysis of overall fatigue and of each of the subcategories of fatigueindicated significant and consistent downward trends in the fatigue data,suggesting that further reductions in fatigue would have been likely if the trialhad been continued. The regression R2 values for the various subgroups were (1) behavior/severity, 0.956; (2)affective meaning, 0.960; (3) sensory, 0.950; and (4) cognitive/mood, 0.980.Regression analysis of the overall fatigue yielded R2 = 0.960. This finding indicated that a highlevel of confidence and reproducibility existed in the downward trends in allfatigue data. The combination LRT supplement was safe, and no safety issuescame up during the trial.116 Examination of scores from individualswith chronic fatigue syndrome, Lyme disease, or other diagnosis categories didnot reveal major differences in overall fatigue or its reduction by thecombination supplement.116,117
Oral natural supplements containingmembrane phospholipids, CoQ10, microencapsulated NADH, L-carnitine, a-lipoic acid, and other nutrients can helprestore mitochondrial function and reduce intractable fatigue in patients withchronic illnesses. The combination of these supplements can result in a safeand effective method to reduce fatigue and help restore quality of life.
AUTHOR DISCLOSURE STATEMENT
The author has receivedno financial benefit from and has no conflict of interest regarding theproducts discussed in this article.
1. Swerdlow RH. Brain aging, Alzheimer’sdisease, and mitochondria. Biochim Biophys Acta. 2011;1812(12):1630-1639.
2. Reddy PH.Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med. 2008;10(4):291-315.
3. GreenDR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell deathaxis in organismal aging. Science. 2011;333(6046):1109-1112.
4. ReddyPH, Reddy TP. Mitochondria as a therapeutic target for aging andneurodegenerative diseases. CurrAlzheimer Res. 2011;8(4):393-409.
5. Karbowski M, Neutzner A. Neurodegeneration as a consequence of failedmitochondrial maintenance. Acta Neuropathol. 2012;123(2):157-171.
6. VictorVM, Apostolova N, Herance R, Hernandez-Mijares A, Rocha M. Oxidative stress andmitochondrial dysfunction in atherosclerosis: mitochondria-targeted antioxidantsas potential therapy. Curr Med Chem.2009;16(35):4654-4667.
7. Limongelli G, Masarone D, D’Alessandro R, Elliott PM. Mitochondrial diseasesand the heart: an overview of molecular basis, diagnosis, treatment andclinical course. FutureCardiol. 2012;8(1):71-88.
8. Ma ZA,Zhao Z, Turk J. Mitochondrial dysfunction and beta-cell failure in type 2diabetes mellitus. Exp Diabetes Res. 2012;2012:703538. doi:10.1155/2012/703538.
9. Joseph AM, Joanisse DR, Baillot RG, Hood DA. Mitochondrialdysregulation in the pathogenesis of diabetes: potential for mitochondrialbiogenesis-mediated interventions. ExpDiabetes Res. 2012;2012:642038.doi:10.1155/2012/642038.
10. Nicolson GL. Metabolic syndrome and mitochondrial function: molecularreplacement and antioxidant supplements to prevent membrane peroxidation andrestore mitochondrial function. J Cell Biochem. 2007;100(6):1352-1369.
11. Ghafourifar P, Mousavizadeh K, Parihar MS, Nazarewicz RR, Parihar A, Zenebe WJ. Mitochondria in multiple sclerosis. Front Biosci. Jan 2008;13:3116-3126.
12. Mao P,Reddy PH. Is multiple sclerosis a mitochondrial disease? Biochim Biophys Acta. 2010;1802(1):66-79.
13. Fernandez D, Perl A. Metabolic control of T cell activation and death in SLE. Autoimmun Rev. 2009;8(3):184-189.
14. MaieseK, Morhan SD, Chong ZZ. Oxidative stress biology and cellinjury during type 1 and type 2 diabetes mellitus. Curr Neurovasc Res. 2007;4(1):63-71.
12. Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders:a systematic review and meta-analysis. Mol Psychiatry. 2012;17(3):290-314.
13. Palmieri L, Persico AM. Mitochondrial dysfunction inautism spectrum disorders: cause or effect? Biochim Biophys Acta. 2010;1797(6-7):1130-1137.
14. PrinceJA, Harro J, Blennow K, Gottfries CG, Oreland L. Putamen mitochondrial energymetabolism is highly correlated to emotional and intellectual impairment inschizophrenics. Neuropsychopharmacology. 2000;22(3):284-292.
15. Marazziti D, Baroni S, Piccheti M, et al. Psychiatric disorders and mitochondrialdysfunctions. Eur Rev Med Pharmacol Sci.2012;16(2):270-275.
16. KonradiC, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S. Molecular evidence formitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry. 2004;61(3):300-308.
17. Chitkara DK, Nurko S, Shoffner JM, Buie T, Flores A.Abnormalities in gastrointestinal motility are associated with diseases ofoxidative phosphorylation in children. Am J Gastroenterol. 2003;98(4):871-877.
18. Di Donato S. Multisystem manifestations of mitochondrialdisorders. J Neurol. 2009;256(5):693-710.
19. NorheimKB, Jonsson G, Omdal R. Biological mechanisms of chronic fatigue. Rheumatology (Oxford). 2011;50(6):1009-1018.
20. Nicolson GL, Nicolson NL, Berns P, Nasralla MY, Haier J, NassM. Gulf War illnesses. J Chronic Fatigue Syndr. 2003;11(1):135-154.
21. MyhillS, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrialdysfunction. Int J Clin Exp Med. 2009;2(1):1-16.
22. Cordero MD, de Miguel M, Carmona-Lopez I, Bonal P, CampaF, Moreno-Fernandez AM. Oxidative stress and mitochondrialdysfunction in fibromyalgia. Neuro Endocrinol Lett. 2010;31(2):169-173.
23. Rabinovich RA, Vilaro J. Structural and functional changes of peripheralmuscles in chronic obstructive pulmonary disease patients. Curr Opin Pulm Med. 2010;16(2):123-133.
24. Breeding PC, Russell NC, Nicolson GL. Integrative modelof chronically activated immune-hormonal pathways important in the generationof fibromyalgia. Br JMed Pract. 2012;5(3):a524-a534.
25. SotgiaF, Martinez-Outschoorn UE, Lisanti MP. Mitochondrial oxidative stress drivestumor progression and metastasis: should we use antioxidants as a key componentof cancer treatment and prevention? BMCMed. May 2011;9:62-67.
26. Nicolson GL. Lipid replacement therapy: a nutraceutical approach for reducingcancer-associated fatigue and the adverse effects of cancer therapy whilerestoring mitochondrial function. CancerMetastasis Rev. 2010;29(3):543-552.
27. Gabridge MG. Metabolic consequences of Mycoplasma pneumoniaeinfection. Isr J Med Sci. 1987;23(6):574-579.
28. AshidaH, Mimuro H, Ogawa M, et al. Cell death and infection: a double-edged sword forhost and pathogen survival. J Cell Biol.2011;195(6):931-942.
29. Kerr DS. Treatment of mitochondrial electron transportchain disorders: a review of clinical trials over the past decade. Mol Genet Metab. 2010;99(3):246-255.
30. Twig G, Shirihai OS. The interplaybetween mitochondrial dynamics and mitophagy. Antioxid Redox Signal. 2011;14(10):1939-1951.
31. Priault M, Salin B, Schaeffer J, Vallette FM, di RagoJP, Martinou JC. Impairing the bioenergetic status and thebiogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ. 2005;12(12):1613-1621.
32. Lee J, Giordano S, Zhang J. Autophagy, mitochondria andoxidative stress: cross-talk and redox signaling. Biochem J. 2012;441(2):523-540.
33. RichPR, Marechal A. The mitochondrial respiratory chain. Essays Biochem. 2010;47:1-23.
34. Nicholls DG. Mitochondrial ioncircuits. EssaysBiochem. 2010;47:25-35.
35. Divakaruni AS, Brand MD. The regulation and physiology of mitochondrial protonleak. Physiology(Bethesda). 2011;26(3):192-205.
36. Richter C, Park JW, Ames BN. Normal oxidative damage tomitochondrial and nuclear DNA is extensive. ProcNat Acad Sci USA. 1998;85(17):6465-6467.
37. Stadtman E. Introduction to serial reviews on oxidatively modified proteins inaging and disease. Free Radic Biol Med.2002;32(9):789.
38. SpectorAA, Yorek MA. Membrane lipid composition and cellularfunction. J Lipid Res. 1985;26(9):1015-1035.
39. Spiteller G. Is lipid peroxidation of polyunsaturatedacids the only source of free radicals that induce aging and age-relateddiseases? Rejuvenation Res. 2010;13(1):91-103.
40. Duchen MR, Szabadkai G. Roles of mitochondria in humandisease. Essays Biochem. 2010;47:115-137.
41. Chicco AJ, Sparagna GC. Role ofcardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol. 2007;292(1):C33-C44.
42. Houtkooper RH, Vaz FM. Cardiolipin, the heart of mitochondrialmetabolism. Cell Mol Life Sci. 2008;65(16):2493-2506.
43. Barber DA, Harris SR. Oxygen free radicals andantioxidants: a review. Am Pharm.1994;NS34(9):26-35.
44. Sun Y. Free radicals, antioxidant enzymes, andcarcinogenesis. Free Radic Biol Med.1990;8(6):583-599.
45. Fridovich I. Superoxide radical and superoxidedismutases. Annu RevBiochem. 1995;64:97-112.
46. Chandra Jagetia G, Rajanikant GK, Rao SK, ShrinathBaliga M. Alteration in the glutathione, glutathione peroxidase, superoxide dismutaseand lipid peroxidation by ascorbic acid in the skin of mice exposed tofractionated gamma radiation. Clin Chim Acta. 2003;332(1-2):111-121.
47. Aeschbach R, Loliger J, Scott BC, et al. Antioxidantactions of thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol. Food Chem Toxicol. 1994;32(1):31-36.
48. Schwartz JL. The dual roles of nutrients as antioxidantsand prooxidants: their effects on tumor cell growth. J Nutr. 1996;126(4)(suppl):1221S-1227S.
49. Prasad KN, Cole WC, Kumar B, Prasad KC. Scientificrationale for using high-dose multiple micronutrients as an adjunct to standardand experimental cancer therapies. J AmColl Nutr. 2001;20(5)(suppl):450S-453S.
50. Kroenke K, Wood DR, Mangelsdorff AD, Meier NJ, PowellJB. Chronic fatigue in primary care: prevalence, patient characteristics, andoutcome. JAMA. 1988;260(7):929-934.
51. Nicolson GL, Settineri R. Lipid Replacement Therapy: a functional food approachwith new formulations for reducing cellular oxidative damage, cancer-associatedfatigue and the adverse effects of cancer therapy. Funct Foods Health Dis. 2011;1(4):135-160.
52. Agadjanyan M, Vasilevko V, Ghochikyan A, et al.Nutritional supplement (NTFactor) restores mitochondrial function and reducesmoderately severe fatigue in aged subjects. J Chronic Fatigue Syndr. 2003;11(3):23-26.
53. Booth NE, Myhill S, McLaren-Howard J. Mitochondrialdysfunction and the pathophysiology of Myalgic Encephalomyelitis/ChronicFatigue Syndrome (ME/CFS). Int J Clin EspMed. 2012;5(3):208-220.
54. Morrison JD. Fatigue as a presenting complaint in family practice. J Family Pract. 1980;10(5):795-801.
55. Piper BF, Linsey AM, Dodd MJ. Fatigue mechanisms in cancer patients:developing nursing theory. Oncol Nurs Forum. 1987;14(6):17-23.
56. Wei YH, Lee HC. Oxidative stress,mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood). 2002;227(9):671-682.
57. Huang H, Manton KG. The role of oxidative damage inmitochondria during aging: a review. FrontBiosci. May 2004;9:1100-1117.
58. Logan AC, Wong C. Chronic fatigue syndrome: oxidativestress and dietary modifications. AlternMed Rev. 2001;6(5):450-459.
59. Manuel y Keenoy B, Moorkens G, Vertommen J, De Leeuw I.Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome. Life Sci. 2001;68(17):2037-2049.
60. Richards RS, Roberts TK, McGregor NR, Dunstan RH, ButtHL. Blood parameters indicative of oxidative stress are associated with symptomexpression in chronic fatigue syndrome. RedoxRep. 2000;5(1):35-41.
61. Fulle S, Mecocci P, Fano G, et al. Specific oxidativealterations in vastus lateralis muscle of patients with the diagnosis ofchronic fatigue syndrome. Free Radic BiolMed. 2000;29(12):1252-1259.
62. Pall ML. Elevated, sustained peroxynitrite levels as thecause of chronic fatigue syndrome. Med Hypotheses. 2000;54(1):115-125.
63. Dimauro S, Rustin P. A criticalapproach to the therapy of mitochondrial respiratory chain and oxidativephosphorylation diseases. Biochim Biophys Acta. 2009;1792(12):1159-1167.
64. Chambers D, Bagnall AM, Hempel S, Forbes C.Interventions for the treatment management and rehabilitation of patients withchronic fatigue syndrome/myalgic encepthalomyelitis: an updated systematicreview. J R Soc Med. 2006;99(10):506-520.
65. Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM.Lipoic acid as a pote