Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview.

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown causes characterised by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS); fibromyalgia (FM); and more recently post-COVID-19 condition (long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders. Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. The accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and long COVID. To address this issue, this article aims to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, it aims to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.

Coenzyme Q10 and Endocrine Disorders: An Overview.

Mitochondrial dysfunction and oxidative stress have been implicated in the pathogenesis of a number of endocrine disorders; this, in turn, suggests a potential role for the vitamin-like substance coenzyme Q10 (CoQ10) in the pathogenesis and treatment of these disorders, on the basis of its key roles in mitochondrial function, and as an antioxidant. In this article we have therefore reviewed the role of CoQ10 deficiency and supplementation in disorders of the thyroid, pancreas, gonads, pituitary and adrenals, with a particular focus on hyperthyroidism, type II diabetes, male infertility and polycystic ovary syndrome.

Coenzyme Q10 Metabolism: A Review of Unresolved Issues.

The variable success in the outcome of randomised controlled trials supplementing coenzyme Q10 (CoQ10) may in turn be associated with a number of currently unresolved issues relating to CoQ10 metabolism. In this article, we have reviewed what is currently known about these factors and where gaps in knowledge exist that need to be further elucidated. Issues addressed include (i) whether the bioavailability of CoQ10 could be improved; (ii) whether CoQ10 could be administered intravenously; (iii) whether CoQ10 could be administered via alternative routes; (iv) whether CoQ10 can cross the blood-brain barrier; (v) how CoQ10 is transported into and within target cells; (vi) why some clinical trials supplementing CoQ10 may have been unsuccessful; and (vii) which is the most appropriate tissue for the clinical assessment of CoQ10 status.

Mitochondrial Dysfunction and Neurodegenerative Disorders: Role of Nutritional Supplementation.

Mitochondrial dysfunction has been implicated in the pathogenesis of a number of neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, and progressive supranuclear palsy. This article is concerned specifically with mitochondrial dysfunction as defined by reduced capacity for ATP production, the role of depleted levels of key nutritionally related metabolites, and the potential benefit of supplementation with specific nutrients of relevance to normal mitochondrial function in the above neurodegenerative disorders. The article provides a rationale for a combination of CoQ10, B-vitamins/NADH, L-carnitine, vitamin D, and alpha-lipoic acid for the treatment of the above neurodegenerative disorders.

Depletion and Supplementation of Coenzyme Q10 in Secondary Deficiency Disorders.

Coenzyme Q10 (CoQ10) deficiency is broadly divided into two types, primary and secondary. Primary CoQ10 deficiencies are relatively rare disorders resulting from mutations in genes directly involved in the CoQ10 biosynthetic pathway, and are not a subject of this article. Secondary CoQ10 disorders are relatively common, and may occur for a variety of reasons; these include mutations in genes not directly related to the synthetic pathway, oxidative stress induced reduction of CoQ10, and the effects of pharmacological agents such as statins. CoQ10 is of key importance in cell metabolism; in addition to its role in mitochondrial oxidative phosphorylation, it is a major endogenous antioxidant, and has a role in the metabolism of sulphides, lipids and amino acids. Given its importance in cell metabolism, it is unsurprising that secondary CoQ10 deficiency has been linked with a wide range of disorders. In this article, we have reviewed evidence of secondary CoQ10 deficiency in both common and less common disorders, and highlighted those disorders in which CoQ10 supplementation has been shown to be of significant clinical benefit.

Targeted Treatment of Age-Related Fibromyalgia with Supplemental Coenzyme Q10.

Fibromyalgia is a common chronic pain condition of unknown aetiology, although mitochondrial dysfunction, oxidative stress, and inflammation have been implicated in the pathophysiology of this disorder. Treatment generally involves physiotherapy, anticonvulsants, and antidepressant therapy; however, the symptomatic relief conferred by these treatments can be very variable, and there is a need for additional therapeutic strategies. One such treatment which is gaining a lot of interest is the use of coenzyme Q10 (CoQ10) supplementation. The therapeutic efficacy associated with CoQ10 supplementation is thought to arise from the ability of supplementation to restore an underlying deficit in CoQ10 status which has been associated with fibromyalgia together with the ability of CoQ10 to improve mitochondrial activity, restore cellular antioxidant capacity, and ameliorate inflammation. This chapter outlines the evidence supporting the therapeutic utility of CoQ10 in the treatment of fibromyalgia.

Coenzyme Q10, Ageing and the Nervous System: An Overview.

The ageing brain is characterised by changes at the physical, histological, biochemical and physiological levels. This ageing process is associated with an increased risk of developing a number of neurological disorders, notably Alzheimer's disease and Parkinson's disease. There is evidence that mitochondrial dysfunction and oxidative stress play a key role in the pathogenesis of such disorders. In this article, we review the potential therapeutic role in these age-related neurological disorders of supplementary coenzyme Q10, a vitamin-like substance of vital importance for normal mitochondrial function and as an antioxidant. This review is concerned primarily with studies in humans rather than in vitro studies or studies in animal models of neurological disease. In particular, the reasons why the outcomes of clinical trials supplementing coenzyme Q10 in these neurological disorders is discussed.

Disorders of Human Coenzyme Q10 Metabolism: An Overview.

Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extramitochondrial. In addition to its key role in mitochondrial oxidative phosphorylation, CoQ10 serves as a lipid soluble antioxidant, plays an important role in fatty acid, pyrimidine and lysosomal metabolism, as well as directly mediating the expression of a number of genes, including those involved in inflammation. In view of the central role of CoQ10 in cellular metabolism, it is unsurprising that a CoQ10 deficiency is linked to the pathogenesis of a range of disorders. CoQ10 deficiency is broadly classified into primary or secondary deficiencies. Primary deficiencies result from genetic defects in the multi-step biochemical pathway of CoQ10 synthesis, whereas secondary deficiencies can occur as result of other diseases or certain pharmacotherapies. In this article we have reviewed the clinical consequences of primary and secondary CoQ10 deficiencies, as well as providing some examples of the successful use of CoQ10 supplementation in the treatment of disease.

Bioavailability of Coenzyme Q10: An Overview of the Absorption Process and Subsequent Metabolism.

A lack of understanding of the processes determining the absorption and subsequent metabolism of coenzyme Q10 (CoQ10) has resulted in some manufacturers' making incorrect claims regarding the bioavailability of their CoQ10 supplements, with potential consequences for the use of such products in clinical trials. The purpose of the present review article is, therefore, to describe the various stages of exogenous CoQ10 metabolism, from its first ingestion, stomach transit, absorption from the small intestine into the lymphatic system, transport in blood, and access into cells. In particular, the importance of CoQ10 crystal dispersion in the initial formulation is emphasised, the absence of which reduces bioavailability by 75%. In addition, evidence comparing the relative bioavailability and efficacy of ubiquinone and ubiquinol forms of CoQ10 has been reviewed.

Efficacy and safety of supplemental melatonin for delayed sleep-wake phase disorder in children: an overview.

Delayed sleep-wake phase disorder (DSPD) is the most frequently occurring intrinsic circadian rhythm sleep-wake disorder, with the highest prevalence in adolescence. Melatonin is the first-choice drug treatment. However, to date melatonin (in a controlled-release formulation) is only authorised for the treatment of insomnia in children with autism or Smiths-Magenis syndrome. Concerns have been raised with respect to the safety and efficacy of melatonin for more general use in children, as melatonin has not undergone the formal safety testing required for a new drug, especially long-term safety in children. Melatonin is known to have profound effects on the reproductive systems of rodents, sheep and primates, as well as effects on the cardiovascular, immune and metabolic systems. The objective of the present article was therefore to establish the efficacy and safety of exogenous melatonin for use in children with DSPD, based on in vitro, animal model and clinical studies by reviewing the relevant literature in the Medline database using PubMed. Acute toxicity studies in rats and mice showed toxic effects only at extremely high melatonin doses (>400 mg/kg), some tens of thousands of times more than the recommended dose of 3-6 mg in a person weighing 70 kg. Longer-term administration of melatonin improved the general health and survival of ageing rats or mice. A full range of in vitro/in vivo genotoxicity tests consistently found no evidence that melatonin is genotoxic. Similarly long term administration of melatonin in rats or mice did not have carcinogenic effects, or negative effects on cardiovascular, endocrine and reproductive systems. With regard to clinical studies, in 19 randomised controlled trials comprising 841 children and adolescents with DSPD, melatonin treatment (usually of 4 weeks duration) consistently improved sleep latency by 22-60 min, without any serious adverse effects. Similarly, 17 randomised controlled trials, comprising 1374 children and adolescents, supplementing melatonin for indications other than DSPD, reported no relevant adverse effects. In addition, 4 long-term safety studies (1.0-10.8 yr) supplementing exogenous melatonin found no substantial deviation of the development of children with respect to sleep quality, puberty development and mental health scores. Finally, post-marketing data for an immediate-release melatonin formulation (Bio-melatonin), used in the UK since 2008 as an unlicensed medicine for sleep disturbance in children, recorded no adverse events to date on sales of approximately 600,000 packs, equivalent to some 35 million individual 3 mg tablet doses (MHRA yellow card adverse event recording scheme). In conclusion, evidence has been provided that melatonin is an efficacious and safe chronobiotic drug for the treatment of DSPD in children, provided that it is administered at the correct time (3-5 h before endogenous melatonin starts to rise in dim light (DLMO)), and in the correct (minimal effective) dose. As the status of circadian rhythmicity may change during long-time treatment, it is recommended to stop melatonin treatment at least once a year (preferably during the summer holidays).

Coenzyme Q10 Supplementation in Fibrosis and Aging.

Coenzyme Q10 (CoQ10) is a vitamin-like substance which functions as an electron carrier within the mitochondrial respiratory chain, as well as serving as an important intracellular antioxidant. Most of the body's CoQ10 requirements are met by endogenous synthesis, although the capacity for CoQ10 production decreases substantially with increasing age. In this article we have reviewed the potential role of CoQ10 supplementation in the treatment of tissue fibrosis, which has been implicated in the age-related loss of function of various organs including the heart. Clinical studies have indicated that CoQ10 supplementation may decrease the level of cardiovascular fibrosis to which older individuals are subjected, and thereby improve cardiovascular function and reduce the risk of cardiovascular associated mortality. Although the factors responsible for the anti-fibrotic action of CoQ10 have yet to be fully elucidated, its antioxidant and anti-inflammatory functions are thought to be major contributors to its clinical efficacy in the treatment of this age-related disorder.

Coenzyme Q10 and Degenerative Disorders Affecting Longevity: An Overview.

Longevity is determined by a number of factors, including genetic, environmental and lifestyle factors. A major factor affecting longevity is the development of degenerative disorders such as cardiovascular disease, diabetes, kidney disease and liver disease, particularly where these occur as co-morbidities. In this article, we review the potential role of supplementation with coenzyme Q10 (CoQ10) for the prevention or management of these disorders. Thus, randomised controlled clinical trials have shown supplementation with CoQ10 or CoQ10 plus selenium reduces mortality by approximately 50% in patients with cardiovascular disease, or in the normal elderly population, respectively. Similarly, CoQ10 supplementation improves glycaemic control and vascular dysfunction in type II diabetes, improves renal function in patients with chronic kidney disease, and reduces liver inflammation in patients with non-alcoholic fatty liver disease. The beneficial role of supplemental CoQ10 in the above disorders is considered to result from a combination of its roles in cellular energy generation, as an antioxidant and as an anti-inflammatory agent.

Comparison of antioxidant activity in commercial Ginkgo biloba preparations.

AIM: To compare the relative levels of antioxidant activity in vitro in Ginkgo biloba samples (in tablet or capsule form) from different commercial suppliers, to determine whether some brands may be more efficacious in their potential to increase endogenous antioxidant activity, and thereby counter oxidative stress related disorders. DESIGN: Antioxidant activity of the above sample extracts was determined in vitro against the ABTS.(+) (2-2'-amino-bis-3-ethylbenzthiazoline-6-sulfonic acid) radical, relative to Trolox (water-soluble vitamin E analogue) antioxidant standards, using an established assay procedure. OUTCOME MEASURES: The relative antioxidant activity of G. biloba sample extracts was expressed in terms of millimoles per liter of Trolox equivalent (TE) for the initial extract, micromol TE per whole tablet, nmol TE per mg tablet, and nmol TE per mg ginkgo content. RESULTS: Data (as mean +/- standard deviation (SD) from 4 separate estimations) obtained in this study showed a considerable variation (approximately 50-fold) in the level of antioxidant activity in preparations from different suppliers, particularly when compared on an equivalent (i.e., nmol TE/mg ginkgo) basis. Of the 18 products investigated, the highest level of antioxidant activity (whether expressed as micromol TE per whole tablet or nmol TE/mg ginkgo) was obtained for Pharma Nord Bio-Biloba (Pharma Nord, Morpeth, UK) tablets (p < 0.05, Dunnett's statistical test). CONCLUSIONS: Some of the apparent variation in antioxidant activity of the various products investigated can be accounted for in terms of the physical nature of the G. biloba (i.e., dried leaf powder or standardized concentrated extract) used in tablet formulation. However, even when comparing products based on concentrated extract, the data demonstrated that there is still a considerable variation in antioxidant activity. Presumably this may result from differences in the manufacturing process between suppliers, which in turn may limit the efficacy of these preparations in the prevention or treatment of disease.

Endogenous antioxidant activities in relation to concurrent vitamins A, C, and E intake in dementia.

Previous reports on the activities of essential endogenous antioxidants such as superoxide dismutase, catalase, and glutathione in dementia patients have not included a simultaneous quantitative assessment of dietary antioxidant intake. This is important because the reported differences in endogenous antioxidant levels among dementia patients may have reflected variations in the total antioxidants' intake. In this study we measured the levels of antioxidant vitamins A, C, and E in the diet of 81 dementia patients and controls at the same time as assessing blood levels of three endogenous antioxidants. Results showed a significant decrease in the intake of vitamins C (p < .001) and E (p < .01) in patients with severe Alzheimer's disease (AD) when compared to controls. Patients with mild/moderate AD differed from controls only in the intake of vitamin C (p < .01). The blood levels of catalase but not superoxide dismutase and glutathione were significantly decreased in the patients with severe AD when compared to controls (p < .01), patients with mild/moderate AD (p < .0 1), and patients with dementia with Lewy bodies (p < .05). The blood catalase levels of dementia patients, as a whole, were significantly and positively associated with the intake of vitamins A (p < .05), C (p < .01), and E (p < .05). The results indicated that dietary intake of vitamins A, C, and E may influence blood levels of catalase possibly through their antioxidant effects on free radicals. The data underscore the importance of concurrent quantitative assessment of nutritional intake when measuring endogenous antioxidant activities and support a role for antioxidant supplementation in the treatment of dementia disorders.

Free radicals in alcoholic myopathy: indices of damage and preventive studies.

Chronic alcoholic myopathy affects up to two-thirds of all alcohol misusers and is characterized by selective atrophy of Type II (glycolytic, fast-twitch, anaerobic) fibers. In contrast, the Type I fibers (oxidative, slow-twitch, aerobic) are relatively protected. Alcohol increases the concentration of cholesterol hydroperoxides and malondialdehyde-protein adducts, though protein-carbonyl concentration levels do not appear to be overtly increased and may actually decrease in some studies. In alcoholics, plasma concentrations of alpha-tocopherol may be reduced in myopathic patients. However, alpha-tocopherol supplementation has failed to prevent either the loss of skeletal muscle protein or the reductions in protein synthesis in alcohol-dosed animals. The evidence for increased oxidative stress in alcohol-exposed skeletal muscle is thus inconsistent. Further work into the role of ROS in alcoholic myopathy is clearly warranted.