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. 2014 Mar 13;5(3-4):187–197. doi: 10.1159/000360101

Coenzyme Q10 Therapy

Juan Garrido-Maraver a, Mario D Cordero b,c, Manuel Oropesa-Ávila a, Alejandro Fernández Vega a, Mario de la Mata a, Ana Delgado Pavón a, Manuel de Miguel c, Carmen Pérez Calero a, Marina Villanueva Paz a, David Cotán a, José A Sánchez-Alcázar a,b,*
PMCID: PMC4112525  PMID: 25126052

Abstract

For a number of years, coenzyme Q10 (CoQ10) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in blood plasma, and extensively investigated its antioxidant role. These 2 functions constitute the basis for supporting the clinical use of CoQ10. Also, at the inner mitochondrial membrane level, CoQ10 is recognized as an obligatory cofactor for the function of uncoupling proteins and a modulator of the mitochondrial transition pore. Furthermore, recent data indicate that CoQ10 affects the expression of genes involved in human cell signaling, metabolism and transport, and some of the effects of CoQ10 supplementation may be due to this property. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, aging-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer, and muscular and cardiovascular diseases have been associated with low CoQ10 levels as well as different ataxias and encephalomyopathies. CoQ10 treatment does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption and tissue distribution. Oral administration of CoQ10 is a frequent antioxidant strategy in many diseases that may provide a significant symptomatic benefit.

Key Words: Clinical indications, Coenzyme Q10, Coenzyme Q10-related compounds, Pharmacokinetics

Coenzyme Q10 (CoQ10) is an essential compound found naturally in virtually every cell in the human body. Because of its ubiquitous presence in nature and its quinone structure, CoQ10 is also known as ubiquinone. CoQ10 is a lipid-soluble substance whose primary role is as an essential intermediate of the electron transport system in the mitochondria. Adequate amounts of CoQ10 are necessary for cellular respiration and ATP production. CoQ10 also functions as an intercellular antioxidant, and its presence was then demonstrated in all cell membranes and in blood, both in high- and in low-density lipoproteins, where it is endued with antioxidant properties [Crane, 2001]. CoQ10 was also recognized to have an effect on gene expression [Groneberg et al., 2005; Schmelzer et al., 2008]. Dietary supplementation affecting CoQ10 levels has been shown in a number of organisms to cause multiple phenotypic effects, which can be explained on the basis of its significant impact on the expression of many genes mainly involved in cell signaling, intermediary metabolism, transport and transcription control, and inflammation, among others, indicating an important role for CoQ10 as a potent gene regulator [Groneberg et al., 2005; Santos-González et al., 2007]. However, the molecular mechanisms whereby CoQ10 induces these pleiotropic effects has yet to be completely understood [Schmelzer et al., 2008].

Numerous disease processes associated with CoQ10 deficiency can benefit from CoQ10 supplementation, including primary and secondary CoQ10 deficiencies, mitochondrial diseases, fibromyalgia, cardiovascular disease, neurodegenerative diseases, cancer, diabetes mellitus, male infertility, and periodontal disease (table 1).

Table 1.

The most frequent physiological and clinical indications of CoQ10

References
Clinical indications
 Human CoQ10 deficiencies Quinzii and Hirano, 2011
 Mitochondrial diseases Kerr, 2010
 Fibromyalgia Cordero et al., 2011, 2012
 Cardiac failure Adarsh et al., 2008
 Ischemic heart disease Celik and Iyisoy, 2009
 Interaction with statins Caso et al., 2007
 Hypertension Rosenfeldt et al., 2007
 Endothelial function Belardinelli et al., 2006
 Diabetes Golbidi et al., 2011
 Cancer Roffe et al., 2004
Neurodegenerative diseases
 Parkinson's disease Henchcliffe and Beal, 2008
 Huntington's disease Stack et al., 2008
 Alzheimer's disease Lee et al., 2009
 Friedreich's ataxia Cooper et al., 2008
Other conditions
 Asthenozoospermia Mancini and Balercia, 2011
 Periodontal disease Prakash et al., 2010
 Migraine Sándor et al., 2005
 Pre-eclampsia Teran et al., 2009
 Down's syndrome Tiano and Busciglio, 2011
 Aging López-Lluch et al., 2010
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CoQ10 Deficiency States

Tissue deficiencies or subnormal serum levels of CoQ10 have been reported in a wide range of medical conditions, including primary CoQ10 deficiencies [Emmanuele et al., 2012] and secondary CoQ10 deficiencies such as mitochondrial diseases [Sacconi et al., 2010]. CoQ10 levels decline with advancing age, and this decline may contribute in part to some of the manifestations of aging [Sohal and Forster, 2007]. CoQ10 deficiency could result from: (1) impaired CoQ10 synthesis due to nutritional deficiencies (such as vitamin B6 deficiency, a cofactor essential for CoQ10 biosynthesis), (2) a genetic or acquired defect in CoQ10 synthesis or utilization, or (3) increased tissue needs resulting from a particular disease. Clinical presentations of severe CoQ10 deficiency include encephalomyopathy, severe infantile multisystemic disease, cerebellar ataxia, Leigh syndrome with growth retardation, and isolated myopathy. Since oral administration of CoQ10 can increase tissue levels of the nutrient, it is possible to correct CoQ10 deficiency and is particularly essential in the life-threatening infantile encephalopathy [Quinzii et al., 2007].

Absorption, Tissue Uptake and Pharmacokinetics

Plasma CoQ10 concentrations are usually used for the estimation of the CoQ10 status in humans primarily because of easy sample collection. Reported plasma CoQ10 ranged from 0.40 to 1.91 μmol/l (0.34-1.65 μg/ml) [Bhagavan and Chopra, 2006]. CoQ10 is also naturally found in dietary sources, with large amounts present in heart, chicken leg, herring, and trout. The daily intake from food was estimated to be 3-5 mg CoQ10 a day. However, in tissues with unimpaired synthetic capacity, it appears that CoQ10 reaches a saturation level, and nutritional supplement of CoQ10 in the diet does not increase tissue levels above normal [Beal, 1999; Weber et al., 1997].

Intestinal absorption is 3-fold faster if CoQ10 is administrated with food intake [Ochiai et al., 2007]. Following absorption, CoQ10 appears in plasma lipoproteins and in liver, but usually not in heart or kidney [Zhang et al., 1995]. However, with higher supplementations (150 mg/kg/day), heart and the skeletal muscle showed a significant increase in total CoQ10, suggesting that higher plasma CoQ10 concentrations are necessary to facilitate uptake by peripheral tissues [Kwong et al., 2002]. Biochemical characteristics of CoQ10 are important for our understanding of uptake and distribution following oral ingestion. CoQ10 is absorbed slowly from the small intestine, possibly because it has a high molecular weight and is not very water soluble, passes into the lymphatics, and finally to the blood and tissues. Research on exogenous CoQ10 absorption and bioavailability varies greatly depending on the type of CoQ10 preparation studied. CoQ10 absorption is probably a complex process and dependent upon active and passive transport mechanisms [Palamakula et al., 2005]. A study on intestinal absorption of 30 mg CoQ10 administered in a meal or as powder in capsules to healthy subjects found no significant difference in absorption for these 2 routes of administration [Weber et al., 1997]. Although not all research is in agreement, the general consensus is that slightly better absorption is achieved with oil-based forms of CoQ10 [Weis et al., 1994; Lyon et al., 2001]. Further studies are needed to elucidate whether age, gender, lipoprotein status, diet, dosage formulation, or other factors may affect the bioavailability of CoQ10 with chronic dosing [Miles, 2007].

CoQ10 dosage guidelines, which appeared to be safe and well tolerated, were suggested for adults (up to 1,200 mg/day) [Hathcock and Shao, 2006] and for children (up to 10 mg/kg/day) [Miles et al., 2006]. Monitoring CoQ10 plasma concentrations may be considered after 3-4 weeks of constant dosing, when steady-state conditions exist [Hosoe et al., 2007]. Steady-state plasma concentrations at these dosage levels generally ranged from 5 to 10 μg/ml [Miles, 2007].

Mechanism of Action

Due to its involvement in ATP synthesis, CoQ10 affects the function of all cells in the body, especially those with high-energy demand, making it essential for the health of all tissues and organs. CoQ10 is our only lipid-soluble antioxidant synthesized endogenously and efficiently prevents oxidation of proteins, lipids and DNA. The fundamental role of CoQ10 in mitochondrial bioenergetics and its well-acknowledged antioxidant properties constitute the basis for its clinical applications, although some of its effects may be related to a gene induction mechanism [Littarru and Tiano, 2010]. Today, several other important functions are also associated with this lipid [Bentinger et al., 2010].

Clinical Indications

Treatment of CoQ10 Deficiencies

CoQ10 deficiency is a treatable condition; therefore, its diagnosis is essential, especially for pediatricians and child neurologists. An early treatment with high-dose CoQ10 may radically change the natural history of this group of diseases [DiMauro et al., 2007]. Patients with all forms of CoQ10 deficiency have shown clinical improvement with oral CoQ10 supplementation, but cerebral symptoms are only partially ameliorated (probably because of irreversible structural brain damage before treatment and because of poor penetration of CoQ10 across the blood-brain barrier) [Rötig et al., 2007].

CoQ10 deficiency is involved in cardiomyopathies and degenerative muscle and neuronal diseases. The major phenotypes provoked by CoQ10 deficiencies are encephalomyopathy, severe infantile multisystemic disease, cerebellar ataxia, Leigh syndrome with growth retardation, ataxia, nephrotic syndrome, and isolated myopathy [Quinzii and Hirano, 2011].

The cerebellum may have the narrowest safety margin and, therefore, would be the first tissue to suffer from a pathological shortage of CoQ10 [Naini et al., 2003]. The most severe human CoQ10 deficiencies are due to autosomal recessive mutations and can be classified as primary deficiencies when mutations affect CoQ10 biosynthetic genes or secondary if the cause is related to other genetic defects [Quinzii and Hirano, 2011].

The first CoQ10-deficient patients reported by Ogasahara et al. [1989] were 2 sisters (12 and 14 years old), and symptoms were alleviated after 3 months of receiving 50 mg of CoQ10 3 times daily [Ogasahara et al., 1989]. Patients with encephalomyopathy and renal failure were treated with oral CoQ10 at doses from 5 mg/kg/day [Rötig et al., 2000] or 30 mg/kg/day [Salviati et al., 2005]; a patient with myopathic phenotype of CoQ10 deficiency received 500 mg/day of CoQ10 [Gempel et al., 2007], and a patient with cerebellar ataxia was treated with oral CoQ10 supplementation with an initial dose of 2,500 mg/day. The doses were decreased every 3 months [Artuch et al., 2006]. These cases showed a good to very good response to CoQ10 supplementation, with the main symptoms related to cerebellar dysfunction disappearing and the international cooperative ataxia rating scale (ICARS) scores decreasing after 16 months of supplementation.

However, a daily oral therapy that included 50 mg CoQ10 beginning at age 3 months did not lead to clinical improvement in an infant with Leigh syndrome and nephropathy; the child died after 5 months [Quinzii et al., 2006]. The lack of clinical improvement may have been due to low dosage, poor penetration of CoQ10 formulation, the severity of brain damage prior to oral supplementation, or a combination of these factors.

Patients with secondary deficiency in CoQ10 and cerebellar ataxias also improved with CoQ10 supplementation [Quinzii et al., 2005; Gempel et al., 2007] or even resulted in full recovery [Gempel et al., 2007]. Furthermore, myopathic CoQ10 deficiency also responded dramatically to CoQ10 supplementation, and after 8 months of treatment, excessive lipid storage resolved, CoQ10 level normalized, mitochondrial enzymes increased, and the proportion of apoptotic fibers decreased from 30 to 10% in 2 brothers with myopathic CoQ10 deficiency [Di Giovanni et al., 2001]. Mancuso et al. [2010] reported another case of the myopathic form of CoQ10 deficiency with excellent response to therapy.

Mitochondrial Disorders

CoQ10 is frequently reduced in muscle tissue of patients with mitochondrial myopathy [Sacconi et al., 2010], and CoQ10 is very widely used for primary mitochondrial disorders treatment [Kerr, 2010]. Numerous case reports and small, open-label studies describe mitochondrial diseases of varying severity that have responded to CoQ10 supplementation, typically in dosages from 30 to 300 mg/day [Gold et al., 1996; Berbel-Garcia et al., 2004]. A 3-month trial included 8 patients with mitochondrial encephalomyopathies supplemented with 160 mg CoQ10/day. Although the researchers reported a trend towards improved muscle endurance, less fatigue during daily duties, and decreased serum lactate and pyruvate levels, only the muscle endurance results reached statistical significance. The study authors hypothesized the dosage was too low to provide significant benefit [Chen et al., 1997]. In a 6-month double-blind clinical trial, 44 patients with mitochondrial myopathies from multiple centers were treated with 2 mg/kg CoQ10 daily. Sixteen of 24 patients experienced at least a 25% decrease in post-exercise lactate levels and were selected as ‘responders’ to continue the study. After a further 3 months at the same dose, no significant differences were observed between the responder and placebo groups. The lack of long-term therapeutic effects in the responders may be attributed to the relatively low dose and short duration of the study [Bresolin et al., 1990]. Overall, it appears that larger CoQ10 dosages are indicated for mitochondrial disorders. Recently, our group has demonstrated the benefits of CoQ10 supplementation in several cellular models of mitochondrial diseases [Rodríguez-Hernández et al., 2009; Cotán et al., 2011; De la Mata et al., 2012; Garrido-Maraver et al., 2012]. However, the clinical evidence supporting a benefit of CoQ10 treatment in primary mitochondrial disease is limited. Reasons for this include the relative rarity and heterogeneity of mitochondrial diseases [Haas, 2007].

Fibromyalgia

Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology and a wide spectrum of symptoms such as allodynia, debilitating fatigue, joint stiffness, and migraine. Recent studies have shown some evidences demonstrating that oxidative stress is associated to clinical symptoms in FM. Recent findings of our group have shown reduced levels of CoQ10, a decreased mitochondrial membrane potential, increased levels of mitochondrial superoxide, and increased levels of lipid peroxidation in blood mononuclear cells from FM patients. Mitochondrial dysfunction was also associated with increased expression of autophagic genes and the elimination of dysfunctional mitochondria by mitophagy [Cordero et al., 2010]. In another study, FM patients were clinically evaluated using the Visual Analogical Scale of pain (VAS), and the Fibromyalgia Impact Questionnaire (FIQ). FM patients with CoQ10 deficiency showed a significant reduction on symptoms after CoQ10 treatment [Cordero et al., 2011, 2012]. Determination of CoQ10 deficiency and subsequent supplementation in FM may result in significant clinical improvement.

Cardiovascular Disease

Oxidative stress plays a central role in the pathogenesis of cardiovascular diseases including heart failure and hypertension. Heart failure is often characterized by a loss of contractile function due to an energy depletion status in the mitochondria that has been associated with low endogenous CoQ10 levels. Myocardial deficiency of CoQ10 has been demonstrated in endomyocardial biopsy samples from patients with cardiomyopathy, and deficiency of CoQ10 correlated with the severity of disease, suggesting that therapy with CoQ10 can result in improving the quality of life of cardiac patients by enhancing myocardial contractility [Folkers et al., 1985b]. Numerous studies have investigated the benefit of CoQ10 supplementation for improving cardiovascular function via enhanced energy production, improved contractility of cardiac muscles, and its potent antioxidant activity, particularly the prevention of low-density lipoproteins oxidation. Langsjoen et al. [1994a] published a study summarizing 8 years of research on the benefits of CoQ10 in clinical cardiology. Since this study, numerous other studies have demonstrated the usefulness of CoQ10 supplementation for various cardiovascular conditions. Research has shown CoQ10 levels are depleted in both serum and myocardial tissue samples of patients with chronic heart failure [Folkers et al., 1970, 1985a]. Two important meta-analyses reported significant benefits of CoQ10 on heart failure of various causes [Mortensen, 2003; Sander et al., 2006]. Dilated cardiomyopathy is a form of cardiac muscle disease characterized by ventricular dilation, contractile dysfunction and eventual congestive heart failure. In patients with stable moderate congestive heart failure, oral CoQ10 supplementation was shown to ameliorate cardiac contractility and endothelial dysfunction [Littarru and Tiano, 2007].

Atherosclerosis

CoQ10 in its reduced form, ubiquinol (CoQ10H2), inhibits protein and DNA oxidation, but it is the effect on lipid peroxidation that has been most deeply studied. Ubiquinol inhibits the peroxidation of cell membrane lipids and lipoprotein lipids present in circulation. Dietary supplementation with CoQ10 results in increased resistance of low-density lipoproteins to the initiation of lipid peroxidation [Mohr et al., 1992]. Moreover, CoQ10 has a direct anti-atherogenic effect, which has also been demonstrated in apolipoprotein E-deficient mice fed with a high-fat diet [Witting et al., 2000]. CoQ10 supplement at a dose of 150 mg/day can decrease oxidative stress, increase antioxidant enzyme activity and decrease the inflammatory marker IL-6 in patients with atherosclerosis [Lee et al. 2012a, b].

Dyslipidemia and Statin Drugs

Elevated cholesterol and the associated dyslipidemia are commonly treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibiting drugs (statins). Because both cholesterol and CoQ10 synthesis depend on HMG-CoA reductase, both can be blocked. Different mechanisms have been proposed to explain statin-induced myopathy, including reduction of mevalonate pathway products, induction of apoptosis, mitochondrial dysfunction, and genetic predisposition [Mas and Mori, 2010]. Depletion in CoQ10 may account for the statin-induced myopathies observed in some patients, the most serious of which is rhabdomyolysis. From 1990 to 2004, 13 controlled trials demonstrated significant CoQ10 depletion secondary to statin therapy [Hargreaves et al., 2005]. Consequently, supplementing with CoQ10 is highly recommended to prevent the myopathic side effects associated with the statin drugs. Recently, it has also been reported statin has side effects on energy and exertional fatigue [Golomb et al., 2012]. However, clinical evidence supporting CoQ10's use in the treatment of statin-induced myopathy is limited and controversial [Wyman et al., 2010].

Hypertension

Depending on the class, various antihypertensive drugs can have adverse effects, such as depression, cough, and cardiac and renal dysfunction [Hadj et al., 2007; Pepe et al., 2007]. Furthermore, many patients need to take more than one drug to control their blood pressure, increasing their risk of side effects. Some researchers believe CoQ10 supplementation may reduce the need to take multiple antihypertensive drugs [Langsjoen et al., 1994b].

CoQ10 appears to lower blood pressure. The exact mechanism is not known, but one theory is that it reduces peripheral resistance by preserving nitric oxide [Pepe et al., 2007]. Nitric oxide relaxes peripheral arteries, lowering blood pressure. In some forms of hypertension, superoxide radicals that inactivate nitric oxide are overproduced; CoQ10, with its antioxidant effects, may prevent the inactivation of nitric oxide by these free radicals. Alternatively, CoQ10 may boost the production of the prostaglandin prostacyclin, a potent vasodilator and inhibitor of platelet aggregation, or it may enhance the sensitivity of arterial smooth muscles to prostaglandin prostacyclin, or both [Lönnrot et al., 1998]. A recent meta-analysis of clinical trials investigating the use of CoQ10 for hypertension assessed overall efficacy. Blood pressure reduction was noted in all 12 trials, regardless of whether CoQ10 was given alone or as an adjunct to standard antihypertensive medication, without significant side effects [Rosenfeldt et al., 2007]. In some cases, it seems reasonable to recommend this product as an adjunct to conventional antihypertensive therapy. However, larger, well-designed clinical trials of CoQ10's antihypertensive effects on specific clinical outcomes, such as the risk of stroke or myocardial infarction, are needed to define its true therapeutic value [Wyman et al., 2010].

Diabetes

Diabetes is a chronic metabolic disorder that continues to present as a major health problem worldwide. It is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action and is associated with chronic hyperglycemia and disturbances of carbohydrate, lipid and protein metabolism. Many studies suggest a central role for oxidative stress in the pathogenesis of this multifaceted metabolic disorder. This has prompted investigations in the use of antioxidants as a complementary therapeutic approach [Golbidi et al., 2011]. Serum CoQ10 levels in type 2 diabetic patients are often decreased and may be associated with subclinical diabetic cardiomyopathy, reversible by CoQ10 supplementation [Miyake et al., 1999]. In 3 separate randomized, double-blind clinical trials, a total of 194 dyslipidemic type 2 diabetic patients received 200 mg CoQ10 or a placebo daily for 12 weeks. One study also compared CoQ10 stand-alone treatment to a CoQ10-fenofibrate combination and to fenofibrate (a lipid-lowering medication) alone. Primary outcomes were endothelial function of the brachial artery [Watts et al., 2002], blood pressure [Hodgson et al., 2002], glycemic control [Hodgson et al., 2002], and forearm microcirculatory function [Playford et al., 2003]. CoQ10 supplementation in this population raised plasma CoQ10 levels, improved endothelial function in the brachial artery, significantly decreased both systolic and diastolic blood pressure, decreased glycosylated hemoglobin (HbA1C), and, in combination with fenofibrate, markedly improved both endothelial and non-endothelial forearm vasodilation.

Furthermore, it has been demonstrated that a 12-week treatment with ubiquinone improves clinical outcomes and nerve conduction parameters of diabetic polyneuropathy; furthermore, it reduces oxidative stress without significant adverse events [Hernández-Ojeda et al., 2012].

Cancer

Decreased levels of CoQ10 have been found in plasma of women with breast cancer and in cancerous breast tissue, and low levels correlated with a worse prognosis [Jolliet et al., 1998]. Case reports demonstrated 390 mg CoQ10 daily resulted in tumor regression and disappearance of previously diagnosed metastasis. Approximately 1-3 years later, depending on the case, metastases had not reappeared [Lockwood et al., 1994; Rusciani et al., 2006].

In 117 melanoma patients without metastasis, plasma CoQ10 levels were significantly lower than in control subjects and were associated with primary tumor thickness, with the highest CoQ10 levels associated with thinner tumors. In addition, patients who developed metastases had lower CoQ10 levels than those who did not, and subjects with lower baseline CoQ10 levels had shorter disease-free intervals [Rusciani et al., 2006]. Low plasma levels of CoQ10 have been demonstrated in cervical intraepithelial neoplasia and cervical cancer [Palan et al., 2003].

Mechanisms for CoQ10's benefit for cancer may include immune system enhancement and antioxidant activity. CoQ10 can be depleted by the use of the chemotherapeutic drug doxorubicin (Adriamycin®), resulting in cardiotoxicity if a high enough cumulative dose is achieved. Supplemental CoQ10 (100-200 mg/day) can prevent cardiac damage, as well as diarrhea and stomatitis that are caused by this agent, without decreasing its chemotherapeutic effectiveness [Domae et al., 1981]. A systematic review of controlled trials in cancer patients revealed CoQ10 provides protection against cardiotoxicity and liver toxicity in patients receiving anthracycline chemotherapy drugs, such as doxorubicin [Roffe et al., 2004]. Recently, it has been reported that chemotherapeutic drugs such as camptothecin, etoposide, doxorubicin and methotrexate induced an increase in CoQ10 levels in cancer cell lines by upregulation of COQ7, COQ4 and COQ8 gene expression, as part of an antioxidant response against free radical production [Brea-Calvo et al., 2006]. On the other hand, compositions containing reduced CoQ10 (in foods and beverages) have been proposed for preventing cancer and for mitigating the adverse reactions of anticancer agents [Villalba et al., 2010].

Neurological Conditions

Parkinson's Disease

A number of preclinical studies in both in vitro and in vivo models of Parkinson's disease (PD) have demonstrated that CoQ10 can protect the nigrostriatal dopaminergic system. Some clinical trials have looked at the neuroprotective effects of CoQ10 in patients in early and mid-stage PD [Liu et al., 2011]. Research suggests CoQ10 may play a role in the cellular dysfunction found in PD, providing a protective agent for Parkinsonian patients [Shults et al., 1999]. Significantly reduced levels of CoQ10 have been observed in blood and platelet mitochondria [Shults et al., 1997] and plasma [Sohmiya et al., 2004] of PD patients. Since 1998, at least 4 clinical trials on the efficacy of CoQ10 in PD have been conducted [Shults et al., 1998, 2004; Horstink and van Engelen, 2003; Müller et al., 2003].

Results seem to indicate a positive effect, warranting larger double-blind, placebo-controlled trials. Recently, it has been demonstrated that cellular pathophysiological alterations associated with mitochondrial dysfunction in induced pluripotent stem cell-derived neural cells from familial PD patients and at-risk individuals could be rescued with CoQ10 [Cooper et al., 2012].

Huntington's Disease

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion of CAG repeats in the HD gene encoding for huntingtin (Htt), resulting in progressive death of striatal neurons, with clinical symptoms of chorea, dementia and dramatic weight loss. Metabolic and mitochondrial dysfunction caused by the expanded polyglutamine sequence have been described along with other mechanisms of neurodegeneration previously described in human tissues and animal models of HD [Naia et al., 2011]. Strong evidence exists for early oxidative stress in HD, coupled with mitochondrial dysfunction, each exacerbating the other and leading to an energy deficit [Stack et al., 2008]. If oxidative damage plays a role in HD, then therapeutic strategies that reduce reactive oxygen species may ameliorate the neurodegenerative process. One such strategy using CoQ10 has been proposed. High-dose CoQ10 is safe and tolerable in HD patients. In addition, there are parallels in reducing markers of oxidative stress in both HD mice and HD patients after CoQ10 treatment [Stack et al., 2008].

Alzheimer's Disease

Increasing evidence suggests that Alzheimer's disease is associated with oxidative damage that is caused in part by mitochondrial dysfunction [Wadsworth et al., 2008]. Studies have shown CoQ10 to be neuroprotective in Alzheimer's disease through protection of oxidative damage and attenuation of mitochondrial dysfunction [Lee et al., 2009].

However, in a recent double-blind, placebo-controlled clinical trial (Trial Registration clinicaltrials.gov Identifier: NCT00117403), antioxidant treatment, including CoQ10, did not influence cerebrospinal fluid biomarkers related to amyloid or tau pathology [Galasko et al., 2012].

Friedreich's Ataxia

There is extensive evidence that mitochondrial respiratory chain dysfunction, oxidative damage and iron accumulation play significant roles in the disease mechanism. Therapeutic avenues for patients with Friedreich's ataxia (FRDA) are beginning to be explored in particular targeting antioxidant protection, enhancement of mitochondrial oxidative phosphorylation, iron chelation, and more recently increasing FRDA transcription. The use of quinone therapy has been the most extensively studied to date with clear benefits demonstrated using evaluations of both disease biomarkers and clinical symptoms [Cooper and Schapira, 2007].

An open-label pilot trial explored the use of 400 mg CoQ10 plus 2,100 IU of vitamin E daily in 10 patients with FRDA for 47 months. A sustained improvement in mitochondrial energy synthesis was observed that was associated with a decrease of disease progression and improved cardiac function [Hart et al., 2005]. However, results are less satisfactory in shorter studies. Idebenone, a synthetic analog of CoQ10, did not significantly alter neurological function in FRDA during the 6-month study. Larger studies of longer duration may be needed to assess the therapeutic potential of drug candidates on neurological function in FRDA [Lynch et al., 2010].

Other Conditions

Male Infertility

Both the bioenergetic and the antioxidant role of CoQ10 suggest a possible involvement in sperm biochemistry and male infertility [Mancini and Balercia, 2011]. CoQ10 can be quantified in seminal fluid, where its concentration correlates with sperm count and motility [Mancini et al., 1994]. It was found that distribution of CoQ10 between sperm cells and seminal plasma was altered in varicocele patients, who also presented a higher level of oxidative stress and lower total antioxidant capacity. The redox status of CoQ10 in seminal fluid was also determined: an inverse correlation was found between ubiquinol/ubiquinone ratio and hydroperoxide levels and between this ratio and the percentage of abnormal sperm forms. Subsequently, CoQ10 was administered to a group of idiopathic asthenozoospermic infertile patients. Treatment led to a significant increase in the concentration of CoQ10, both in seminal plasma and sperm cells, and improvement in sperm motility [Mancini et al., 2005]. In a recent study, it has been demonstrated that CoQ10 improves semen quality and pregnancy rate [Safarinejad, 2012].

Periodontal Disease

Periodontal disease is an inflammatory disease process resulting from the interaction of a bacterial attack and host inflammatory response. Arrays of molecules are considered to mediate the inflammatory response at one time or another, among these are free radicals and reactive oxygen species (ROS). Periodontal pathogens can induce ROS overproduction and, thus, may cause collagen and periodontal cell breakdown. When ROS are scavenged by antioxidants, there can be a reduction of collagen degradation. Ubiquinol (reduced form of CoQ10) serves as an endogenous antioxidant which increases the concentration of CoQ10 in the diseased gingiva and effectively suppresses advanced periodontal inflammation [Prakash et al., 2010].

Migraine

Evidence indicates that impaired energy metabolism may be present in brains of migraine sufferers. Rozen et al. [2002] supplemented migraine patients with 150 mg CoQ10 daily for 3 months and demonstrated a 50% reduction in the frequency of migraine headaches, regardless of whether patients experienced aura or not. Deficiency of CoQ10 may be common in pediatric and adolescent migraine. Determination of deficiency and consequent supplementation may result in clinical improvement [Hershey et al., 2007].

Pregnancy

Plasma CoQ10 levels rise with each trimester of pregnancy and fetal wasting with subsequent spontaneous abortion has been correlated with low levels of CoQ10 [Noia et al., 1996]. Supplementation with CoQ10 reduces the risk of developing pre-eclampsia (gestational hypertension in association with significant amounts of protein in the urine) in women at risk for the condition [Teran et al., 2009].

Down's Syndrome

Down's syndrome (DS) is a chromosomal abnormality (trisomy 21) associated with a complex phenotype. Oxidative stress is known to play a major role in this pathology both due to genetic and epigenetic factors, suggesting that oxidative imbalance contributes to the clinical manifestation of DS [Tiano et al., 2011]. Structural changes and abnormal function of mitochondria have been documented in DS cells, patients and animal models. DS cells in culture exhibit a wide array of functional mitochondrial abnormalities. Two studies have investigated the effect of CoQ10 treatment on DNA damage in DS patients. Results suggest that the effect of CoQ10 treatment in DS not only reflects antioxidant efficacy, but likely modulates DNA repair mechanisms [Tiano and Busciglio, 2011].

Aging

The decrease of CoQ10 levels during aging could be one of the main factors in the development of chronic diseases in old people. Furthermore, since CoQ10 is not only an antioxidant, but also is involved in a plethora of cellular processes, appropriate uptake of CoQ10 into cells is crucial for the improvement of cell activity during aging. Maintenance of CoQ10 functional levels at cell membranes either by dietary supplementation or by improving endogenous synthesis can be a key strategy to enhance health during aging [López-Lluch et al., 2010].

Drug-Nutrient Interactions

Cholesterol-lowering drugs such as lovastatin and pravastatin inhibit the enzyme HMG-CoA reductase, required for synthesis of cholesterol as well as CoQ10, resulting in a decreased serum CoQ10 [Mortensen et al., 1997]. Beta blockers propranolol and metoprolol [Kishi et al., 1977], and phenothiazines and tricyclic antidepressants have been shown to inhibit CoQ10-dependent enzymes [Moreno-Fernández et al., 2012]. CoQ10's effects on platelet function may increase the risk of bleeding in patients taking antiplatelet drugs such as aspirin [Serebruany et al., 1997]. On the other hand, since it acts like vitamin K, it may counteract the anticoagulant effects of warfarin [Singh et al., 2007]. CoQ10 may have an additive antihypertensive effect when given with antihypertensive drugs [Bonakdar and Guarneri, 2005]. CoQ10 may improve beta-cell function and enhance insulin sensitivity, which may reduce insulin requirements for diabetic patients [Hodgson et al., 2002].

Toxicity

CoQ10 treatment is safe, even at the highest doses cited in the literature. Most clinical trials have not reported significant adverse effects that necessitated stopping therapy [Hidaka et al., 2008]. However, gastrointestinal effects such as abdominal discomfort, nausea, vomiting, diarrhea, and anorexia have occurred [Hidaka et al., 2008]. Allergic rash and headache have also been reported [Hidaka et al., 2008]. In addition, CoQ10's antiplatelet effect may increase the risk of bleeding [Greenberg and Frishman, 1990]. It undergoes biotransformation in the liver and is eliminated primarily via the biliary tract [Greenberg and Frishman, 1990], so it can accumulate in patients with hepatic impairment or biliary obstruction.

CoQ10-Related Compounds

Intestinal absorption of dietary CoQ10 is very limited and only chronic ingestion of relatively large doses of CoQ10 increase CoQ10 concentrations, especially in heart and brain mitochondria in rodent models [Bhagavan and Chopra, 2006]. For this reason, less hydrophobic structural derivatives of CoQ10, and therefore, with better pharmacokinetic profiles, are emerging as promising drugs for treating diseases with mitochondrial dysfunction. Idebenone and MitoQ have already been evaluated in clinical trials for safety, toxicity and their effect for treating different diseases [Villalba et al., 2010].

Acknowledgements

This work was supported by grants (FIS PI10/00543, FIS EC08/00076) from the Ministerio de Sanidad, Spain, and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea); Servicio Andaluz de Salud-Junta de Andalucía (SAS 111242); Proyecto de Investigación de Excelencia de la Junta de Andalucía (CTS-5725); and by AEPMI (Asociación de Enfermos de Patología Mitocondrial), FEEL (Fundación Española de Enfermedades Lisosomales) and ALBA Andalucía (Federación Andaluza de Fibromialgia y Fatiga Crónica).

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