Coenzyme Q deficiency -
Simultaneous measurement of both reduced and oxidized forms of CoQ 10 usually requires a complex pre-analytical management of samples, and chromatographically, this is more complicated than the measurement of total CoQ Furthermore, the propensity of ubiquinol to oxidise to CoQ 10 unless frozen immediately at °C may detract from the clinical utility of this determination [Molyneux et al.
Therefore, the simultaneous assessment of both reduced and oxidised forms of CoQ 10 is probably more suitable for research purposes rather than for clinical diagnosis. However, in appropriately handled tissue samples the ratio of ubiquinol:CoQ 10 has been used as a marker of oxidative stress [Niklowitz et al.
In the following paragraphs, details of the HPLC methods employed to determine tissue CoQ 10 status in the laboratories of the authors will be outlined. Total tissue CoQ 10 status is quantified by reverse-phase HPLC with UV detection at nm according to the method of Duncan et al.
CoQ 10 is separated on a HPLC column Techsphere ODS 5 μm, × 4. The flow rate is maintained at 0. Ubiquinone species are detected at nm. This HPLC method has been used to determine the CoQ 10 status of skeletal muscle and blood mononuclear cells which were prepared and extracted according to the method of Duncan et al.
The total CoQ 10 concentration is quantified by reverse-phase HPLC with electrochemical detection Coulochem II, ESA, Mass. Briefly, CoQ 9 and CoQ 10 are separated in a nucleosil C column 5 μm, 25 × 0.
This HPLC method has been employed to assess the CoQ 10 status of plasma, skeletal muscle, and fibroblasts fig. Reverse-phase HPLC-ED chromatograms of CoQ 9 and CoQ 10 in a standard calibrator Q 10 and internal standard Q 9 profile, b serum profile, c muscle profile, and d fibroblast profile.
A major difficulty encountered when assessing CoQ 10 status in tissue is the lack of commercially available non-physiological internal standards IS. In most cases coenzyme Q 9 is the IS of choice [Okamoto et al.
To avoid the possible influence of endogenous ubiquinones when evaluating tissue CoQ 10 status, the non-physiological ubiquinones, di-ethoxy-CoQ 10 [Edlund, ] and di-propoxy-CoQ 10 [Duncan et al.
Clinical assessment of CoQ 10 deficiency is generally based on plasma measurements, and the reference interval established for plasma CoQ 10 status appears to range from 0. Plasma CoQ 10 levels are also monitored following supplementation therapy to assess absorption and bioavailability of CoQ 10 formulations.
Plasma CoQ 10 levels as high as In Parkinson's disease, plasma CoQ 10 levels of 4. In contrast, a plasma level of 2. Gender does not appear to influence plasma CoQ 10 status [Molyneux et al.
Plasma CoQ 10 status is influenced by both dietary supply and hepatic biosynthesis [Hargreaves et al. This is in contrast to other tissues which are dependent upon de novo biosynthesis [Kalen et al.
The effect of diet is of particular importance, since CoQ 10 has a relatively long circulatory half-life approx. Therefore, in view of its dependence upon both dietary intake and lipoprotein concentration, plasma CoQ 10 status may not truly reflect tissue levels [Duncan et al.
It has been suggested that plasma CoQ 10 levels should be expressed as a ratio to either total plasma cholesterol or LDL cholesterol in order to be of diagnostic value [Kontush et al. Furthermore, expressing plasma CoQ 10 as a ratio to total cholesterol appears to exclude any influence of age on this parameter [Wolters and Hahn, ; Molyneux et al.
Assessment of blood mononuclear cells has been suggested as an alternative surrogate to evaluate endogenous CoQ 10 status [Duncan et al. Blood mononuclear cells are also reported to reflect changes in cellular status following supplementation [Turunen et al.
This is illustrated by the patient described in the study of Duncan et al. Platelets have also been used as surrogates to evaluate endogenous CoQ 10 levels in clinical studies [Shults et al. Furthermore, the CoQ 10 status of platelets was also found to increase following CoQ 10 supplementation indicating these cell fragments may also be used to monitor the effect of CoQ 10 supplementation on endogenous levels [Niklowitz et al.
Skeletal muscle is generally considered as the tissue of choice for CoQ 10 assessment, and this tissue has been used in diagnosis of CoQ 10 deficiency since the first cases of this deficiency were reported by Ogasahara et al.
However, in view of the importance of this tissue in the diagnosis of CoQ 10 deficiency, there appears to be no universally accepted units in which to represent skeletal muscle CoQ 10 status, and therefore it is difficult to compare reference ranges between laboratories table 2.
Interestingly, although HPLC-UV and HPLC-ED detection methods were used to determine skeletal muscle CoQ 10 status in the studies reported by Rahman et al. In the study by Montero et al. When the muscle CoQ 10 content was related to citrate synthase CS activity, the mitochondrial marker enzyme [Selak et al.
A possible explanation for this observation offered by the authors was the possibility that the high degree of muscle injury the patient was experiencing [rhabdomyolysis and elevated plasma creatine kinase levels , UI; reference values UI ] may have resulted in a depletion of skeletal muscle protein.
This is especially important in mitochondrial myopathies where excessive proliferation of mitochondria has been reported in muscle [DiMauro, ] and therefore expressing CoQ 10 to CS activity which takes into account that the mitochondrial enrichment of the sample may highlight evidence of a deficiency which may not be identifiable if CoQ 10 status is solely related to total protein.
Reference values for CoQ 10 levels in muscle and fibroblasts expressed in the different units reported in the literature. Furthermore, the study by Montero et al. However, normal levels of complex I-III or II-III activity do not exclude a decrease in muscle CoQ 10 status as has previously been observed in patients with the ataxic phenotype of CoQ 10 deficiency [Lamperti et al.
In view of the essential role ubiquinol plays in pyrimidine synthesis [Lopez et al. Therefore, the assessment of muscle CoQ 10 status in patients who present with multiple ETC deficiencies should not be discouraged.
Furthermore, in view of the association between mitochondrial DNA mutations and muscle coenzyme Q 10 deficiency, assessment of muscle CoQ 10 status should be considered in addition to the determination of ETC enzyme activities in patients with suspected mitochondrial disease [Sacconi et al.
Assessment of fibroblast CoQ 10 status should also be considered in the diagnosis of CoQ 10 deficiency. Published reference ranges for fibroblast CoQ 10 status are shown in table 2. In view of the suggested tissue specificity of CoQ 10 deficiency, a normal level of CoQ 10 in fibroblasts does not exclude a deficit in CoQ 10 status in other tissues [Ogasahara et al.
Indeed, normal levels of fibroblast CoQ 10 have been reported in patients with genetically confirmed defects in CoQ 10 biosynthesis [Lagier-Tourenne et al. In contrast, however, fibroblast assessment has been used to reveal evidence of a CoQ 10 deficiency in a patient with a normal muscle CoQ 10 status [Montero et al.
These radiolabelled incorporation studies can be used to confirm a deficiency in CoQ 10 biosynthesis, identify the position of the defect in the biosynthetic pathway in some cases, as well as to discriminate between primary and secondary CoQ 10 deficiencies.
In view of the preponderance of neurological dysfunction associated with CoQ 10 deficiency [Mancuso et al. Cerebral spinal fluid CSF is considered the appropriate surrogate to assess cerebral CoQ 10 status.
However, in view of the low levels of CoQ 10 detected in CSF with HPLC-UV, detection would be insufficiently sensitive for this analysis [Duncan et al. Tentative reference ranges for CSF CoQ 10 levels of 1. The discrepancies in these ranges may in part result from the different analytical techniques and sample preparations employed for this determination.
In the study by Artuch et al. In contrast, tandem spectrometry was employed to determine the CoQ 10 status in unfiltered CSF in the study by Duberley et al. Although Isobe et al. Therefore, in order to establish a more reliable and robust reference interval for CSF CoQ 10 status, further studies are required that evaluate the effects of age, gender, as well as the rostral-caudal gradient upon CSF levels of this ubiquinone.
The actual prevalence of human CoQ 10 deficiency is at present unknown, but it is suspected that this condition is under-diagnosed [Rahman et al. This is compounded by the lack of specialist centres which are able to determine tissue CoQ 10 status together with the extreme clinical heterogeneity of this condition [Rahman et al.
It is recommended that the CoQ 10 status is determined in the muscle biopsies of all patients with suspected mitochondrial disease. Once evidence of a CoQ 10 deficiency is detected, further studies will be required to elucidate the underlying cause of this defect. Genetic investigations and radiolabelled biosynthetic studies in fibroblasts may help to distinguish between primary or secondary causes of the deficiency.
However, in a number of patients with CoQ 10 deficiency it has not been possible to elucidate the underlying cause of the defect [Rahman et al. Since muscle biopsies may not always be available, there is a need for a less invasive means to assess tissue CoQ 10 status.
Although there are some concerns over the diagnostic value of plasma CoQ 10 levels, platelet and blood mononuclear cell determinations may offer an alternative means for this assessment.
It has been suggested that there may be tissue specific isoenzymes in the CoQ 10 biosynthetic pathway; therefore the CoQ 10 status of one tissue may not reflect that of another [Ogasahara et al. Since neurological dysfunction is a constant clinical feature in CoQ 10 deficiency syndromes, although some defects may be expressed in muscle or peripheral tissue, other defects such as those in cerebral CoQ 10 biosynthesis may not be expressed and may remain undiagnosed.
The ability to accurately assess CSF CoQ 10 status may therefore enhance the diagnosis yield of patients with neurological dysfunction and previously undiagnosed cerebral CoQ 10 deficiency. In view of the differences in the tissue of choice for CoQ 10 assessment, units in which CoQ 10 is expressed and the reference intervals used for this diagnosis between laboratories a more unified approach is required for monitoring patients and their treatment.
The establishment of an external quality control Ex-QC scheme for the measurement of tissue CoQ 10 status is suggested for laboratories offering this clinical diagnostic service. At present, a trial Ex-QC scheme is running between laboratories in the UK and Spain and, if successful, will be offered on a more global scale.
Part of this work was undertaken at the University College of London Hospitals who received a proportion of their funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.
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Advanced Search. Skip Nav Destination Close navigation menu Article navigation. Volume 5, Issue Methods Used to Determine Tissue CoQ 10 Status. Tissue Assessment. Article Navigation. Review Articles May 17 The encephalomyopathic form of CoQ 10 deficiency, manifesting as a triad of mitochondrial myopathy, recurrent myoglobinuria, and encephalopathy, has been reported in 4 patients eTable 2.
The myopathic form of CoQ 10 deficiency presents with muscle weakness, myoglobinuria, exercise intolerance, cramps, myalgia, and elevated creatine kinase. This condition has been described in 10 patients.
Among the 17 patients including 2 new patients with the infantile multisystemic form, the combination of encephalopathy and nephropathy has been the most common presentation eTable 4.
The renal involvement is mainly nephrotic syndrome but occasionally tubulopathy. Three patients required kidney transplantation. Early-onset isolated steroid-resistant nephrotic syndrome owing to collapsing glomerulopathy and focal segmental glomerulosclerosis has been reported in 2 patients.
Cerebellar ataxia is the most common phenotype, with 94 patients including 23 new patients eTable 6. Among the patients classified as atypical cases, there were 2 adult sisters with childhood-onset Leigh syndrome, growth retardation, infantilism, ataxia, deafness, and lactic acidosis, 34 a 4-year-old girl with cardiofaciocutaneous syndrome, 35 2 unrelated patients with neonatal hypotonia and infantile spasm 1 reported , 36 2 sisters with adult-onset cerebellar ataxia and nephrotic syndrome, and a year-old girl with onset at age 4 years of exercise intolerance, fatigue, recurrent headaches, short stature, deafness, retinopathy, and mental retardation.
One new patient was the father of a child with cerebellar ataxia P in eTable 6 who had mild creatine kinase elevation but normal examination and brain magnetic resonance imaging results. Initial biochemical evaluation of patients with suspected CoQ 10 deficiency should include blood lactate measurement, although normal values do not exclude ubiquinone deficiency.
Muscle biopsies occasionally show mitochondrial proliferation or lipid droplets, but they can be normal or show only nonspecific changes.
Reduction of these enzyme activities and deficiency of CoQ 10 in skin fibroblasts can be an important confirmation of ubiquinone deficiency; however, normal levels do not exclude deficiency in muscle.
Direct measurement of CoQ 10 in skeletal muscle by high-performance liquid chromatography is the most reliable test for the diagnosis.
In contrast, plasma concentrations of ubiquinone are significantly influenced by dietary uptake, therefore not reliable. Measurements of CoQ 10 in peripheral blood mononuclear cells has detected deficiency in a small number of patients; however, correlations with muscle CoQ 10 measurements in a larger cohort of patients will be necessary to assess clinical use of mononuclear cell ubiquinone levels.
Morphologic and biochemical findings differ in the various clinical forms. In contrast, fibroblast CoQ 10 levels have varied and were normal in 1 patient with encephalomyopathy but low in 1 of 2 patients with the myopathic form and in 7 of 8 patients with the infantile multisystemic form.
In 2 patients with isolated nephropathy , CoQ 10 levels and respiratory chain enzyme activities were reduced in either fibroblasts or muscle. Ragged-red—like fibers were observed in the only patient who underwent muscle biopsy. Muscle biopsies revealed mitochondrial proliferation, cytochrome c oxidase—negative fibers, or lipid accumulation in 15 of 49 patients and reduced respiratory chain enzyme activities in 27 of 51 patients with the ataxic form.
Levels of CoQ 10 were low in muscle but reduced in 18 of 30 fibroblasts. Primary CoQ 10 deficiency is due to mutations in genes involved in CoQ 10 biosynthesis Figure.
Secondary deficiencies include diseases caused by mutations in genes unrelated to ubiquinone biosynthesis, for example, the aprataxin APTX gene causing ataxia and oculomotor apraxia, 20 , 26 , 27 , 29 the electron-transferring-flavoprotein dehydrogenase gene ETFDH causing isolated myopathy, 7 and the BRAF gene causing cardiofaciocutaneous syndrome.
In most cases, family history suggests autosomal recessive inheritance. Pathogenic mutations have been reported in 63 patients Table 1. Except for the patients reported by Gempel and colleagues in , 7 we did not find other mutations in ETFDH in our cohort of patients with isolated myopathy, indicating that other genes may be responsible for this phenotype.
Most patients with the infantile-onset multisystemic variant have genetically confirmed primary CoQ 10 deficiency. Mutations have been described in COQ2 3 patients , 11 , 12 , 16 PDSS2 1 patient , 8 COQ9 1 patient , 9 PDSS1 2 patients , 16 and COQ6 3 patients.
There are 3 potential explanations for the divergent phenotypes. First, variations in the phenotypes may be due to genetic or environmental modifiers. Second, patients with isolated nephropathies may develop multisystemic disease later in life. Third, CoQ 10 treatment may have altered the clinical course of the disease by preventing neurologic complications in both patients with only renal disease.
In contrast, in 9 patients, mutations in the COQ6 gene have been associated with kidney involvement nephrotic syndrome and nephrolithiasis and sensorineural hearing loss. A subgroup of patients with juvenile-onset cerebellar ataxia have primary CoQ 10 deficiency owing to mutations in the ADCK3 gene 22 patients.
Patients with CoQ 10 deficiency showed variable responses to CoQ 10 treatment Table 3. In patients with encephalomyopathy, muscle symptoms improved after therapy.
Six patients with pure myopathy 4 - 7 including 1 unreported improved after CoQ 10 supplementation, while 2 patients with ETFDH mutations improved only after addition of treatment with riboflavin, mg daily. In some patients with the infantile multisystemic form, CoQ 10 supplementation has halted progression of the encephalopathy and improved the myopathy.
Published data for 2 patients with mutations in the COQ6 gene noted decreased proteinuria in both patients after CoQ 10 treatment, but hearing improved in only 1 patient.
Response to CoQ 10 supplementation in patients with cerebellar ataxia is also variable. Three patients with mutations in the ADCK3 gene showed mild clinical improvement after treatment, 17 , 30 , 31 but 7 patients carrying mutations in the same gene did not improve 24 , 32 and another patient, despite dramatic muscle improvement, developed tremor, myoclonic jerks, and cerebellar atrophy.
Among the clinically atypical cases of CoQ 10 deficiency, 2 sisters with Leigh syndrome and 1 patient with cardiofaciocutaneous syndrome improved after CoQ 10 supplementation.
It is important to identify CoQ 10 deficiency as this condition often responds to supplementation. Molecular genetic testing has revealed causative mutations in a small proportion of patients, indicating that screening for DNA mutations is not yet effective for diagnosing CoQ 10 deficiency.
Our observations not only highlight the clinical heterogeneity of CoQ 10 deficiency but also the genetic heterogeneity that is likely related to the large number of proteins involved in ubiquinone biosynthesis and regulation and of secondary CoQ 10 deficiencies.
Clinical improvement after CoQ 10 supplementation was documented in many patients, but treatment protocols have not been standardized and results have not been uniform. Progress in our knowledge of the genetic bases of CoQ 10 deficiencies may help researchers develop a more accurate molecular classification of this syndrome, while additional studies of the pathogenesis of CoQ 10 deficiency may lead to more effective therapies.
Correspondence: Michio Hirano, MD, H. Published Online: April 9, Corrected on May 2, Author Contributions: All authors contributed equally to this article. Study concept and design : Emmanuele, DiMauro, Quinzii, and Hirano.
Analysis and interpretation of data : Emmanuele, López, Berardo, DiMauro, Quinzii, and Hirano. Drafting of the manuscript : Emmanuele, López, Solomon, Quinzii, and Hirano. Statistical analysis : Emmanuele and Solomon. Obtained funding : Quinzii and Hirano.
Administrative, technical, and material support : Emmanuele, López, Naini, Tadesse, Wen, and Hirano. Study supervision : Emmanuele, DiMauro, and Quinzii.
Dr Hirano's work is supported by grants R01HD and 1RC1NS from the National Institutes of Health, as well as grants from the Muscular Dystrophy Association and the Marriott Mitochondrial Disorder Clinical Research Fund. Additional Contributions: We are grateful to all of the patients and relatives for their participation.
We thank all of the clinicians who referred patients and samples to us. full text icon Full Text. Download PDF Top of Article Abstract Table 1. Clinical Features of Major Forms of CoQ 10 Deficiency Methods Clinical features Diagnosis Genetics Therapy Conclusions Article Information References.
View Large Download. Table 1. Clinical Features of Major Forms of CoQ 10 Deficiency. Table 2. Laboratory Features of Major Forms of CoQ 10 Deficiency. Table 3. Clinical Response to CoQ 10 Supplementation in Major Forms of CoQ 10 Deficiency. When LDL is oxidized, CoQ 10 H 2 is the first antioxidant consumed.
In isolated mitochondria , coenzyme Q 10 can protect membrane proteins and mitochondrial DNA from the oxidative damage that accompanies lipid peroxidation 5. Moreover, when present, CoQ 10 H 2 was found to limit the formation of oxidized lipids and the consumption of α-tocopherol a form of vitamin E with antioxidant properties 6.
Indeed, in addition to neutralizing free radicals directly, CoQ 10 H 2 is capable of regenerating antioxidants like α-tocopherol and ascorbate vitamin C 4.
α-Tocopherol vitamin E and coenzyme Q 10 are the principal fat-soluble antioxidants in membranes and lipoproteins.
When α-tocopherol α-TOH neutralizes a free radical , such as a lipid peroxyl radical LOO· , it becomes oxidized itself, forming α-TO·, which can in turn promote the oxidation of lipoproteins under certain conditions in the test tube, thus propagating a chain reaction. However, when the reduced form of coenzyme Q 10 CoQ 10 H 2 reacts with α-TO·, α-TOH is regenerated and the semiquinone radical CoQ 10 H· is formed.
It is possible for CoQ 10 H· to react with oxygen O 2 to produce superoxide anion radical O 2 · - , which is a less reactive pro-oxidant than LOO·.
However, CoQ 10 H· can also reduce α-TO· back to α-TOH, resulting in the formation of fully oxidized coenzyme Q 10 CoQ 10 , which does not react with O 2 to form O 2 · - Figure 3 6, 8.
Coenzyme Q 10 deficiency has not been described in the general population, so it is generally assumed that normal biosynthesis , with or without a varied diet, provides sufficient coenzyme Q 10 to sustain energy production in healthy individuals 9.
Primary coenzyme Q 10 deficiency is a rare genetic disorder caused by mutations in genes involved in coenzyme Q 10 biosynthetic pathway. To date, mutations in at least nine of these genes have been identified 1. As a result, primary coenzyme Q 10 deficiency is a clinically heterogeneous disorder that includes five major phenotypes: i severe infantile multi-systemic disease, ii encephalomyopathy, iii cerebellar ataxia , iv isolated myopathy , and v nephrotic syndrome.
Whereas most mitochondrial respiratory chain disorders are hardly amenable to treatments, oral coenzyme Q 10 supplementation has been shown to improve muscular symptoms in some yet not all patients with primary coenzyme Q 10 deficiency Neurological symptoms in patients with cerebellar ataxia are only partially relieved by coenzyme Q 10 CoQ 10 H 2 supplementation Secondary coenzyme Q 10 deficiency results from mutations or deletions in genes that are not directly related to coenzyme Q 10 biosynthetic pathway.
Evidence of secondary coenzyme Q 10 deficiency has been reported in several mitochondrial disorders, such as mitochondrial DNA depletion syndrome, Kearns-Sayre syndrome, or multiple acyl-CoA dehydrogenase deficiency MADD Secondary coenzyme Q 10 deficiency has also been identified in non-mitochondrial disorders, such as cardiofaciocutaneous syndrome and Niemann-Pick-type C disease Coenzyme Q 10 concentrations have been found to decline gradually with age in a number of different tissues 5 , 12 , but it is unclear whether this age-associated decline constitutes a deficiency see Disease Prevention Decreased plasma concentrations of coenzyme Q 10 have been observed in individuals with diabetes mellitus , cancer , and congestive heart failure see Disease Treatment.
Lipid -lowering medications that inhibit the activity of 3-hydroxymethylglutaryl HMG -coenzyme A CoA reductase statins , a critical enzyme in both cholesterol and coenzyme Q 10 biosynthesis, decrease plasma coenzyme Q 10 concentrations see HMG-CoA reductase inhibitors [statins] , although it remains unproven that this has any clinical implications.
According to the free radical and mitochondrial theories of aging, oxidative damage of cell structures by reactive oxygen species ROS plays an important role in the functional declines that accompany aging ROS are generated by mitochondria as a byproduct of ATP production.
If not neutralized by antioxidants , ROS may damage mitochondria over time, causing them to function less efficiently and to generate more damaging ROS in a self-perpetuating cycle.
Coenzyme Q 10 plays an important role in mitochondrial ATP synthesis and functions as an antioxidant in mitochondrial membranes see Biological Activities. One of the hallmarks of aging is a decline in energy metabolism in many tissues, especially liver, heart, and skeletal muscle.
Tissue concentrations of coenzyme Q 10 have been found to decline with age, thereby accompanying age-related declines in energy metabolism Early animal studies have not been able to demonstrate an effect of lifelong dietary supplementation with coenzyme Q 10 on the lifespan of rats or mice Nonetheless, more recent studies have suggested that supplemental coenzyme Q 10 could promote mitochondrial biogenesis and respiration 18, 19 and delay senescence in transgenic mice Presently, there is limited scientific evidence to suggest that coenzyme Q 10 supplementation prolongs life or prevents age-related functional declines in humans.
Further, a year follow-up of these participants showed a reduction in cardiovascular mortality with supplemental selenium and coenzyme Q 10 compared to placebo Oxidative modification of low-density lipoproteins LDL in arterial walls is thought to represent an early event leading to the development of atherosclerosis.
Reduced coenzyme Q 10 CoQ 10 H 2 inhibits the oxidation of LDL in the test tube in vitro and works together with α-tocopherol α-TOH to inhibit LDL oxidation by regenerating α-TO· back to α-TOH.
In the absence of a co- antioxidant , such as CoQ 10 H 2 or vitamin C, α-TO· can, under certain conditions, promote the oxidation of LDL in vitro 6. Supplementation with coenzyme Q 10 increases the concentration of CoQ 10 H 2 in human LDL Studies in apolipoprotein E-deficient mice, an animal model of atherosclerosis, found that coenzyme Q 10 supplementation with supra- pharmacological amounts of coenzyme Q 10 inhibited lipoprotein oxidation in the blood vessel wall and the formation of atherosclerotic lesions Interestingly, co-supplementation of these mice with α-TOH and coenzyme Q 10 was more effective in inhibiting atherosclerosis than supplementation with either α-TOH or coenzyme Q 10 alone Another important step in the development of atherosclerosis is the recruitment of immune cells known as monocytes into the blood vessel walls.
This recruitment is dependent in part on monocyte expression of cell adhesion molecules integrins. Although coenzyme Q 10 supplementation shows promise as an inhibitor of LDL oxidation and atherosclerosis, more research is needed to determine whether coenzyme Q 10 supplementation can inhibit the development or progression of atherosclerosis in humans.
Inherited coenzyme Q 10 deficiencies are rare diseases that are clinically and genetically heterogeneous see Deficiency. Early treatment with pharmacological doses of coenzyme Q 10 is essential to limit irreversible organ damage in coenzyme Q 10 -responsive deficiencies 1.
It is not clear to what extent coenzyme Q 10 supplementation might have therapeutic benefit in patients with inherited secondary Q 10 deficiencies. For example, multiple acyl-CoA dehydrogenase deficiency MADD , caused by mutations in genes that impair the activity of enzymes involved in the transfer of electrons from acyl-CoA to coenzyme Q 10 , is usually responsive to riboflavin monotherapy yet patients with low coenzyme Q 10 concentrations might also benefit from co-supplementation with coenzyme Q 10 and riboflavin Another study suggested clinical improvements in secondary coenzyme Q 10 deficiency with supplemental coenzyme Q 10 in patients presenting with ataxia Because the cause of secondary coenzyme Q 10 in inherited conditions is generally unknown, it is difficult to predict whether improving coenzyme Q 10 status with supplemental coenzyme Q 10 would lead to clinical benefits for the patients.
Finally, coenzyme Q 10 deficiency can be secondary to the inhibition of HMG-CoA reductase by statin drugs see Deficiency. The trials failed to establish a diagnosis of relative coenzyme Q 10 deficiency before the intervention started, hence limiting the conclusion of the meta-analysis.
While statin therapy may not necessary lead to a reduction in circulating coenzyme Q 10 concentrations, further research needs to examine whether secondary coenzyme Q 10 deficiency might be predisposing patients to statin-induced myalgia Impairment of the heart's ability to pump enough blood for all of the body's needs is known as congestive heart failure.
In coronary heart disease CHD , accumulation of atherosclerotic plaque in the coronary arteries may prevent parts of the cardiac muscle from getting adequate blood supply, ultimately resulting in heart damage and impaired pumping ability. Heart failure can also be caused by myocardial infarction , hypertension , diseases of the heart valves, cardiomyopathy , and congenital heart diseases.
Because physical exercise increases the demand on the weakened heart, measures of exercise tolerance are frequently used to monitor the severity of heart failure.
Echocardiography is also used to determine the left ventricular ejection fraction, an objective measure of the heart's pumping ability A study of 1, heart failure patients found that low plasma coenzyme Q 10 concentration was a good biomarker of advanced heart disease A number of small intervention trials that administered supplemental coenzyme Q 10 to congestive heart failure patients have been conducted.
Pooling data from some of the trials showed an increase in serum coenzyme Q 10 concentrations three studies but no effect on left ventricular ejection fraction two studies or exercise capacity two studies The heart muscle may become oxygen-deprived ischemic as the result of myocardial infarction or during cardiac surgery.
Increased generation of reactive oxygen species ROS when the heart muscle's oxygen supply is restored reperfusion might be an important contributor to myocardial damage occurring during ischemia-reperfusion Pretreatment of animals with coenzyme Q 10 has been found to preserve myocardial function following ischemia-reperfusion injury by increasing ATP concentration, enhancing antioxidant capacity and limiting oxidative damage , regulating autophagy , and reducing cardiomyocyte apoptosis Another potential source of ischemia-reperfusion injury is aortic clamping during some types of cardiac surgery, such as coronary artery bypass graft CABG surgery.
In a small randomized controlled trial in 30 patients, oral administration of coenzyme Q 10 for 7 to 10 days before CABG surgery reduced the need for mediastinal drainage, platelet transfusion, and positive inotropic drugs e.
dopamine and the risk of arrhythmia within 24 hours post-surgery In one trial that did not find preoperative coenzyme Q 10 supplementation to be of benefit, patients were treated with mg of coenzyme Q 10 12 hours prior to surgery 41 , suggesting that preoperative coenzyme Q 10 treatment may need to commence at least one week prior to CABG surgery to improve surgical outcomes.
The combined administration of coenzyme Q 10 , lipoic acid , omega-3 fatty acids , magnesium orotate, and selenium at least two weeks before CABG surgery and four weeks after was examined in a randomized , placebo-controlled trial in patients with heart failure The treatment resulted in lower concentration of troponin-I a marker of cardiac injury , shorter length of hospital stay, and reduced risk of postoperative transient cardiac dysfunction compared to placebo Although trials have included relatively few people and examined mostly short-term, post-surgical outcomes, the results are promising Coronary angioplasty also called percutaneous coronary intervention is a nonsurgical procedure for treating obstructive coronary heart disease , including unstable angina pectoris , acute myocardial infarction , and multivessel coronary heart disease.
Angioplasty involves temporarily inserting and inflating a tiny balloon into the clogged artery to help restore the blood flow to the heart. Periprocedural myocardial injury that occurs in up to one-third of patients undergoing otherwise uncomplicated angioplasty increases the risk of morbidity and mortality at follow-up.
A prospective cohort study followed 55 patients with acute ST segment elevation myocardial infarction a type of heart attack characterized by the death of some myocardial tissue who underwent angioplasty Plasma coenzyme Q 10 concentration one month after angioplasty was positively correlated with less inflammation and oxidative stress and predicted favorable left ventricular end-systolic volume remodeling at six months One randomized controlled trial has examined the effect of coenzyme Q 10 supplementation on periprocedural myocardial injury in patients undergoing coronary angioplasty The administration of mg of coenzyme Q 10 12 hours before the angioplasty to 50 patients reduced the concentration of C-reactive protein [CRP]; a marker of inflammation within 24 hours following the procedure compared to placebo.
However, there was no difference in concentrations of two markers of myocardial injury creatine kinase and troponin-I or in the incidence of major adverse cardiac events one month after angioplasty between active treatment and placebo Additional trials are needed to examine whether coenzyme Q 10 therapy can improve clinical outcomes in patients undergoing coronary angioplasty.
Myocardial ischemia may also lead to chest pain known as angina pectoris. People with angina pectoris often experience symptoms when the demand for oxygen exceeds the capacity of the coronary circulation to deliver it to the heart muscle, e.
In most of the studies, coenzyme Q 10 supplementation improved exercise tolerance and reduced or delayed electrocardiographic changes associated with myocardial ischemia compared to placebo.
However, only two of the studies found significant decreases in symptom frequency and use of nitroglycerin with coenzyme Q 10 supplementation. Presently, there is only limited evidence suggesting that coenzyme Q 10 supplementation would be a useful adjunct to conventional angina therapy.
Very few high-quality trials have examined the potential therapeutic benefit of coenzyme Q 10 supplementation in the treatment of primary hypertension In contrast, a meta-analysis that used less stringent selection criteria included 17 small trials and found evidence of a blood pressure-lowering effect of coenzyme Q 10 in patients with cardiovascular disease or metabolic disorders The effect of coenzyme Q 10 on blood pressure needs to be examined in large, well-designed clinical trials.
Endothelial dysfunction: Normally functioning vascular endothelium promotes blood vessel relaxation vasodilation when needed for example, during exercise and inhibits the formation of blood clots. Atherosclerosis is associated with impairment of vascular endothelial function, thereby compromising vasodilation and normal blood flow.
Endothelium-dependent vasodilation is impaired in individuals with elevated serum cholesterol concentrations, as well as in patients with coronary heart disease or diabetes mellitus. Evidence from larger studies is needed to further establish the effect of coenzyme Q 10 on endothelium-dependent vasodilation.
Recently published pooled analyses of these trials have given mixed results Larger studies are needed to examine the effect of coenzyme Q 10 supplementation on low-grade inflammation.
Blood lipids : Elevated plasma lipoprotein a concentration is an independent risk factor for cardiovascular disease. Other effects of coenzyme Q 10 on blood lipids have not been reported 51, 53, A therapeutic approach combining coenzyme Q 10 with other antioxidants might prove to be more effective to target co-existing metabolic disorders in individuals at risk for cardiovascular disease Diabetes mellitus is a condition of increased oxidative stress and impaired energy metabolism.
Plasma concentrations of reduced coenzyme Q 10 CoQ 10 H 2 have been found to be lower in diabetic patients than healthy controls after normalization to plasma cholesterol concentrations 56, Randomized controlled trials that examined the effect of coenzyme Q 10 supplementation found little evidence of benefits on glycemic control in patients with diabetes mellitus.
Maternally inherited diabetes mellitus-deafness syndrome MIDD is caused by a mutation in mitochondrial DNA , which is inherited exclusively from one's mother. Of note, the pathogenesis of type 2 diabetes mellitus involves the early onset of glucose intolerance and hyperinsulinemia associated with the progressive loss of tissue responsiveness to insulin.
Recent experimental studies tied insulin resistance to a decrease in coenzyme Q 10 expression and showed that supplementation with coenzyme Q 10 could restore insulin sensitivity 7. Coenzyme Q 10 supplementation might thus be a more useful tool for the primary prevention of type 2 diabetes rather than for its management.
Parkinson's disease is a degenerative neurological disorder characterized by tremors, muscular rigidity, and slow movements. Mitochondrial dysfunction and oxidative damage in a part of the brain called the substantia nigra may play a role in the development of the disease Decreased ratios of reduced -to- oxidized coenzyme Q 10 have been found in platelets of individuals with Parkinson's disease 61, Two recent meta-analyses of randomized, placebo-controlled trials found no evidence that coenzyme Q 10 improved motor-related symptoms or delayed the progression of the disease when compared to placebo 68, Huntington's disease is an inherited neurodegenerative disorder characterized by selective degeneration of nerve cells known as striatal spiny neurons.
Symptoms, such as movement disorders and impaired cognitive function, typically develop in the fourth decade of life and progressively deteriorate over time. Animal models indicate that impaired mitochondrial function and glutamate -mediated neurotoxicity may be involved in the pathology of Huntington's disease.
Interestingly, co-administration of coenzyme Q 10 with remacemide an NMDA receptor antagonist , the antibiotic minocycline, or creatine led to greater improvements in most biochemical and behavioral parameters To date, only two clinical trials have examined whether coenzyme Q 10 might be efficacious in human patients with Huntington's disease.
All dosages were generally well tolerated, with gastrointestinal symptoms being the most frequently reported adverse effect. Blood concentrations of coenzyme Q 10 at the end of the study were maximized with the daily dose of 2, mg The trial was prematurely halted because it appeared unlikely to demonstrate any health benefit in supplemented patients — about one-third of participants completed the trial at the time of study termination Although coenzyme Q 10 is generally well tolerated, there is no evidence that supplementation can improve functional and cognitive symptoms in Huntington's disease patients.
Friedreich's ataxia FRDA : FRDA is an autosomal recessive neurodegenerative disease caused by mutations in the gene FXN that encodes for the mitochondrial protein , frataxin.
Frataxin is needed for the making of iron -sulfur clusters ISC. ISC-containing subunits are especially important for the mitochondrial respiratory chain and for the synthesis of heme -containing proteins Frataxin deficiency is associated with imbalances in iron-sulfur containing proteins, mitochondrial respiratory chain dysfunction and lower ATP production, and accumulation of iron in the mitochondria, which increases oxidative stress and oxidative damage to macromolecules of the respiratory chain Clinically, FRDA is a progressive disease characterized by ataxia , areflexia , speech disturbance dysarthria , sensory loss, motor dysfunction, cardiomyopathy , diabetes , and scoliosis Follow-up assessments at 47 months indicated that cardiac and skeletal muscle improvements were maintained and that FRDA patients showed significant increases in fractional shortening, a measure of cardiac function.
Moreover, the therapy was effective at preventing the progressive decline of neurological function Large-scale, randomized controlled trials are necessary to determine whether coenzyme Q 10 , in conjunction with vitamin E, has therapeutic benefit in FRDA.
At present, about one-half of patients use coenzyme Q 10 and vitamin E supplements despite the lack of proven therapeutic benefit Spinocerebellar ataxias SCAs : SCAs are a group of rare autosomal dominant neurodegenerative diseases characterized by gait difficulty, loss of hand dexterity, dysarthria, and cognitive decline.
SCA1, 2, 3, and 6 are the most common SCAs In vitro coenzyme Q 10 treatment of forearm skin fibroblasts isolated from patients with SCA2 was found to reduce oxidative stress and normalize complex I and II-III activity of the mitochondrial respiratory chain Early interest in coenzyme Q 10 as a potential therapeutic agent in cancer was stimulated by an observational study that found that individuals with lung, pancreas , and especially breast cancer were more likely to have low plasma coenzyme Q 10 concentrations than healthy controls Two randomized controlled trials have explored the effect of coenzyme Q 10 as an adjunct to conventional therapy for breast cancer.
Supplementation with coenzyme Q 10 failed to improve measures of fatigue and quality of life in patients newly diagnosed with breast cancer 84 and in patients receiving chemotherapy There is little evidence that supplementation with coenzyme Q 10 improves athletic performance in healthy individuals.
Most did not find significant differences between the group taking coenzyme Q 10 and the group taking placebo with respect to measures of aerobic exercise performance, such as maximal oxygen consumption VO 2 max and exercise time to exhaustion Two studies actually found significantly greater improvement in measures of anaerobic 87 and aerobic 86 exercise performance with a placebo than with supplemental coenzyme Q More recent studies have suggested that coenzyme Q 10 could help reduce both muscle damage-associated oxidative stress and low-grade inflammation induced by strenuous exercise Studies on the effect of supplementation on physical performance in women are lacking, but there is little reason to suspect a gender difference in the response to coenzyme Q 10 supplementation.
Coenzyme Q 10 is synthesized in most human tissues. The biosynthesis of coenzyme Q 10 involves three major steps: 1 synthesis of the benzoquinone structure from 4-hydroxybenzoate derived from either tyrosine or phenylalanine, two amino acids; 2 synthesis of the polyisoprenoid side chain from acetyl-coenzyme A CoA via the mevalonate pathway; and 3 the joining condensation of these two structures to form coenzyme Q In the mevalonate pathway, the enzyme 3-hydroxymethylglutaryl HMG -CoA reductase, which converts HMG-CoA into mevalonate, is common to the biosynthetic pathways of both coenzyme Q 10 and cholesterol and is inhibited by statins cholesterol-lowering drugs; see Drug interactions 1.
Of note, pantothenic acid formerly vitamin B 5 is the precursor of coenzyme A, and pyridoxine vitamin B 6 , in the form of pyridoxal-5'-phosphate, is required for the conversion of tyrosine to 4-hydroxyphenylpyruvic acid that constitutes the first step in the biosynthesis of the benzoquinone structure of coenzyme Q The extent to which dietary consumption contributes to tissue coenzyme Q 10 concentrations is not clear.
Rich sources of dietary coenzyme Q 10 include mainly meat, poultry, and fish. Other good sources include soybean, corn, olive, and canola oils; nuts; and seeds. Fruit, vegetables, eggs, and dairy products are moderate sources of coenzyme Q 10 Some dietary sources are listed in Table 1.
Coenzyme Q 10 is available without a prescription as a dietary supplement in the US. Coenzyme Q 10 is fat-soluble and is best absorbed with fat in a meal. Oral supplementation with coenzyme Q 10 is known to increase blood and lipoprotein concentrations of coenzyme Q 10 in humans 2 , 15 , Nonetheless, under certain physiological circumstances e.
During pregnancy, the use of coenzyme Q 10 supplements mg twice daily from 20 weeks' gestation was found to be safe Because reliable data in lactating women are not available, supplementation should be avoided during breast-feeding Concomitant use of warfarin Coumadin and coenzyme Q 10 supplements has been reported to decrease the anticoagulant effect of warfarin in a few cases An individual on warfarin should not begin taking coenzyme Q 10 supplements without consulting the health care provider who is managing his or her anticoagulant therapy.
HMG-CoA reductase is an enzyme that catalyzes a biochemical reaction that is common to both cholesterol and coenzyme Q 10 biosynthetic pathways see Biosynthesis. Statins are HMG-CoA reductase inhibitors that are widely used as cholesterol-lowering medications.
Statins can thus also reduce the endogenous synthesis of coenzyme Q Therapeutic use of statins, including simvastatin Zocor , pravastatin Pravachol , lovastatin Mevacor, Altocor, Altoprev , rosuvastatin Crestor , and atorvastatin Lipitor , has been shown to decrease circulating coenzyme Q 10 concentrations However, because coenzyme Q 10 circulates with lipoproteins , plasma coenzyme Q 10 concentration is influenced by the concentration of circulating lipids , It is likely that circulating coenzyme Q 10 concentrations are decreased because statins reduce circulating lipids rather than because they inhibit coenzyme Q 10 synthesis In addition, very few studies have examined coenzyme Q 10 concentrations in tissues other than blood such that the extent to which statin therapy affects coenzyme Q 10 concentrations in the body's tissues is unknown , , Finally, there is currently little evidence to suggest that secondary coenzyme Q 10 deficiency is responsible for statin-associated muscle symptoms in treated patients.
In addition, supplementation with coenzyme Q 10 failed to relieve myalgia in statin-treated patients see Disease Treatment , Originally written in by: Jane Higdon, Ph.
Linus Pauling Institute Oregon State University. Updated in February by: Victoria J. Drake, Ph. Updated in March by: Victoria J. Updated in April by: Barbara Delage, Ph.
Reviewed in May by: Roland Stocker, Ph. Centre for Vascular Research School of Medical Sciences Pathology and Bosch Institute Sydney Medical School The University of Sydney Sydney, New South Wales, Australia. Acosta MJ, Vazquez Fonseca L, Desbats MA, et al. Coenzyme Q biosynthesis in health and disease.
Biochim Biophys Acta. Crane FL. Biochemical functions of coenzyme Q J Am Coll Nutr. Nohl H, Gille L. The role of coenzyme Q in lysosomes. In: Kagan VEQ, P.
Coenzyme Q: Molecular Mechanisms in Health and Disease. Boca Raton: CRC Press; Navas P, Villalba JM, de Cabo R. The importance of plasma membrane coenzyme Q in aging and stress responses.
Official websites use. gov Coenzume. gov website Coenzyme Q deficiency to an official government organization in the United States. gov website. Share sensitive information only on official, secure websites. Ubiquinone coenzyme Coenzyme Q deficiency 10 or CoQ 10 Coenzyme Q deficiency a lipid-soluble component of Cienzyme all cell membranes and has deficinecy Coenzyme Q deficiency functions. Prediabetes symptoms in adults of CoQ 10 Deficiench has been associated with five different clinical presentations that suggest genetic heterogeneity, which may be related to the multiple steps in CoQ 10 biosynthesis. Patients with all forms of CoQ 10 deficiency have shown clinical improvements after initiating oral CoQ 10 supplementation. Thus, early diagnosis is of critical importance in the management of these patients. This year, the first molecular defect causing the infantile form of primary human CoQ 10 deficiency has been reported.
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