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Primary coenzyme Q10 deficiency and the brain
Abstract
Our findings in 19 new patients with cerebellar ataxia establish the existence of an ataxic syndrome due to primary CoQ10 deficiency and responsive to CoQ10 therapy. As all patients presented cerebellar ataxia and cerebellar atrophy, this suggests a selective vulnerability of the cerebellum to CoQ10 deficiency. We investigated the regional distribution of coenzyme Q10 in the brain of adult rats and in the brain of one human subject. We also evaluated the levels of coenzyme Q9 (CoQ9) and CoQ10 in different brain regions and in visceral tissues of rats before and after oral administration of CoQ10. Our results show that in rats, amongst the seven brain regions studied, cerebellum contains the lowest level of CoQ. However, the relative proportion of CoQ10 was the same (about 30% of total CoQ) in all regions studied. The level of CoQ10 is much higher in brain than in blood or visceral tissue, such as liver, heart, or kidney. Daily oral administration of CoQ10 led to substantial increases of CoQ10 concentrations only in blood and liver. Of the four regions of one human brain studied, cerebellum again had the lowest CoQ10y concentration.
... CoQ 10 deficiency has been observed in patients with Parkinsons disease, Huntington,s disease, tuberous sclerosis, motor neuron disease, and cerebellar ataxia, CoQ 10 supplementation may be useful in these conditions [4] [5] [6] [7]. CoQ 10 deficiency has also been observed in patients receiving statins , which is known to cause myopathy and rhabdomyolysis [8] [9] [10]. ...
... Naini and coworkers in 19 new patients with cerebellar ataxia established the existence of an ataxic syndrome due to primary CoQ 10 deficiency and responsive to CoQ 10 treatment [6]. Since all patients presented with cerebellar ataxia and cerebellar atrophy, this poses the possibility of a selective vulnerability of the cerebellam to CoQ 10 deficiency. ...
... CoQ 10 and the level of CoQ 10 was much higher in brain than in blood or visceral tissue, such as heart,liver or kidney indicating that it has vital role in brain function and degeneration [6]. However, there is lack of evidence, to demonstrate the cerebrospinal fluid levels of CoQ 10 in normal subjects, compared to neurological degenerative diseases. ...
There is significant interest in coenzyme Q10(CoQ10) as a potential treatment for neurodegenerative diseases and in its promise as a neuroprotectant. Experimental studies indicate that CoQ10 can protect against brain disorders by in- hibiting neuronal damage. There is a need to demonstrate CSF levels of CoQ10 in humans. Subjects and Methods: After clearance from the hospital ethical committee, all of the subjects presenting with a suspicion of neurological diseases were asked to give written informed consent for lumber puncture for testing of CSF. CoQ10 con- centration in CSF was examined by HPLC with electrochemical detection system at the Division of Molecular Neuroge- netics, College of Physicians and Surgeons, New York,USA. Clinical and laboratory data were obtained from all of the patients (n=38) to confirm clinical diagnosis. CAT scan of the head was done in all of the patients presenting with seizures and stroke. All CSF specimens were examined for cells, sugar and proteins and those suspected of being contaminated with blood were excluded from study. Results: The age varied between 17 to 60 years and the number of males (n=16) were less than females (n=21). Patients were suffering from epileptic seizures (n=19), tuberculous meningitis (n=5) and stroke (n=4). The rest of the 9 patients presented with headache of non-neurological condition with or without fever. The CSF concentration of CoQ10 was sig- nificantly lower among these subjects; mean ± SD ( 0.59 ± 0.12 ng/ml), which appears to represent the normal level of CoQ10 in healthy subjects. The concentration of CoQ10 in CSF tended to be higher among patients with TBM ( 1.27 ± 0.60 ng/ml), seizures ( 1.26 ± 0.34 ng/ml) and stroke ( 0.83 ± 0.20 ng/ml) compared to subjects without neurological problem. These findings indicate that there is greater release of CoQ10 or increased synthesis in the tissues possibly to fight against oxidative stress caused by brain disorders. Conclusions: This study shows that the level of CoQ10 in the csf is substantially lower than that in serum by three orders of magnitude and tends to be elevated under pathological conditions associated with brain injury. Further studies in a larger number of subjects are necessary to confirm our findings.
... It has been shown that CoQ 10 levels and its redox state are variable among human tissues. Specifically, the brain exhibits variations in CoQ 10 content between different brain regions in humans and rats [77,78]. Moreover, many markers of cell-type-specific mitochondria and mtDNA copy number in health and disease have been reported, which could also influence the cellular CoQ 10 status [79,80]. ...
Originally identified as a key component of the mitochondrial respiratory chain, Coenzyme Q (CoQ or CoQ10 for human tissues) has recently been revealed to be essential for many different redox processes, not only in the mitochondria, but elsewhere within other cellular membrane types. Cells rely on endogenous CoQ biosynthesis, and defects in this still-not-completely understood pathway result in primary CoQ deficiencies, a group of conditions biochemically characterised by decreased tissue CoQ levels, which in turn are linked to functional defects. Secondary CoQ deficiencies may result from a wide variety of cellular dysfunctions not directly linked to primary synthesis. In this article, we review the current knowledge on CoQ biosynthesis, the defects leading to diminished CoQ10 levels in human tissues and their associated clinical manifestations.
... 7 This could explain the biochemical process by which exogenous CoQ10 improves the bioenergetic impairment in some mitochondrial myopathies and in cardiomyopathy. 8,9 Coenzyme Q10 has been administered in patients affected by DS, attempting to counteract the oxidative imbalance present due to its secondary deficiency, with promising results. 10,11 Individuals having DS are more prone to infections and autoimmune disorders. ...
Objective:
Evidence of oxidative stress was reported in individuals with Down syndrome. There is a growing interest in the contribution of the immune system in Down syndrome. The aim of this study is to evaluate the coenzyme Q10 (CoQ10) and selected pro-inflammatory markers such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) in children with Down syndrome.
Methods:
Eighty-six children (5-8 years of age) were enrolled in this case-control study from two public institutions. At the time of sampling, the patients and controls suffered from no acute or chronic illnesses and received no therapies or supplements. The levels of IL-6, TNFα, CoQ10, fasting blood glucose, and intelligence quotient were measured.
Results:
Forty-three young Down syndrome children and forty-three controls were included over a period of eight months (January-August 2014). Compared with the control group, the Down syndrome patients showed significant increase in IL-6 and TNFα (p=0.002), while CoQ10 was significantly decreased (p=0.002). Also, body mass index and fasting blood glucose were significantly increased in patients. There was a significantly positive correlation between CoQ10 and intelligence quotient levels, as well as between Il-6 and TNFα.
Conclusion:
IL-6 and TNFα levels in young children with Down syndrome may be used as biomarkers reflecting the neurodegenerative process in them. Coenzyme Q10 might have a role as a good supplement in young children with Down syndrome to ameliorate the neurological symptoms.
... The low levels of CoQ 10 in normal cerebellum compared with the other brain regions observed in this and previous studies suggest that a threshold is necessary for CoQ 10 biological function. In MSA, CoQ 10 may be below a physiological threshold necessary for normal cerebellar function (30). However, we observed reduced TOM20 and increased COX activity in MSA striatum samples. ...
... CoQ10 deficiency has been observed in patients with Parkinsons disease, Huntington,s disease, tuberous sclerosis, motor neuron disease, and cerebellar ataxia, CoQ10 supplementation may be useful in these conditions [53][54][55][56]. Low levels of CoQ10 have been described also in myocardial biopsies from patients with various cardiovascular diseases [57,58]. ...
Statins are currently the most effective drugs in reducing low-density lipoprotein cholesterol (LDL-C). With their mechanism of action, by inhibiting 3-hydroxy-3 methylglutharyl coenzyme A reductase, statins decrease cholesterol production. The same biosynthetic pathway is shared by ubiquinone or coenzyme Q10. Statins block production of dekaprenyl-4-benzoate, a precursor of coenzyme Q10 (CoQ10), which is an essential component in mitochondrial transport system. Ubiquinone deficiency may affect oxidative phosphorylation and adenosine triphosphate production, which can subsequently result in impairing of muscle energy metabolism and contribute to development of myopathy. Statin therapy also decreases antioxidant status in the body, resulting in to increase in free radical damage to cells in various parts of body; liver, nerves, muscles. Statins can decrease natural antioxidant protection present in our body and predispose toxicity. Statin-associated myopathy is the most common side effect of statin treatment often lead to statin dose reduction, or therapy cessation, which can negatively affect cardiovascular risk management. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare. Statins lower circulating levels of CoQ10 up to 54%, whereas several studies did not confirmed a lowering of CoQ10 levels in muscles during statin therapy and the evidence was given also on low dose of statin therapy, which did not appear to reduce intramuscular levels of CoQ10 in symptomatic patients with statin myopathy. The conflicting results have been published on the impaired mitochondrial function, which was found during the analysis of the myocyte cells in patients treated with statins. The supplementation of CoQ10 results in increasing of serum CoQ10, but it is not clear if it relieves myopatic symptoms in statin treated patients. Yet available intervention studies reported contrasting results and just two of them proved benefit of CoQ10 supplementation. Hence coenzyme Q10 supplementation is not currently recommended for routine use in the prophylaxis of statin toxicity.
... Beyindeki CoQ 10 seviyesi kan, karaciğer, kalp ve böbrek dokularındaki CoQ 10 seviyelerinden daha yüksektir ve tüm beyin bölgelerinde CoQ 10 'un göreceli oranı aynıdır (38). Çalışmamızda CoQ 10 takviyesi beyin MDA seviyesini önemli düzeyde etkilememiştir. ...
Objective: The aim of the study was to evaluate the effects of coenzyme Q10 supplementation (CoQ10) and regular exercise on exhaustive-exercise induced oxidative stress and antioxidant response in rat brain.
Material and Methods: The experiments were carried out with young adult male Wistar rats. The rats were randomly assigned to one of the following eight groups: Untrained, trained, untrained exhausted, trained exhausted, untrained+CoQ10, trained+CoQ10, untrained exhausted+CoQ10 and trained exhausted+CoQ10. The rats in the trained groups swam for 60 min/day, five days per week for six weeks. The CoQ10 supplements were administered at a daily dose of 10 mg.kg-1 of body weight five days/week.
Results: The levels of malondialdehyde and 8-hydroxydeoxyguanosine in the brain were not affected by exhaustive exercise, training and CoQ10 supplementation. The exhaustive exercise decreased GSH levels in the control group, while it increased in untrained and trained exhausted+CoQ10 groups. Swimming training increased SOD activity in the brain, but exhaustive exercise did not change its activity. CoQ10 supplementation increased SOD activity in control group, while it decreased in the trained group.
Conclusion: The results suggested that exhaustive exercise does not cause lipid peroxidation and DNA damage in the brain. It can be said that regular exercise alone may be adequate for the positive effects on antioxidant enzymes in brain.
... Cell pellets were stored at −20°C until CoQ10 level was quantified using a modified form of a previously established high performance liquid chromotography (HPLC) method. 11,12 For mitochondrial fractions, Mitosciences Mitochondria Isolation Kit for Cultured Cells (MS852) was used to separate the mitochondrial portion of the cells before following the same HPLC protocol to quantify the CoQ10 levels. Immunoblotting was used to validate separation of mitochondria. ...
Background/hypotheses. Doxorubicin is a standard adjuvant therapy for early-stage breast cancer, and it significantly improves disease-free and overall survival. However, 3% to 20% of breast cancer patients develop chronic cardiomyopathic changes and congestive heart failure because of doxorubicin therapy. Doxorubicin-induced cardiotoxicity is thought to be due to the increased generation of reactive oxygen species within cardiac myocyte mitochondria. Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant that may protect against mitochondrial reactive oxygen species and thus prevent doxorubicin-induced cardiotoxicity. Despite the potential benefits of CoQ10 in preventing cardiotoxicity, it is not known if CoQ10 diminishes the antineoplastic effects of doxorubicin therapy.
In vitro cell culture experiments.
Breast cancer cell lines (MDA-MB-468 and BT549) were tested for their ability to uptake exogenous CoQ10 using high-performance liquid chromatography. Breast cancer cell lines were then treated with doxorubicin and a range of CoQ10 concentrations to determine the effect of CoQ10 on doxorubicin's cytotoxicity.
This study demonstrated that intracellular and mitochondrial CoQ10 concentrations increased substantially as higher exogenous concentrations were administered to breast cancer cells. CoQ10 had no effect on the ability of doxorubicin to induce apoptosis or inhibit growth or colony formation in both the cell lines tested when applied over a wide dose range, which encompassed typical basal plasma levels and plasma levels above those typically achieved by supplemented patients.
The clinical testing of CoQ10 as a supplement to prevent doxorubicin-induced cardiotoxicity requires confidence that it does not decrease the efficacy of chemotherapy. These results support the hypothesis that CoQ10 does not alter the antineoplastic properties of doxorubicin. Further in vivo studies, as well as combination chemotherapy studies, would be reassuring before a large-scale clinical testing of CoQ10 as a cardioprotective drug.
Coenzyme Q (CoQ) is a ubiquitous lipid serving essential cellular functions. It is the only component of the mitochondrial respiratory chain that can be exogenously absorbed. Here, we provide an overview of current knowledge, controversies, and open questions about CoQ intracellular and tissue distribution, in particular in brain and skeletal muscle. We discuss human neurological diseases and mouse models associated with secondary CoQ deficiency in these tissues and highlight pharmacokinetic and anatomical challenges in exogenous CoQ biodistribution, recent improvements in CoQ formulations and imaging, as well as alternative therapeutical strategies to CoQ supplementation. The last section proposes possible mechanisms underlying secondary CoQ deficiency in human diseases with emphasis on neurological and neuromuscular disorders.
The cardinal symptom of acute encephalopathy is impairment of consciousness of acute onset during the course of an infectious disease, with duration and severity meeting defined criteria. Acute encephalopathy consists of multiple syndromes such as acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion and clinically mild encephalitis/encephalopathy with reversible splenial lesion. Among these syndromes, there are both similarities and differences. In 2016, the Japanese Society of Child Neurology published ‘Guidelines for the Diagnosis and Treatment of Acute Encephalopathy in Childhood’, which made recommendations and comments on the general aspects of acute encephalopathy in the first half, and on individual syndromes in the latter half. Since the guidelines were written in Japanese, this review article describes extracts from the recommendations and comments in English, in order to introduce the essence of the guidelines to international clinicians and researchers.
Primary coenzyme Q10 (CoQ10; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10, and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures and cognitive disability. Whole exome and subsequent whole genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement and increased the concentrations of CoQ10 in blood. This is the first report of primary CoQ10 deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological and molecular features, and insights regarding targeted treatment with CoQ10 supplementation. This article is protected by copyright. All rights reserved
Objective: Evidence of oxidative stress was reported in individuals with Down syndrome. There is a growing interest in the contribution of the immune system in Down syndrome. The aim of this study is to evaluate the coenzyme Q10 and selected pro-inflammatory markers such as interleukin 6 and tumor necrosis factor α in children with Down syndrome.
Methods: Eighty-six children (5–8 years of age) were enrolled in this case-control study from two public institutions. At the time of sampling, the patients and controls suffered from no acute or chronic illnesses and received no therapies or supplements. The levels of interleukin 6, tumor necrosis factor α, coenzyme Q10, fasting blood glucose, and intelligence quotient were measured.
Results: Forty-three young Down syndrome children and forty-three controls were included over a period of eight months (January–August 2014). Compared with the control group, the Down syndrome patients showed significant increase in interleukin 6 and tumor necrosis factor α (p = 0.002), while coenzyme Q10 was significantly decreased (p = 0.002). Also, body mass index and fasting blood glucose were significantly increased in patients. There was a significantly positive correlation between coenzyme Q10 and intelligence quotient levels, as well as between interleukin 6 and tumor necrosis factor α.
Conclusion: Interleukin 6 and tumor necrosis factor α levels in young children with Down syndrome may be used as biomarkers reflecting the neurodegenerative process in them. Coenzyme Q10 might have a role as a good supplement in young children with Down syndrome to ameliorate the neurological symptoms.
Human coenzyme Q (CoQ10) or ubiquinone is mainly known for its bioenergetic role as a proton and electron carrier in the inner mitochondrial membrane and is also an endogenous lipophilic antioxidant, ubiquitous in biological membranes. It is also present in plasma lipoproteins, where it plays a well-recognized antioxidant role. More recently coenzyme Q10 was also shown to affect gene expression by modulating the intracellular redox status. Its involvement in many cellular and extracellular functions suggests that its use as a food supplement could be beneficial in conditions associated with increased oxidative stress underlying different pathological conditions. In reproductive biology, CoQ10 has been shown to play a role in fertility of both males and females.
The knowledge about the genetic spectrum underlying paediatric mitochondrial diseases is rapidly growing. As a consequence, the range of neuroimaging findings associated with mitochondrial diseases became extremely broad. This has important implications for radiologists and clinicians involved in the care of these patients. Here, we provide a condensed overview of brain magnetic resonance imaging (MRI) findings in children with genetically confirmed mitochondrial diseases. The neuroimaging spectrum ranges from classical Leigh syndrome with symmetrical lesions in basal ganglia and/or brain stem to structural abnormalities including cerebellar hypoplasia and corpus callosum dysgenesis. We highlight that, although some imaging patterns can be suggestive of a genetically defined mitochondrial syndrome, brain MRI-based candidate gene prioritization is only successful in a subset of patients.
The COQ2 gene encodes an essential enzyme for biogenesis, coenzyme Q10 (CoQ10). Recessive mutations in this gene have recently been identified in families with multiple system atrophy (MSA). Moreover, specific heterozygous variants in the COQ2 gene have also been reported to confer susceptibility to sporadic MSA in Japanese cohorts. These findings have suggested the potential usefulness of CoQ10 as a blood-based biomarker for diagnosing MSA. This study measured serum levels of CoQ10 in 18 patients with MSA, 20 patients with Parkinson’s disease and 18 control participants. Although differences in total CoQ10 (i.e., total levels of serum CoQ10 and its reduced form) among the three groups were not significant, total CoQ10 level corrected by serum cholesterol was significantly lower in the MSA group than in the Control group. Our findings suggest that serum CoQ10 can be used as a biomarker in the diagnosis of MSA and to provide supportive evidence for the hypothesis that decreased levels of CoQ10 in brain tissue lead to an increased risk of MSA.
Introduction Mitochondrial diseases that primarily affect oxidative metabolism are increasingly recognized as one of the most common genetic disorders seen in neurology. These disorders may be a result of the involvement of either the nuclear or the mitochondrial genome. Mitochondrial DNA genetics is particularly complicated because of the presence of multiple copies of mitochondrial DNA in the cell, the presence of both heteroplasmic and homoplasmic mutations, and the maternal pattern of transmission. The clinical features of mitochondrial disease are also extremely variable and make both clinical and laboratory diagnosis a challenge. In this chapter, we review the basics of mitochondrial genetics and the clinical features and investigation of mitochondrial disease and, finally, we discuss the management of these patients. Genetics of mitochondrial disorders Mitochondria are intracellular organelles the major (but not only) function of which is the generation of ATP from the metabolic fuels. This process is called oxidative phosphorylation and results in the formation of adenosine triphosphate (ATP), a readily utilizable energy source. It is dependent on five multi-subunit polypeptide complexes (I–V) located within the inner mitochondrial membrane. Only one complex, complex II, is entirely encoded by the nuclear genome, the others comprising subunits encoded by both the nuclear and mitochondrial genomes.
Background
Loss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). It has also been proposed that specific heterozygous variants in the COQ2 gene may confer susceptibility to sporadic MSA. To assess the frequency of COQ2 variants in patients with MSA, we sequenced the entire coding region and investigated all exonic copy number variants of the COQ2 gene in 97 pathologically-confirmed and 58 clinically-diagnosed MSA patients from the United States.
Results
We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients. In two patients, we identified two heterozygous COQ2 variants (p.S54W and c.403 + 10G > T) of unknown significance, which were not observed in 360 control subjects. We also identified one heterozygous carrier of a known loss of function p.S146N substitution in a severe MSA-C pathologically-confirmed patient.
Conclusions
The COQ2 p.S146N substitution has been previously reported as a pathogenic mutation in primary CoQ10 deficiency (including infantile multisystem disorder) in a recessive manner. This variant is the third primary CoQ10 deficiency mutation observed in an MSA case (p.R387X and p.R197H). Therefore it is possible that in the heterozygous state it may increase susceptibility to MSA. Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-44) contains supplementary material, which is available to authorized users.
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 two functions constitute the basis for supporting the clinical use of CoQ10. Also at the inner mitochondrial membrane level, CoQ10 is recognized as an obligatory co-factor for the function of uncoupling proteins and a modulator of the mitochondrial transition pore. Furthermore, recent data indicate that CoQ10 affects expression of genes involved in human cell signalling, 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, ageing-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 CoQ10 is a frequent antioxidant strategy in many diseases that may provide a significant symptomatic benefit.
Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the accumulation of alpha-synuclein protein in the cytoplasm of oligodendrocytes, the myelin-producing support cells of the central nervous system (CNS). The brain is the most lipid-rich organ in the body and disordered metabolism of various lipid constituents is increasingly recognized as an important factor in the pathogenesis of several neurodegenerative diseases. alpha-Synuclein is a 17 kDa protein with a close association to lipid membranes and biosynthetic processes in the CNS, yet its precise function is a matter of speculation, particularly in oligodendrocytes. alpha-Synuclein aggregation in neurons is a well-characterized feature of Parkinson's disease and dementia with Lewy bodies. Epidemiological evidence and in vitro studies of alpha-synuclein molecular dynamics suggest that disordered lipid homeostasis may play a role in the pathogenesis of alpha-synuclein aggregation. However, MSA is distinct from other alpha-synucleinopathies in a number of respects, not least the disparate cellular focus of alpha-synuclein pathology. The recent identification of causal mutations and polymorphisms in COQ2, a gene encoding a biosynthetic enzyme for the production of the lipid-soluble electron carrier coenzyme Q10 (ubiquinone), puts membrane transporters as central to MSA pathogenesis, although how such transporters are involved in the early myelin degeneration observed in MSA remains unclear. The purpose of this review is to bring together available evidence to explore the potential role of membrane transporters and lipid dyshomeostasis in the pathogenesis of alpha-synuclein aggregation in MSA. We hypothesize that dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes underlies the unique neuropathology of MSA.
Coenzyme Q₁₀ (Co Q₁₀) or ubiquinone was known for its key role in mitochondrial bioenergetics as electron and proton carrier; later studies demonstrated its presence in other cellular membranes and in blood plasma, and extensively investigated its antioxidant role. These two functions constitute the basis for supporting the clinical indication of Co Q₁₀. Furthermore, recent data indicate that Co Q₁₀ affects expression of genes involved in human cell signalling, metabolism and transport and some of the effects of Co Q₁₀ supplementation may be due to this property. Co Q₁₀ deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress and carcinogenesis processes, and also a secondary effect of statin treatment. Many neurodegenerative disorders, diabetes, cancer, fibromyalgia, muscular and cardiovascular diseases have been associated with low Co Q₁₀ levels. Co Q₁₀ treatment does not cause serious adverse effects in humans and new formulations have been developed that increase Co Q₁₀ absorption and tissue distribution. Oral Co Q₁₀ treatment is a frequent mitochondrial energizer and antioxidant strategy in many diseases that may provide a significant symptomatic benefit.
Co-Q10 is a lipid-soluble benzoquinone that is an important factor in free radical scavenging, mitochondrial membrane stability and ATP synthesis. Dietary Co-Q10 is a powerful antioxidant that has been useful in lessening the damage associated with ischemia-reperfusion injuries and aiding in the recovery of myocardial function after myocardial infarction. However, the role of dietary Co-Q10 in oxidative damage and repair is not well understood. Previous LC-EC methods have used packed carbon bed electrodes with high overpotentials that were sufficient to oxidize and reduce several biological compounds, thereby decreasing the selectivity that can be achieved with EC detection. Thin-layer cell dual electrode detection enables monitoring of reduced and oxidized forms of Co-Q10 simultaneously and selectively. The oxidation (+0.45 V vs. Ag/AgCl) and reduction (−0.4 V vs. Ag/AgCl) electrode potentials were optimized to oxidize and reduce the electroactive quinone moiety. The reduced form of Co-Q10 was prepared from the commercially available oxidized form using a Jones reductor. Confirmation of its formation was determined using the current ratios of the peak and half wave potentials from previously generated hydrodynamic voltammograms, using the oxidized form with electrodes in a series configuration. This analytical system was successfully applied to determine basal concentrations of oxidized (510 nM) and reduced (500 nM) Co-Q10 in human plasma. Peak identity of oxidized and reduced Co-Q10 was confirmed by two orthogonal methods: by the current ratios at +0.45 V and +0.25 V and −0.4 V and −0.2 V (vs. Ag/AgCl) as well as by retention time. Detection limits were determined to be 5 nM, with a linear range of three orders of magnitude.
Mitochondrial redox imbalance has been implicated in mechanisms of aging, various degenerative diseases and drug-induced toxicity. Statins are safe and well-tolerated therapeutic drugs that occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Previous studies indicate that myotoxicity caused by statins may be linked to impairment of mitochondrial functions. Here, we report that 1-h incubation of permeabilized rat soleus muscle fiber biopsies with increasing concentrations of simvastatin (1-40 μM) slowed the rates of ADP-or FCCP-stimulated respiration supported by glutamate/malate in a dose-dependent manner, but caused no changes in resting respiration rates. Simvastatin (1 μM) also inhibited the ADP-stimulated mitochondrial respiration supported by succinate by 24% but not by TMPD/ascorbate. Compatible with inhibition of respiration, 1 μM simvastatin stimulated lactate release from soleus muscle samples by 26%. Co-incubation of muscle samples with 1 mM L-carnitine, 100 μM mevalonate or 10 μM coenzyme Q10 (Co-Q10) abolished simvastatin effects on both mitochondrial glutamate/malate-supported respiration and lactate release. Simvastatin (1 μM) also caused a 2-fold increase in the rate of hydrogen peroxide generation and a decrease in Co-Q10 content by 44%. Mevalonate, Co-Q10 or L-carnitine protected against stimulation of hydrogen peroxide generation but only mevalonate prevented the decrease in Co-Q10 content. Thus, independently of Co-Q10 levels, L-carnitine prevented the toxic effects of simvastatin. This suggests that mitochondrial respiratory dysfunction induced by simvastatin, is associated with increased generation of superoxide, at the levels of complexes-I and II of the respiratory chain. In all cases the damage to these complexes, presumably at the level of 4Fe-4S clusters, is prevented by L-carnitine.
Ubiquinone (UQ), also known as coenzyme Q (CoQ), is a redox-active lipid present in all cellular membranes where it functions in a variety of cellular processes. The best known functions of UQ are to act as a mobile electron carrier in the mitochondrial respiratory chain and to serve as a lipid soluble antioxidant in cellular membranes. All eukaryotic cells synthesize their own UQ. Most of the current knowledge on the UQ biosynthetic pathway was obtained by studying Escherichia coli and Saccharomyces cerevisiae UQ-deficient mutants. The orthologues of all the genes known from yeast studies to be involved in UQ biosynthesis have subsequently been found in higher organisms. Animal mutants with different genetic defects in UQ biosynthesis display very different phenotypes, despite the fact that in all these mutants the same biosynthetic pathway is affected. This review summarizes the present knowledge of the eukaryotic biosynthesis of UQ, with focus on the biosynthetic genes identified in animals, including Caenorhabditis elegans, rodents, and humans. Moreover, we review the phenotypes of mutants in these genes and discuss the functional consequences of UQ deficiency in general.
Purpose: To collate evidence on nutrient deficiencies caused by drugs. Design: Search of Medline and other databases, and published literature. Materials and methods: Medline, Scirus and Google Scholar databases, journal articles and books. Results: There is evidence that many drugs, medicinal or recreational, produce deficiencies in vitamins, minerals, fatty acids and/or amino acids. Some drugs cause multiple deficiencies. They may reduce conversion of vitamins to their active forms, or inhibit the production of important metabolites. By killing beneficial bacteria in the gut, they may cause vitamin deficiency. They may reduce absorption, or cause excretion of nutrients. Conclusions: Many drugs have been identified, which appear to cause deficiencies in essential nutrients and their metabolites. Nutrients could be prescribed with drugs, to limit the damage done, provided that this does not undermine the action of the drugs. Further research is needed to confirm the results of those studies that have been carried out, and to find out about nutrient depletion from new drugs.
Background: Several cardiovascular, neurological and other diseases are associated with coenzyme Q10(CoQ) deficiency. The objective is to evaluate possible benefits of ubiquinone supplementation in cardiovascular diseases and degenerative diseases of the brain. Methods: An internet search in PubMed, Vitasearch, In Circulation. Net, till 2008, discussions with colleagues, own experiences. Results: Ubiquinone (Coenzyme Q10) deficiency has been observed in several cardiovascular and neurological diseases. CoQ10 has strong influence on lipid metabolism, oxidation of blood lipids, vascular inflammation and on the cell mem-branes of cardiac and arterial cells and neurons. These pathogenetic mechanisms seem to be important in patients with neurological and cardiac disease as well as in brain-heart connection. Its supplementation has several beneficial effects in-cluding the stabilisation of atherosclerotic plaque and decreasing the size of myoacardial infarction and the protection of neurons. Antioxidant properties of CoQ10 are responsible for the prevention of many drug side effects. Several studies have suggested the beneficial effect of CoQ10 in neuro-cardiovascular diseases, that will require further confirmation. Adverse effects such as nausea and vomiting may be reduced by using highly bio-available brands, that reduce the oral dosage of COQ. Conclusions: CoQ10 is still in the investigational stages and the list of possible indications related to brain and heart dis-eases and their linkage, appears to be quite extensive. There is still the need for a number of large, double blind multicen-ter, randomized, controlled clinical trials, in order to confirm the possible beneficial effects of CoQ10 supplementation in different neurocardiological conditions.
For a number of years, coenzyme Q (CoQ10 in humans), was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular
fractions and in plasma, and also extensively investigated its antioxidant role. This chapter discusses the relationship between
the acknowledged bioenergetic role of CoQ10 and some clinical effects. The antioxidant properties of CoQ10 are then analyzed especially for their consequences on protection of circulating human low-density lipoproteins and prevention
of atherogenesis. The relationship between CoQ10 and statins is also discussed in the light of possible involvement of CoQ10 deficiency in the issue of statin side effects. New aspects of the antioxidant involvement of coenzyme Q are also discussed
together with their relevance in cardiovascular disease. Data are reported on the efficacy of CoQ10 in ameliorating endothelial dysfunction in patients affected by ischemic heart disease. Many of the effects of CoQ10, which were classically ascribed to its bioenergetic properties, are now considered as the result of its biochemical interaction
with nitric oxide (NO), NO synthase and reactive oxygen species capable of inactivating NO. Clinical studies are reported
highlighting the effect of CoQ10 on extracellular SOD, which is deeply involved in endothelial dysfunction.
Previous studies have shown decreased levels of CoQ10 in the seminal plasma and sperm cells of infertile men with different kinds of asthenospermia. Research has been extended
to supplementation with CoQ10 of infertile men affected by idiopathic asthenozoospermia. CoQ10 levels increased significantly in seminal plasma and sperm cells after 6 months of treatment with concomitant improvement
of sperm cell motility.
Seasonal and inter-individual variabilities of Co-enzyme Q10 (CoQ10) concentration were studied in various tissues (flesh, heart) of pelagic fish (mackerel and herring) from Eastern Quebec Fisheries (Canada). A simple and efficient extraction procedure followed by fast reverse-phase HPLC with photodiode array detection (PDA) has been optimized and validated for the determination of CoQ10 levels. Extraction used a first step of homogenization with sodium dodecyl sulphate (SDS) and NaCl, followed by a solvent extraction with ethanol–hexane. No further purification step was required before HPLC analysis. Method validation indicated excellent sensitivity (2.5 ng/injection), reproducibility (CV%=1.5–1.6) and recovery (100.3–105.1%). Good accuracy was also statistically demonstrated since no matrix effect was found. For both fish species, CoQ10 concentrations were the highest in heart (105–148 μg/g fresh tissue). In mackerel, CoQ10 concentrations in red and white flesh were respectively 67 and 15 μg/g fresh tissue. In herring, CoQ10 concentration in flesh was 15–24 μg/g fresh tissue. Slight seasonal variations of CoQ10 concentration were observed in mackerel white flesh and herring flesh. Results indicated that mackerel and herring from Eastern Quebec are good sources of Co-enzyme Q10, whose by-products could be used industrially for the extraction of such a high-value biomolecule.
Structural changes and abnormal function of mitochondria have been documented in Down's syndrome (DS) cells, patients, and animal models. DS cells in culture exhibit a wide array of functional mitochondrial abnormalities including reduced mitochondrial membrane potential, reduced ATP production, and decreased oxido-reductase activity. New research has also brought to central stage the prominent role of oxidative stress in this condition. This review focuses on recent advances in the field with a particular emphasis on novel translational approaches involving the utilization of coenzyme Q(10) (CoQ(10) ) to treat a variety of clinical phenotypes associated with DS that are linked to increased oxidative stress and energy deficits. CoQ(10) has already provided promising results in several different conditions associated with altered energy metabolism and oxidative stress in the CNS. Two studies conducted in Ancona investigated the effect of CoQ(10) treatment on DNA damage in DS patients. Although the effect of CoQ(10) was evidenced only at single cell level, the treatment affected the distribution of cells according to their content in oxidized bases. In fact, it produced a strong negative correlation linking cellular CoQ(10) content and the amount of oxidized purines. Results suggest that the effect of CoQ(10) treatment in DS not only reflects antioxidant efficacy, but likely modulates DNA repair mechanisms.
Coenzyme Q(10) (CoQ(10) ) is a key component of the mitochondrial respiratory chain and, therefore, is essential for the bioenergetics of oxidative phosphorylation. It is also endowed with antioxidant properties, and recent studies pointed out its capability of affecting the expression of different genes. In this review, we analyze the data on the mechanisms by which CoQ(10) interacts with skin aging processes. The effect of CoQ(10) in preserving mitochondrial function cooperates in maintaining a proper energy level, which serves to prevent the aging skin from switching to anaerobic energy production mechanisms. Furthermore, the antioxidant capacity of CoQ(10) contributes to a positive effect against UV-mediated oxidative stress. Some of these effects have been assessed also in vivo, by the sensitive technique of ultraweak photoemission. Finally, CoQ(10) has been shown to influence, through a gene induction mechanism, the synthesis of some key proteins of the skin and to decrease the expression of some metalloproteinase such as collagenase. These mechanisms may also contribute to preserve collagen content of the skin.
We report the first case of a child with recessive hereditary methemoglobinemia type II with demonstrated cerebellar atrophy. This very rare blood disorder results in mild cyanosis, profound mental and motor impairment, and movement disorders in infancy and childhood. We suggest that children with unexplained severe encephalopathy and cerebellar atrophy should also be tested for hereditary methemoglobinemia type II.
Coenzyme Q(10) (CoQ(10)) is found in blood and in all organs. CoQ(10) deficiencies are due to autosomal recessive mutations, ageing-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 CoQ(10) levels, as well as different ataxias and encephalomyopathies.
We review the efficacy of a variety of commercial formulations which have been developed to solubilise CoQ(10) and promote its better absorption in vivo, and its use in the therapy of pathologies associated with low CoQ(10) levels, with emphasis in the results of the clinical trials. Also, we review the use of its analogues idebenone and MitoQ.
This review covers the most relevant aspects related with the therapeutic use of CoQ(10), including existing formulations and their effects on its bioavailability.
CoQ(10) does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ(10) absorption. Oral CoQ(10) is a viable antioxidant strategy in many diseases, providing a significant to mild symptomatic benefit. Idebenone and MitoQ are promising substitutive CoQ(10)-related drugs which are well tolerated and safe.
Increased production of free radicals and impairment of mitochondrial function are important factors in the pathogenesis of hypertension. This study examined the impact of hypertension on mitochondrial respiratory chain function, coenzyme Q(9) (CoQ(9)), coenzyme Q(10) (CoQ(10)), and alpha-tocopherol content in brain mitochondria, and the effect of blockade of angiotensin II type 1 receptors (AT1R) in the prehypertensive period on these parameters. In addition, blood pressure, heart and brain weight to body weight ratios, and the geometry of the basilar artery supplying the brain were evaluated. In the 9th week blood pressure and heart weight/body weight ratio were significantly increased and brain weight/body weight ratio was significantly decreased in spontaneously hypertensive rats (SHR) when compared to Wistar rats (WR). The cross-sectional area of the basilar artery was increased in SHR. Glutamate-supported respiration, the rate of ATP production, and concentrations of CoQ(9), CoQ(10), and alpha-tocopherol were decreased in SHR. The succinate-supported function and cytochrome oxidase activity were not changed. The treatment of SHR with losartan (20 mg/kg/day) from 4th to 9th week of age exerted preventive effect against hypertension, heart and arterial wall hypertrophy, and brain weight/body weight decline. After the therapy, the rate of ATP production and the concentration of CoQ increased in comparison to untreated SHR. The impairment of energy production and decreased level of lipid-soluble antioxidants in brain mitochondria as well as structural alterations in the basilar artery may contribute to increased vulnerability of brain tissue in hypertension. Long-term treatment with AT1R blockers may prevent brain dysfunction in hypertension.
The use of lipid-lowering statins has been associated with raised serum muscle enzymes and, occasionally, with rhabdomyolysis, especially in patients with pre-existing metabolic myopathies. The A3243G mutation is one of the most common mutations associated with mitochondrial disorders. A teenager harboring the A3243G mutation had the unusual association of hereditary glomerulopathy and recurrent episodes of raised creatine kinase levels with the use of lipid-lowering agents. Muscle biopsy showed both normal respiratory chain enzyme activities and normal coenzyme Q(10) levels, although decreased muscle coenzyme Q(10) concentration had been postulated to have a pathogenic role in statin-related myopathies. The close temporal relationship of statin administration and raised creatine kinase levels in this patient suggests caution in the use of statins in children and teenagers with mitochondrial myopathies.
Childhood obesity is associated with lower plasma levels of lipophilic antioxidants which may contribute to a deficient protection of low-density lipoproteins (LDL). An increased plasma level of oxidized LDL in obese people with insulin resistance has been demonstrated. The lipophilic antioxidant coenzyme Q10 (CoQ10) is known as an effective inhibitor of oxidative damage in LDL as well. The aim of the present study was to compare the CoQ10 levels in obese and normal weight children.
The CoQ10 plasma concentrations were measured in 67 obese children (BMI>97th percentile) and related to their degree of insulin resistance. Homeostasis model assessment (HOMA) was used to detect the degree of insulin resistance. The results were compared to a control group of 50 normal weight and apparently healthy children. The results of the CoQ10 levels were related to the plasma cholesterol concentrations.
After adjustment to plasma cholesterol, no significant difference in the CoQ10 levels between obese and normal weight children could be demonstrated. Furthermore, there was no difference between insulin-resistant and non-insulin-resistant obese children.
CoQ10 plasma levels are not reduced in obese children and are not related to insulin resistance.
Predominant cerebellar involvement has not been previously reported as a common neuroradiologic feature in pediatric mitochondrial cytopathies. Here we report the neuroradiologic findings of predominant cerebellar volume loss in children with various mitochondrial disorders.
A retrospective analysis of the medical records of 400 consecutive patients referred for evaluation of mitochondrial encephalomyopathies was performed. In 113 cases, definite diagnosis of mitochondrial disease was based on the modified adult criteria that include clinical, histologic, biochemical, functional, molecular, and metabolic parameters.
Predominant cerebellar volume loss with progressive cerebellar atrophy and, less often, cerebellar hypoplasia were found in a heterogeneous group of patients with mitochondrial disease that consisted of four patients with complex I deficiency; four patients with multiple respiratory chain deficiencies; two patients with combined complex I + III and II + III deficiencies, including one patient with partial coenzyme Q10 deficiency; three patients with complex II deficiency; two patients with complex IV deficiency; one patient with mitochondrial neurogastrointestinal encephalomyopathy; and two patients with mitochondrial encephalomyopathy, lactic acidosis, and strokes.
Our retrospective study shows that isolated or predominant cerebellar involvement can be found in various respiratory chain defects or mitochondrial disorders expanding the classical neuroradiologic findings observed in mitochondrial encephalomyopathies. The diagnostic workup in patients with neuromuscular features whose brain MR imaging exhibits cerebellar volume loss should include the evaluation for mitochondrial encephalomyopathies.
Ubiquinone (Ub) is the only known endogenously synthesized lipid soluble antioxidant. It is synthesized from intermediates in the cholesterol metabolic pathway. Our goal was to identify the Ubs and determine the concentration and distribution of Ubs in the rat lens and the effect of treatment with simvastatin, a cholesterol synthesis inhibitor, on lens levels.
Intact lenses and separated lens fractions from young rats were homogenized in organic solvents, the Ubs recovered, and identified by HPLC analysis. Rats were fed Ub-10 to determine effects of supplementation on tissue levels. Sprague-Dawley (SD) and Chbb:Thom (CT) rats were treated with simvastatin, an inducer of cataracts in CT rats, to determine its effects on lens Ubs.
Ubiquinone-9 (9 isoprenes in its hydrocarbon tail) was the main Ub in the rat lens. The intact lens contained about 3.0 microg Ub/g lens wet weight of which 80-90% was Ub-9 and the remainder Ub-10. No reduced Ubs were detected. Although the epithelial fraction contained the highest Ub concentration (about 8 microg/g), the cortex and nucleus combined accounted for about 90% of the lens' total content. Dietary supplementation with Ub-10 markedly increased the Ub-10 concentration in liver but not lens. Treatment with simvastatin decreased lens Ubs of both SD and CT rats by about 20%.
The abundance of mitochondria in lens epithelium likely accounted for its high level of Ubs; but, finding most of the lens' total Ub in the cortex plus nucleus also suggests roles in maintaining the fiber cell membrane. The decrease in lens Ubs caused by simvastatin is interpreted to reflect a response to drug induced cellular stress rather than to inhibition of the cholesterol synthesis pathway.
Ubiquinone (coenzyme Q(10) or CoQ(10)) is a lipid-soluble component of virtually all cell membranes, where it functions as a mobile electron and proton carrier. CoQ(10) deficiency is inherited as an autosomal recessive trait and has been associated with three main clinical phenotypes: a predominantly myopathic form with central nervous system involvement, an infantile encephalomyopathy with renal dysfunction, and an ataxic form with cerebellar atrophy. In two siblings of consanguineous parents with the infantile form of CoQ(10) deficiency, we identified a homozygous missense mutation in the COQ2 gene, which encodes para-hydroxybenzoate-polyprenyl transferase. The A-->G transition at nucleotide 890 changes a highly conserved tyrosine to cysteine at amino acid 297 within a predicted transmembrane domain. Radioisotope assays confirmed a severe defect of CoQ(10) biosynthesis in the fibroblasts of one patient. This mutation in COQ2 is the first molecular cause of primary CoQ(10) deficiency.
Our aim was to report a new case with cerebellar ataxia associated with coenzyme Q10 (CoQ) deficiency, the biochemical findings caused by this deficiency and the response to CoQ supplementation.
A 12-year-old girl presenting ataxia and cerebellar atrophy. BIOCHEMICAL STUDIES: Coenzyme Q10 in muscle was analysed by HPLC with electrochemical detection and mitochondrial respiratory chain (MRC) enzyme activities by spectrophotometric methods. CoQ biosynthesis in fibroblasts was assayed by studying the incorporation of radiolabeled 4-hydroxy[U 14C] benzoic acid by HPLC with radiometric detection.
Mitochondrial respiratory chain enzyme analysis showed a decrease in complex I + III and complex II + III activities. CoQ concentration in muscle was decreased (56 nmol/g of protein: reference values: 157-488 nmol/g protein). A reduced incorporation of radiolabeled 4-hydroxy[U- 14C] benzoic acid was observed in the patient (19% of incorporation respect to the median control values). After 16 months of CoQ supplementation, the patient is now able to walk unaided and cerebellar signs have disappeared.
Cerebellar ataxia associated with CoQ deficiency in our case might be allocated in the transprenylation pathway or in the metabolic steps after condensation of 4-hydroxybenzoate and the prenyl side chain of CoQ. Clinical improvement after CoQ supplementation was remarkable, supporting the importance of an early diagnosis of this kind of disorders.
Coenzyme Q10 (CoQ10) widely occurs in organisms and tissues, and is produced and used as both a drug and dietary supplement. Increasing evidence of health benefits of orally administered CoQ10 are leading to daily consumption in larger amounts, and this increase justifies research and risk assessment to evaluate the safety. A large number of clinical trials have been conducted using a range of CoQ10 doses. Reports of nausea and other adverse gastrointestinal effects of CoQ10 cannot be causally related to the active ingredient because there is no dose-response relationship: the adverse effects are no more common at daily intakes of 1200 mg than at a 60 mg. Systematic evaluation of the research designs and data do not provide a basis for risk assessment and the usual safe upper level of intake (UL) derived from it unless the newer methods described as the observed safe level (OSL) or highest observed intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence of safety is strong at intakes up to 1200 mg/day, and this level is identified as the OSL. Much higher levels have been tested without adverse effects and may be safe, but the data for intakes above 1200 mg/day are not sufficient for a confident conclusion of safety.
Background:
HMG-CoA reductase inhibitors ('statins') have been associated with a decrease in ubidecarenone (ubiquinone) levels, a lipophilic enzyme also known as coenzyme Q10 (CoQ10), due to inhibition of mevalonate synthesis. There is speculation that a decrease in CoQ10 levels may be associated with statin-induced myopathy. The cholesterol absorption inhibitor ezetimibe increases endogenous cholesterol synthesis. The purpose of this study was to examine (i) the effects of ezetimibe and simvastatin on plasma CoQ10 levels and (ii) whether ezetimibe coadministered with simvastatin abrogates the suggested statin-induced decrease in the CoQ10 plasma levels.
Methods:
Seventy-two healthy male subjects were enrolled in a single-centre, randomised, parallel-group study with three arms. Subjects received ezetimibe 10 mg/day, simvastatin 40 mg/day or the combination of ezetimibe 10 mg/day plus simvastatin 40 mg/day for 14 days.
Results:
Baseline CoQ10 (0.99 +/- 0.30 mg/L) levels for the combined groups remained unchanged in the ezetimibe group (0.95 +/- 0.24 mg/L), and significantly decreased in the simvastatin and combination groups (0.82 +/- 0.18 mg/L, p = 0.0002 and 0.7 +/- 0.22 mg/L, p < 0.0001, respectively). There was a correlation between the percentage change in the levels of low-density lipoprotein-cholesterol (LDL-C) and the percentage change in CoQ10 levels in all treatment groups (correlation coefficient [R] = 0.67, p < 0.0001). The ratios of CoQ10 levels to LDL-C levels were significantly increased in all treatment groups (p < 0.0001). CoQ10 level was independent of cholesterol synthesis or absorption markers.
Conclusions:
Simvastatin and the combination of simvastatin and ezetimibe significantly decrease plasma CoQ10 levels whereas ezetimibe monotherapy does not. There is a significant correlation between the CoQ10 level decrease and the decrease in total and LDL-C levels in all three treatment groups, suggesting that the CoQ10 decrease may reflect the decrease in the levels of its lipoprotein carriers and might not be statin-specific. The statin-associated CoQ10 reduction is not abrogated through ezetimibe coadministration. Changes of CoQ10 levels are independent of cholesterol synthesis and absorption.
Ubiquinone (coenzyme Q(10) or CoQ(10)) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions. Deficiency of CoQ(10) (MIM 607426) 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. The availability of genetic testing will allow for a better understanding of the pathogenesis of this disease and early initiation of therapy (even presymptomatically in siblings of patients) in this otherwise life-threatening infantile encephalomyopathy.
Coenzyme Q(10) (CoQ(10)) is a vital lipophilic molecule that transfers electrons from mitochondrial respiratory chain complexes I and II to complex III. Deficiency of CoQ(10) has been associated with diverse clinical phenotypes, but, in most patients, the molecular cause is unknown. The first defect in a CoQ(10) biosynthetic gene, COQ2, was identified in a child with encephalomyopathy and nephrotic syndrome and in a younger sibling with only nephropathy. Here, we describe an infant with severe Leigh syndrome, nephrotic syndrome, and CoQ(10) deficiency in muscle and fibroblasts and compound heterozygous mutations in the PDSS2 gene, which encodes a subunit of decaprenyl diphosphate synthase, the first enzyme of the CoQ(10) biosynthetic pathway. Biochemical assays with radiolabeled substrates indicated a severe defect in decaprenyl diphosphate synthase in the patient's fibroblasts. This is the first description of pathogenic mutations in PDSS2 and confirms the molecular and clinical heterogeneity of primary CoQ(10) deficiency.
Coenzyme Q(10) (CoQ) deficiency is an autosomal recessive disorder presenting five phenotypes: a myopathic form, a severe infantile neurological syndrome associated with nephritic syndrome, an ataxic variant, Leigh syndrome and a pure myopathic form. The third is the most common phenotype related with CoQ deficiency and it will be the focus of this review. This new syndrome presents muscle CoQ deficiency associated with cerebellar ataxia and cerebellar atrophy as the main neurological signs. Biochemically, the hallmark of CoQ deficiency syndrome is a decreased CoQ concentration in muscle and/or fibroblasts. There is no molecular evidence of the enzyme or gene involved in primary CoQ deficiencies associated with cerebellar ataxia, although recently a family has been reported with mutations at COQ2 gene who present a distinct phenotype. Patients with primary CoQ deficiency may benefit from CoQ supplementation, although the clinical response to this therapy varies even among patients with similar phenotypes. Some present an excellent response to CoQ while others show only a partial improvement of some symptoms and signs. CoQ deficiency is the mitochondrial encephalomyopathy with the best clinical response to CoQ supplementation, highlighting the importance of an early identification of this disorder.
Primary coenzyme Q(10) (CoQ(10)) deficiency includes a group of rare autosomal recessive disorders primarily characterized by neurological and muscular symptoms. Rarely, glomerular involvement has been reported. The COQ2 gene encodes the para-hydroxybenzoate-polyprenyl-transferase enzyme of the CoQ(10) synthesis pathway. We identified two patients with early-onset glomerular lesions that harbored mutations in the COQ2 gene. The first patient presented with steroid-resistant nephrotic syndrome at the age of 18 months as a result of collapsing glomerulopathy, with no extrarenal symptoms. The second patient presented at five days of life with oliguria, had severe extracapillary proliferation on renal biopsy, rapidly developed end-stage renal disease, and died at the age of 6 months after a course complicated by progressive epileptic encephalopathy. Ultrastructural examination of renal specimens from these cases, as well as from two previously reported patients, showed an increased number of dysmorphic mitochondria in glomerular cells. Biochemical analyses demonstrated decreased activities of respiratory chain complexes [II+III] and decreased CoQ(10) concentrations in skeletal muscle and renal cortex. In conclusion, we suggest that inherited COQ2 mutations cause a primary glomerular disease with renal lesions that vary in severity and are not necessarily associated with neurological signs. COQ2 nephropathy should be suspected when electron microscopy shows an increased number of abnormal mitochondria in podocytes and other glomerular cells.
For a number of years, coenzyme Q (CoQ10 in humans) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in plasma, and extensively investigated its antioxidant role. These two functions constitute the basis on which research supporting the clinical use of CoQ10 is founded. Also at the inner mitochondrial membrane level, coenzyme Q is recognized as an obligatory co-factor for the function of uncoupling proteins and a modulator of the transition pore. Furthermore, recent data reveal that CoQ10 affects expression of genes involved in human cell signalling, metabolism, and transport and some of the effects of exogenously administered CoQ10 may be due to this property. Coenzyme Q is the only lipid soluble antioxidant synthesized endogenously. In its reduced form, CoQH2, ubiquinol, 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 also that of lipoprotein lipids present in the circulation. Dietary supplementation with CoQ10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoproteins to the initiation of lipid peroxidation. Moreover, CoQ10 has a direct anti-atherogenic effect, which has been demonstrated in apolipoprotein E-deficient mice fed with a high-fat diet. In this model, supplementation with CoQ10 at pharmacological doses was capable of decreasing the absolute concentration of lipid hydroperoxides in atherosclerotic lesions and of minimizing the size of atherosclerotic lesions in the whole aorta. Whether these protective effects are only due to the antioxidant properties of coenzyme Q remains to be established; recent data point out that CoQ10 could have a direct effect on endothelial function. In patients with stable moderate CHF, oral CoQ10 supplementation was shown to ameliorate cardiac contractility and endothelial dysfunction. Recent data from our laboratory showed a strong correlation between endothelium bound extra cellular SOD (ecSOD) and flow-dependent endothelial-mediated dilation, a functional parameter commonly used as a biomarker of vascular function. The study also highlighted that supplementation with CoQ10 that significantly affects endothelium-bound ecSOD activity. Furthermore, we showed a significant correlation between increase in endothelial bound ecSOD activity and improvement in FMD after CoQ10 supplementation. The effect was more pronounced in patients with low basal values of ecSOD. Finally, we summarize the findings, also from our laboratory, on the implications of CoQ10 in seminal fluid integrity and sperm cell motility.
Familial Mediterranean Fever (FMF) is an inherited, recessively transmitted inflammatory condition usually occurred in populations from Mediterranean descent (Armenian, Arab, Jewish, Greek, Turkish and Italian populations). Identification of MEFV gene mutations has been of tremendous help for early diagnosis of most cases. The frequency of FMF is different. The prevalence of heterozygous carriers of one of the mutations of MEFV gene is as high as 1 in 5 healthy individuals in Armenia. Genetic testing of this rare Mendelian disorder (MIM no 249100) is efficient for early and prenatal diagnosis of the disease, especially for atypic cases, for carrier screening and pregnancy planning since certain mutations have been shown to have significant correlation with renal amyloidosis (RA), the most severe possible manifestation of FMF. Also genetic testing is very important for colchicine therapy correction. Twelve MEFV mutations are identified in 7000 Armenian FMF patients. Investigation of MEFV mutations in FMF patients (heterozygotes, homozygotes and compound heterozygotes) in comparison with healthy individuals has revealed the most frequent mutations and genotypes, and the information was received about the heterozygous carriers and genotype-phenotype correlation. In heterozygote carriers the most prevalent and severe cases are caused by the presence of a single M694V mutation. Our results could confirm that the MEFV gene analysis provides the first objective diagnostic criterion for FMF (characterisation of the two MEFV mutated alleles in more than 90% of the patients). Molecular testing is also used to screen the MEFV gene for mutations in patients with a clinical suspicion of FMF. We also demonstrated the unfavourable prognostic value of the M694V homozygous genotype, and provided the first molecular evidence for incomplete penetrance and pseudo-dominant transmission of the disease. Overall, these data, which confirm the involvement of the MEFV gene in the development of FMF, should be essential in clinical practice, leading to new ways of managment and treatment of FMF patients.
Data from the Italian Ministry of Health show that approximately 300-500 per 100.000 Italians are admitted to hospital each year for either TBI or subarachnoid haemorrhage with an annual mortality of 20 per 100.000; 90% of these TBI are of medium severity. Traumatic brain injury-induced hypopituitarism in adults are more common than previously thought. The paucity of clinical reports relating to adolescents with past-TBI induced hypothalamic-pituitary-dysfunction suggests that this phenomenon might be less common that that observed in adults. In the last 25 years, in our Unit a pituitary dysfunction was established during childhood and adolescence in 3 patients (one patient had a precocious puberty, one patient had a gonadal dysfunction and one patient had a partial growth hormone deficiency). In all patients the TBI was severe (unpublished data, 2008). The physiopathological basis of hypopituitarism is lacking. Nevertheless, necrotic, hypoxic, ischemic and shearing lesions are at the hypothalamus and/or the pituitary are likely important factors. The subjects at highest risk appear to be those who have suffered a moderate or severe trauma. Clinical signs of anterior hypopituitarism are often subtle and may be masked by sequalae of TBI. Therefore, post-traumatic anterior pituitary dysfunction may remain undiagnosed and, possibly, aggravate symptoms of brain injury. Moreover it may, if undiagnosed, lead to potentially fatal endocrine crisis. Therefore, adolescents with moderate-severe traumatic brain injury should be screened for such endocrine deficiencies so that replacement therapy can be initiated to optimized the rehabilitation and outcome.
Rates of mitochondrial superoxide anion radical (O·̄2) generation are known to be inversely correlated with the maximum life span potential of different mammalian species. The
objective of this study was to understand the possible mechanism(s) underlying such variations in the rate of O·̄2 generation. The hypothesis that the relative amounts of the ubiquinones or coenzyme Q (CoQ) homologues, CoQ9 and CoQ10, are related with the rate of O·̄2 generation was tested. A comparison of nine different mammalian species, namely mouse, rat, guinea pig, rabbit, pig, goat,
sheep, cow, and horse, which vary from 3.5 to 46 years in their maximum longevity, indicated that the rate of O·̄2 generation in cardiac submitochondrial particles (SMPs) was directly related to the relative amount of CoQ9 and inversely related to the amount of CoQ10, extractable from their cardiac mitochondria. To directly test the relationship between CoQ homologues and the rate of O·̄2 generation, rat heart SMPs, naturally containing mainly CoQ9 and cow heart SMPs, with high natural CoQ10 content, were chosen for depletion/reconstitution experiments. Repeated extractions of rat heart SMPs with pentane exponentially
depleted both CoQ homologues while the corresponding rates of O·̄2 generation and oxygen consumption were lowered linearly. Reconstitution of both rat and cow heart SMPs with different amounts
of CoQ9 or CoQ10 caused an initial increase in the rates of O·̄2 generation, followed by a plateau at high concentrations. Within the physiological range of CoQ concentrations, there were
no differences in the rates of O·̄2generation between SMPs reconstituted with CoQ9 or CoQ10. Only at concentrations that were considerably higher than the physiological level, the SMPs reconstituted with CoQ9 exhibited higher rates of O·̄2 generation than those obtained with CoQ10. These in vitrofindings do not support the hypothesis that differences in the distribution of CoQ homologues are responsible for the variations
in the rates of mitochondrial O·̄2 generation in different mammalian species.
Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.
Uncoupling proteins (UCPs) are thought to be intricately controlled uncouplers that are responsible for the futile dissipation of mitochondrial chemiosmotic gradients, producing heat rather than ATP. They occur in many animal and plant cells and form a subfamily of the mitochondrial carrier family. Physiological uncoupling of oxidative phosphorylation must be strongly regulated to avoid deterioration of the energy supply and cell death, which is caused by toxic uncouplers. However, an H+ transporting uncoupling function is well established only for UCP1 from brown adipose tissue, and the regulation of UCP1 by fatty acids, nucleotides and pH remains controversial. The failure of UCP1 expressed in Escherichia coli inclusion bodies to carry out fatty-acid-dependent H+ transport activity inclusion bodies made us seek a native UCP cofactor. Here we report the identification of coenzyme Q (ubiquinone) as such a cofactor. On addition of CoQ10 to reconstituted UCP1 from inclusion bodies, fatty-acid-dependent H+ transport reached the same rate as with native UCP1. The H+ transport was highly sensitive to purine nucleotides, and activated only by oxidized but not reduced CoQ. H+ transport of native UCP1 correlated with the endogenous CoQ content.
Based on the discovery of coenzyme Q (CoQ) as an obligatory cofactor for H(+) transport by uncoupling protein 1 (UCP1) [Echtay, K. S., Winkler, E. & Klingenberg, M. (2000) Nature (London) 408, 609-613] we show here that UCP2 and UCP3 are also highly active H(+) transporters and require CoQ and fatty acid for H(+) transport, which is inhibited by low concentrations of nucleotides. CoQ is proposed to facilitate injection of H(+) from fatty acid into UCP. Human UCP2 and 3 expressed in Escherichia coli inclusion bodies are solubilized, and by exchange of sarcosyl against digitonin, nucleotide binding as measured with 2'-O-[5-(dimethylamino)naphthalene-1-sulfonyl]-GTP can be restored. After reconstitution into vesicles, Cl(-) but no H(+) are transported. The addition of CoQ initiates H(+) transport in conjunction with fatty acids. This increase is fully sensitive to nucleotides. The rates are as high as with reconstituted UCP1 from mitochondria. Maximum activity is at a molar ratio of 1:300 of CoQ:phospholipid. In UCP2 as in UCP1, ATP is a stronger inhibitor than ADP, but in UCP3 ADP inhibits more strongly than ATP. Thus UCP2 and UCP3 are regulated differently by nucleotides, in line with their different physiological contexts. These results confirm the regulation of UCP2 and UCP3 by the same factors CoQ, fatty acids, and nucleotides as UCP1. They supersede reports that UCP2 and UCP3 may not be H(+) transporters.
The authors measured coenzyme Q10 (CoQ10) concentration in muscle biopsies from 135 patients with genetically undefined cerebellar ataxia. Thirteen patients with childhood-onset ataxia and cerebellar atrophy had markedly decreased levels of CoQ10. Associated symptoms included seizures, developmental delay, mental retardation, and pyramidal signs. These findings confirm the existence of an ataxic presentation of CoQ10 deficiency, which may be responsive to CoQ10 supplementation.
Daily oral or ip administration of coenzyme Q10 to rats for time periods of 2 to 10 weeks leads to its accumulation in liver, concentrating in the soluble fraction of the liver cells. No uptake of coenzyme Q10 can be detected in the heart or kidney. Intraperitoneal administration also results in the accumulation of coenzyme Q10 in the spleen. It is concluded that the normal endogenous levels of quinone in the rat heart and kidney cannot be supplemented over the long term by administration of exogenous quinone.
Ubiquinones and tocopherols (vitamin E) are intrinsic lipid components which have a stabilizing function in many membranes attributed to their antioxidant activity. The antioxidant effects of tocopherols are due to direct radical scavenging. Although ubiquinones also exert antioxidant properties the specific molecular mechanisms of their antioxidant activity may be due to: (i) direct reaction with lipid radicals or (ii) interaction with chromanoxyl radicals resulting in regeneration of vitamin E. Lipid peroxidation results have now shown that tocopherols are much stronger membrane antioxidants than naturally occurring ubiquinols (ubiquinones). Thus direct radical scavenging effects of ubiquinols (ubiquinones) might be negligible in the presence of comparable or higher concentrations of tocopherols. In support of this our ESR findings show that ubiquinones synergistically enhance enzymic NADH- and NADPH-dependent recycling of tocopherols by electron transport in mitochondria and microsomes. If ubiquinols were direct radical scavengers their consumption would be expected. Further proving our conclusion HPLC measurements demonstrated that ubiquinone-dependent sparing of tocopherols was not accompanied by ubiquinone consumption.
The electron transport system of muscle mitochondria was examined in a familial syndrome of lactacidemia, mitochondrial myopathy, and encephalopathy. The propositus, a 14-year-old female, and her 12-year-old sister had suffered from progressive muscle weakness, abnormal fatigability, and central nervous system dysfunction since early childhood. In the propositus, the state 3 respiratory rate of muscle mitochondria with NADH-linked substrates and with succinate was markedly reduced. The levels of cytochromes a + a3, b, and c + c1 were normal. The activities of complexes I, II, III, and IV of the electron transport chain were normal or increased. By contrast, the activities of complex I-III and of complex II-III, both of which need coenzyme Q10 (CoQ10), were abnormally low. On direct measurement, the mitochondrial CoQ10 content was 3.7% of the mean value observed in 10 controls. Serum and cultured fibroblasts of the propositus had normal CoQ10 contents. In the younger sister, the respiratory activities and CoQ10 level of muscle mitochondria were similar to those observed in the propositus. The findings establish CoQ10 deficiency as a cause of a familial mitochondrial cytopathy and suggest that the disease results from a tissue-specific defect of CoQ10 biosynthesis.
The essential role of coenzyme Q in biological energy transduction is well established. Coenzyme Q is a unique carrier for two-electron transfer within the lipid phase of the mitochondrial membrane. The function is essential for proton-based energy coupling. The sites of entry and exit of electrons into the quinone are at specific quinone-binding sites which are constructed to allow only two-electron transfer and thus prevent damaging free radical formation by direct reaction of oxygen with the semiquinone. Failure of proper function with diminished energy supply can be related to insufficient quinone, modification of lipid fluidity, or lipid protein interaction and damage or poisoning in binding sites. Supplementation with coenzyme Q can act by reversal of deficiency or decreased mobility, or by overcoming binding site modification. Coenzyme Q has also been shown to increase antioxidant protection in membranes. New sites for coenzyme Q function in Golgi and plasma membrane show evidence for a role in growth control and secretion-related membrane flow.
Coenzyme Q10 (CoQ10) transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There is one published report of human CoQ10 deficiency describing two sisters with encephalopathy, proximal weakness, myoglobinuria, and lactic acidosis. We report a patient who had delayed motor milestones, proximal weakness, premature exertional fatigue, and episodes of exercise-induced pigmenturia. She also developed partial-complex seizures. Serum creatine kinase was approximately four times the upper limit of normal and venous lactate was mildly elevated. Skeletal muscle biopsy revealed many ragged-red fibers, cytochrome c oxidase-deficient fibers, and excess lipid. In isolated muscle mitochondria, impaired oxygen consumption was corrected by the addition of decylubiquinone. During standardized exercise, ventilatory and circulatory responses were compatible with a defect of oxidation-phosphorylation, which was confirmed by near-infrared spectroscopy analysis. Biochemical analysis of muscle extracts revealed decreased activities of complexes I+II and I+III, while CoQ10 concentration was less than 25% of normal. With a brief course of CoQ10 (150 mg daily), the patient reported subjective improvement. The triad of CNS involvement, recurrent myoglobinuria, and ragged-red fibers should alert clinicians to the possibility of CoQ10 deficiency.
We report severe coenzyme Q10 deficiency of muscle in a 4-year-old boy presenting with progressive muscle weakness, seizures, cerebellar syndrome, and a raised cerebro-spinal fluid lactate concentration. State-3 respiratory rates of muscle mitochondria with glutamate, pyruvate, palmitoylcarnitine, and succinate as respiratory substrates were markedly reduced, whereas ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine were oxidized normally. The activities of complexes I, II, III and IV of the electron transport chain were normal, but the activities of complexes I+III and II+III, both systems requiring coenzyme Q10 as an electron carrier, were dramatically decreased. These results suggested a defect in the mitochondrial coenzyme Q10 content. This was confirmed by the direct assessment of coenzyme Q10 level by high-performance liquid chromatography in patient's muscle homogenate and isolated mitochondria, revealing levels of 16% and 6% of the control values, respectively. We did not find any impairment of the respiratory chain either in a lymphoblastoid cell line or in skin cultured fibroblasts from the patient, suggesting that the coenzyme Q10 depletion was tissue-specific. This is a new case of a muscle deficiency of mitochondrial coenzyme Q in a patient suffering from an encephalomyopathy.
The effect of lifelong oral supplementation with ubiquinone Q10 (10 mg/kg/day) was examined in Sprague-Dawley rats and C57/B17 mice. There were no significant differences in survival or life-span found in either rats or mice. Histopathologic examination of different rat tissues showed no differences between the groups. In Q10 supplemented rats, plasma and liver Q10 levels were 2.6 to 8.4 times higher at all age points than in control rats. Interestingly, in supplemented rats the Q9 levels also were significantly higher (p<0.05) in plasma and liver at ages 18 and 24 months. Neither Q9 nor Q10 levels were affected by supplementation in kidney, heart, or brain tissues. In spite of the significant changes in plasma and liver ubiquinone concentrations, lifelong Q10 supplementation did not prolong or shorten the lifespan of either rats or mice.
The objective of this study was to elucidate the anti-oxidative roles of coenzyme Q (CoQ) and alpha-tocopherol in mitochondrial membranes by determining whether CoQ directly scavenges peroxyl- and alkoxyl-radicals or indirectly regenerates alpha-tocopherol during autooxidation of mitochondrial membranes. A comparison of the interaction between alpha-tocopherol and CoQ during autooxidation was made between bovine and rat heart mitochondria, which differ approximately 15-fold in their alpha-tocopherol content. Autooxidation of both bovine and rat heart mitochondria resulted in the formation of thiobarbituric-acid-reactive substances and protein carbonyls; however, the differences in the autooxidizability of mitochondria between rat and bovine heart mitochondrial membranes were relatively minor. Supplementation of rat heart mitochondria with succinate caused reduction of CoQ to ubiquinol while alpha-tocopherol concentration remained unaffected during autooxidation. In contrast, in the absence of succinate, CoQ was present in the oxidized form (ubiquinone) and the mitochondrial membranes were depleted of alpha-tocopherol. CoQ concentrations remained unchanged over time irrespective of the presence or absence of succinate. In the absence of succinate, autooxidation of bovine SMPs, supplemented with different amounts of alpha-tocopherol, was inversely related to the amount of alpha-tocopherol, whereas in the presence of succinate autooxidation was greatly reduced. Results of this study indicate that during autooxidation of mitochondria, alpha-tocopherol acts as the direct radical scavenger, whereas ubiquinol regenerates alpha-tocopherol.
The respiratory-chain deficiencies are a broad group of largely untreatable diseases. Among them, coenzyme Q10 (ubiquinone) deficiency constitutes a subclass that deserves early and accurate diagnosis.
We assessed respiratory-chain function in two siblings with severe encephalomyopathy and renal failure. We used high-performance liquid chromatography analyses, combined with radiolabelling experiments, to quantify cellular coenzyme Q10 content. Clinical follow-up and detailed biochemical investigations of respiratory chain activity were carried out over the 3 years of oral quinone administration.
Deficiency of coenzyme Q10-dependent respiratory-chain activities was identified in muscle biopsy, circulating lymphocytes, and cultured skin fibroblasts. Undetectable coenzyme Q10 and results of radiolabelling experiments in cultured fibroblasts supported the diagnosis of widespread coenzyme Q10 deficiency. Stimulation of respiration and fibroblast enzyme activities by exogenous quinones in vitro prompted us to treat the patients with oral ubidecarenone (5 mg/kg daily), which resulted in a substantial improvement of their condition over 3 years of therapy.
Particular attention should be paid to multiple quinone-responsive respiratory-chain enzyme deficiency because this rare disorder can be successfully treated by oral ubidecarenone.
To describe a clinical syndrome of cerebellar ataxia associated with muscle coenzyme Q10 (CoQ10) deficiency.
Muscle CoQ10 deficiency has been reported only in a few patients with a mitochondrial encephalomyopathy characterized by 1) recurrent myoglobinuria; 2) brain involvement (seizures, ataxia, mental retardation), and 3) ragged-red fibers and lipid storage in the muscle biopsy.
Having found decreased CoQ10 levels in muscle from a patient with unclassified familial cerebellar ataxia, the authors measured CoQ10 in muscle biopsies from other patients in whom cerebellar ataxia could not be attributed to known genetic causes.
The authors found muscle CoQ10 deficiency (26 to 35% of normal) in six patients with cerebellar ataxia, pyramidal signs, and seizures. All six patients responded to CoQ10 supplementation; strength increased, ataxia improved, and seizures became less frequent.
Primary CoQ10 deficiency is a potentially important cause of familial ataxia and should be considered in the differential diagnosis of this condition because CoQ10 administration seems to improve the clinical picture.
Two brothers with myopathic coenzyme Q10 (CoQ10) deficiency responded dramatically to CoQ10 supplementation. Muscle biopsies before therapy showed ragged-red fibers, lipid storage, and complex I + III and II + III deficiency. Approximately 30% of myofibers had multiple features of apoptosis. After 8 months of treatment, excessive lipid storage resolved, CoQ10 level normalized, mitochondrial enzymes increased, and proportion of fibers with TUNEL-positive nuclei decreased to 10%. The authors conclude that muscle CoQ10 deficiency can be corrected by supplementation of CoQ10, which appears to stimulate mitochondrial proliferation and to prevent apoptosis.
Coenzyme Q (CoQ(10)) is a component of the mitochondrial electron transport chain and also a constituent of various cellular membranes. It acts as an important in vivo antioxidant, but is also a primary source of O(2)(-*)/H(2)O(2) generation in cells. CoQ has been widely advocated to be a beneficial dietary adjuvant. However, it remains controversial whether oral administration of CoQ can significantly enhance its tissue levels and/or can modulate the level of oxidative stress in vivo. The objective of this study was to determine the effect of dietary CoQ supplementation on its content in various tissues and their mitochondria, and the resultant effect on the in vivo level of oxidative stress. Rats were administered CoQ(10) (150 mg/kg/d) in their diets for 4 and 13 weeks; thereafter, the amounts of CoQ(10) and CoQ(9) were determined by HPLC in the plasma, homogenates of the liver, kidney, heart, skeletal muscle, brain, and mitochondria of these tissues. Administration of CoQ(10) increased plasma and mitochondria levels of CoQ(10) as well as its predominant homologue CoQ(9). Generally, the magnitude of the increases was greater after 13 weeks than 4 weeks. The level of antioxidative defense enzymes in liver and skeletal muscle homogenates and the rate of hydrogen peroxide generation in heart, brain, and skeletal muscle mitochondria were not affected by CoQ supplementation. However, a reductive shift in plasma aminothiol status and a decrease in skeletal muscle mitochondrial protein carbonyls were apparent after 13 weeks of supplementation. Thus, CoQ supplementation resulted in an elevation of CoQ homologues in tissues and their mitochondria, a selective decrease in protein oxidative damage, and an increase in antioxidative potential in the rat.
A 31-year-old woman had encephalopathy, growth retardation, infantilism, ataxia, deafness, lactic acidosis, and increased signals of caudate and putamen on brain magnetic resonance imaging. Muscle biochemistry showed succinate:cytochrome c oxidoreductase (complex II-III) deficiency. Both clinical and biochemical abnormalities improved remarkably with coenzyme Q10 supplementation. Clinically, when taking 300mg coenzyme Q10 per day, she resumed walking, gained weight, underwent puberty, and grew 20cm between 24 and 29 years of age. Coenzyme Q10 was markedly decreased in cerebrospinal fluid, muscle, lymphoblasts, and fibroblasts, suggesting the diagnosis of primary coenzyme Q10 deficiency. An older sister has similar clinical course and biochemical abnormalities. These findings suggest that coenzyme Q10 deficiency can present as adult Leigh's syndrome.
Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects
- Matthews R. T.