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ABSTRACT: RATIONALE: Neurological dysfunction is common in primary coenzyme Q10 (2,3-dimethoxy, 5-methyl, 6-polyisoprene parabenzoquinone; CoQ10 ; ubiquinone) deficiencies, the most readily treatable subgroup of mitochondrial disorders. Therapeutic benefit from CoQ10 supplementation has also been noted in other neurodegenerative diseases. CoQ10 can be measured by high-performance liquid chromatography (HPLC) in plasma, muscle or leucocytes; however, there is no reliable method to quantify CoQ10 in cerebrospinal fluid (CSF). Additionally, many methods use CoQ9 , an endogenous ubiquinone in humans, as an internal standard. METHODS: Deuterated CoQ10 (d6 -CoQ10 ) was synthesised by a novel, simple, method. Total CoQ10 was measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) using d6 -CoQ10 as internal standard and 5 mM methylamine as an ion-pairing reagent. Chromatography was performed using a Hypsersil GOLD C4 column (150 × 3 mm, 3 µm). RESULTS: CoQ10 levels were linear over a concentration range of 0-200 nM (R(2) = 0.9995). The lower limit of detection was 2 nM. The inter-assay coefficient of variation (CV) was 3.6% (10 nM) and 4.3% (20 nM), and intra-assay CV 3.4% (10 nM) and 3.6% (20 nM). Reference ranges were established for CoQ10 in CSF (5.7-8.7 nM; n = 17), fibroblasts (57.0-121.6 pmol/mg; n = 50) and muscle (187.3-430.1 pmol/mg; n = 15). CONCLUSIONS: Use of d6 -CoQ10 internal standard has enabled the development of a sensitive LC/MS/MS method to accurately determine total CoQ10 levels. Clinical applications of CSF CoQ10 determination include identification of patients with cerebral CoQ10 deficiency, and monitoring CSF CoQ10 levels following supplementation. Copyright © 2013 John Wiley & Sons, Ltd.
Rapid Communications in Mass Spectrometry 05/2013; 27(9):924-930. · 2.79 Impact Factor
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ABSTRACT: Dopamine is produced first by hydroxylalation of L-tyrosine to L-dihydroxyphenylalanine (L-dopa) and subsequently by the decarboxylation of L-dopa to dopamine catalysed by the enzymes tyrosine hydroxylase and aromatic L-amino acid decarboxylase (AADC) respectively. Reduced glutathione (GSH) acts as a major cellular antioxidant. We have investigated the role of dopamine in the control of GSH homeostasis in brain cells. The SH-SY5Y human neuroblastoma cell line was found to increase intracellular GSH levels in response to 50μM dopamine treatment. Similarly the 1321N1 human astrocytoma cell line was found to increase GSH release in response to 50μM dopamine. The same concentration of L-dopa was also found to increase intracellular GSH in SH-SY5Y cells, however when AADC was inhibited this affect was abolished. Furthermore 1321N1 cells which were found to have almost undetectable levels of AADC activity did not increase GSH release in response to 50μM L-dopa. These results suggest that at these concentrations dopamine has the potential to act as a signal for the upregulation of GSH synthesis within neuronal-like cells and for the increased trafficking of GSH from astrocytes to neurons. This effect could potentially relate to the activation of antioxidant response elements leading to the induction of phase II detoxifying enzymes including those involved in GSH synthesis and release. The inability of L-dopa to produce a similar effect when AADC was inhibited or when AADC activity was absent indicates that these effects are relatively specific to dopamine. Additionally dopamine but not L-dopa treatment led in an increase in complex I activity of the respiratory chain in SH-SY5Y cells which may be related to the effect of dopamine on GSH levels.
Neurochemistry International 12/2012; · 2.86 Impact Factor
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ABSTRACT: Within the central nervous system, tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis. In addition, BH4 is now established to be an essential cofactor for all isoforms of nitric oxide synthase (NOS). Inborn errors of metabolism affecting BH4 availability are well documented and the clinical presentation can be attributed to a paucity of dopamine, serotonin, and nitric oxide (NO) generation. In this article, we have focussed upon the sensitivity of BH4 to oxidative catabolism and the observation that when BH4 is limiting some cellular sources of NOS may generate superoxide whilst other BH4 saturated NOS enzymes may be generating NO. Such a scenario could favor peroxynitrite generation. If peroxynitrite is not scavenged, e.g., by antioxidants such as reduced glutathione, irreversible damage to critical cellular enzymes could ensue. Such targets include components of the mitochondrial electron transport chain, alpha ketoglutarate dehydrogenase and possibly pyruvate dehydrogenase. Such a cascade of events is hypothesized, in this article, to occur in neurodegenerative conditions such as Parkinson's and Alzheimer's disease.
Neurochemical Research 04/2012; 32(4-5):751-6. · 2.24 Impact Factor
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Dalia Kasperavičiūtė,
Claudia B Catarino,
Krishna Chinthapalli,
Lisa M S Clayton,
Maria Thom,
Lillian Martinian,
Hannah Cohen,
Shazia Adalat,
Detlef Bockenhauer,
Simon A Pope,
Nicholas Lench,
Martin Koltzenburg,
John S Duncan,
Peter Hammond,
Raoul C M Hennekam, John M Land,
Sanjay M Sisodiya
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ABSTRACT: Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained.
We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic microdeletions were found during a study of genetic susceptibility to epilepsy. We performed detailed gene-driven clinical investigations in each patient. Disruption of the function of genes in the deleted regions can explain co-morbidities in these patients.
Co-morbidities in patients with epilepsy can be part of a genomic abnormality even in the absence of (known) congenital malformations or intellectual disabilities. Gene-driven phenotype examination can also reveal clinically significant unsuspected condition.
PLoS ONE 01/2011; 6(8):e23182. · 4.09 Impact Factor
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ABSTRACT: Mitochondrial encephalomyopathies resulting from electron transport chain (ETC) dysfunction can present with a wide spectrum of clinical manifestations having significant neuropathology and a progressive nature. Despite advances in diagnosis of ETC disorders, treatment still remains inadequate. A recent study in fibroblasts and myoblasts revealed the ability of fibrate treatment to correct ETC enzyme deficiencies. Therefore, fibrates may represent potential therapeutic agents to correct the neurological ETC impairment responsible for the encephalopathic presentation of these disorders. Consequently, this study assessed the effect of bezafibrate on human astrocytoma (HA) 1321N cell ETC activity and coenzyme Q10 (CoQ10) status. HA cells were incubated for 72 H with 300 μM or 500 μM bezafibrate and for 7 days with only 500 μM bezafibrate. A significant effect on ETC activity was observed after 7 days incubation with 500 μM bezafibrate yielding a 130% (P < 0.05) increase in complex IV activity, accompanied by a 33% (P < 0.05) increase in cellular ATP level and a 25% (P < 0.001) decrease in extracellular lactate/pyruvate ratio compared to control levels. Following 7 days culture with bezafibrate, the CoQ10 status of the HA cells appeared to increase although this was not found to be significant. The results of this study have indicated evidence of a bezafibrate induced increase in ETC complex IV activity. Further studies are required to assess the ability of bezafibrate treatment to correct neurological ETC impairment in available animal models of ETC dysfunction before the therapeutic efficacy of this pharmacological agent can be further considered in the treatment of the encephalopathic presentation of ETC disorders.
BioFactors 10/2010; 36(6):468 - 473. · 4.93 Impact Factor
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ABSTRACT: Pyridoxal 5'-phosphate, the active form of vitamin B(6), is an essential cofactor for multiple enzymes, including aromatic l-amino acid decarboxylase that catalyses the final stage in the production of the neurotransmitters dopamine and serotonin. In two patients with inherited disorders of vitamin B(6) metabolism, we observed reductions in plasma aromatic l-amino acid decarboxylase activity. In one patient, this change was related to an increase in K(m) for pyridoxal 5'-phosphate. Furthermore, pyridoxal 5'-phosphate-deficient human SH-SY5Y neuroblastoma cells were found to exhibit reduced levels of aromatic l-amino acid decarboxylase activity and protein but with no alteration in expression. Further reductions in activity and protein were observed with the addition of the vitamin B(6) antagonist 4-deoxypyridoxine, which also reduced aromatic l-amino acid decarboxylase mRNA levels. Neither pyridoxal 5'-phosphate deficiency nor the addition of 4-deoxypyridoxine affected aromatic l-amino acid decarboxylase stability over 8 h with protein synthesis inhibited. Increasing extracellular availability of pyridoxal 5'-phosphate was not found to have any significant effect on intracellular pyridoxal 5'-phosphate concentrations or on aromatic l-amino acid decarboxylase. These findings suggest that maintaining adequate pyridoxal 5'-phosphate availability may be important for optimal treatment of aromatic l-amino acid decarboxylase deficiency and l-dopa-responsive conditions.
Journal of Neurochemistry 07/2010; 114(1):87-96. · 4.06 Impact Factor
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ABSTRACT: Isolated complex I deficiency is the most commonly reported enzyme defect in paediatric mitochondrial disorders, and may arise due to mutations in nuclear-encoded structural or assembly genes, or the mitochondrial genome. We present the clinical, biochemical and molecular genetic data in a young girl whose clinical picture is dominated by chronic renal failure, myopathy and persistent lactic acidosis. An isolated complex I deficiency in muscle was identified due to a novel mutation (m.12425delA) in the MTND5 gene. This single nucleotide deletion is heteroplasmic and detectable in several tissues from the proband but not her mother, suggesting a de novo mutation event. The description of the first frameshift mutation in a mitochondrial complex I gene affirms mitochondrial DNA mutations as an important cause of isolated complex I deficiency in children and the importance of whole mitochondrial genome sequencing in the diagnostic work-up to elucidate the underlying molecular genetic abnormality and provide important genetic advice.
Neuromuscular Disorders 12/2009; 20(2):131-5. · 2.80 Impact Factor
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ABSTRACT: The final step in production of the neurotransmitters dopamine and serotonin is catalyzed by aromatic l-amino acid decarboxylase (AADC). AADC deficiency is a debilitating genetic condition that results in a deficit in these neurotransmitters, and manifests in infancy as a severe movement disorder with developmental delay. Response to current treatments is often disappointing. We have reviewed the literature to look for improvements to the current treatment strategy and also for new directions for AADC deficiency treatment. There may be differences in the mode of action, side-effect risk and effectiveness between different dopamine agonists and monoamine oxidase inhibitors currently used for AADC deficiency treatment. The range of these drugs used requires re-evaluation as some may have greater efficacy than others. Pyridoxal 5'-phosphate, the AADC cofactor may stabilize AADC and could increase AADC activity. Pyridoxal 5'-phosphate could have advantages as a treatment instead of pyridoxine. Atypical neuroleptics and peripheral AADC inhibitors both increase AADC activity in vivo and could be a future direction for AADC deficiency treatment and related conditions. Parkinson's disease gene therapy to deliver and express the human AADC gene in striatum is being tested in humans. Consequently gene therapy for AADC deficiency could be a realistic aim however an animal model of AADC deficiency is important for further progression.
Molecular Genetics and Metabolism 02/2009; 97(1):6-14. · 3.19 Impact Factor
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ABSTRACT: In order to investigate the potential involvement of mitochondrial electron transport chain (ETC) dysfunction in myotoxicity associated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment, assessment was made of ETC activity and ubiquinone status in two patients experiencing myopathy following treatment with simvastatin (40 mg/day) and cyclosporin (patient 1) and simvastatin (40 mg/day) and itraconazole (patient 2). Analysis of skeletal muscle biopsies revealed a decreased ubiquinone status (77 and 132; reference range: 140-580 pmol/mg) and cytochrome oxidase (complex IV) activity (0.006 and 0.007 reference range: 0.014-0.034). To assess statin treatment in the absence of possible pharmacological interference from cyclosporin or itraconazole, primary astrocytes were cultured with lovastatin (100 microM). Lovastatin treatment resulted in a decrease in ubiquinone (97.9 +/- 14.9; control: 202.9 +/- 18.4 pmol/mg; p < 0.05), and complex IV activity (0.008 +/- 0.001; control: 0.011 +/- 0.001; p < 0.05) relative to control. These data, coupled with the patient findings, indicate a possible association between statin treatment, decreased ubiquinone status, and loss of complex IV activity.
Toxicology mechanisms and methods 01/2009; 19(1):44-50. · 1.03 Impact Factor
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ABSTRACT: We report a patient with relatively mild Leigh syndrome and mitochondrial respiratory chain complex II deficiency caused by a homozygous G555E mutation in the nuclear encoded flavoprotein subunit of succinate dehydrogenase. This mutation has previously been reported in a lethal-infantile presentation of complex II deficiency. Such marked phenotypic heterogeneity, although typical of heteroplasmic mutations in the mitochondrial genome, is unusual for nuclear mutations. Comparable activities and stability of mitochondrial respiratory chain enzymes were demonstrated in both patients, so other reasons for the phenotypic variability are considered.
Molecular Genetics and Metabolism 12/2006; 89(3):214-21. · 3.19 Impact Factor
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Clinical Chemistry 01/2006; 51(12):2380-2. · 7.91 Impact Factor
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ABSTRACT: The HMG-CoA reductase inhibitors, also known as statins, have an enviable safety profile; however, myotoxicity and to a lesser extent hepatotoxicity have been noted in some patients following treatment. Statins target several tissues, depending upon their lipophilicity, where they competitively inhibit HMG-CoA reductase, the rate-limiting enzyme for mevalonic acid synthesis and subsequently cholesterol biosynthesis. HMG-CoA reductase is also the first committed rate-limiting step for the synthesis of a range of other compounds including steroid hormones and ubidecarenone (ubiquinone), otherwise known as coenzyme Q(10) (CoQ(10)). Recent interest has focused on the possible role CoQ(10) deficiency may have in the pathophysiology of the rare adverse effects of statin treatment. Currently, there is insufficient evidence from human studies to link statin therapy unequivocally to pathologically significantly decreased tissue CoQ(10) levels. Although statin treatment has been reported to lower plasma/serum CoQ(10) status, few human studies have assessed tissue CoQ(10) status. The plasma/serum CoQ(10) level is influenced by a number of physiological factors and, therefore, has limited value as a means of assessing intracellular CoQ(10) status. In those limited studies that have assessed the effect of statin treatment upon tissue CoQ(10) levels, none have shown evidence of a fall in CoQ(10) levels. This may reflect the doses of statins used, since many appear to have been used at doses below those recommended for their maximum therapeutic effects. Moreover, the poor bioavailability in those peripheral tissues tested may not reflect the effects the agents are having in liver and muscle, the tissues commonly affected in those patients who do not tolerate statins. This article reviews the biochemistry of CoQ(10), its role in cellular metabolism and the available evidence linking possible CoQ(10) deficiency to statin therapy.
Drug Safety 02/2005; 28(8):659-76. · 3.63 Impact Factor
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ABSTRACT: Formation of nitric oxide (NO), by astrocytes, has been suggested to contribute, via impairment of mitochondrial function, to the neurodegnerative process. Thus co-culture of neuronal cells with NO-generating astrocytes leads to a loss of mitochondrial function, as reflected by diminished activities of complexes IV and II+III. However, such damage may in the first instance be limited due to upregulation of neuronal glutathione metabolism as a result of metabolic trafficking of glutathione from the astrocyte to neurone. Furthermore, exposure of astrocytes to NO leads to increased glutathione metabolism resulting in the preservation of glutathione precursors for neuronal utilization. Failure of glutathione trafficking could render neuronal cells particularly susceptible to NO, leading to cell death. In addition, depletion with time of the nitric oxide synthase cofactor, tetrahydrobiopterin, may result in the astrocytic generation of more potent oxidizing species, which could contribute to the neurodegenerative process.
Neurochemical Research 04/2004; 29(3):513-9. · 2.24 Impact Factor
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ABSTRACT: Roland Luft is credited with describing the first truly mitochondrial disorder in the late 1950s and early 1960s. Cases such as his have proven to be exceptionally rare. Some years later, methods of mitochondrial analysis--enzymatic, polarographic, and spectroscopic, which had been developed primarily by groups in Philadelphia--were applied to the study of mitochondria isolated from skeletal muscle biopsies of patients thought to have defects of oxidative phosphorylation. In the vanguard of these investigations were groups in New York and London. John Clark led the latter group. Application of biochemical studies, more recently supplemented by molecular mtDNA and nuclear DNA studies, have revealed that mitochondrial disorders are among the most common of all metabolic disorders.
Neurochemical Research 04/2004; 29(3):483-91. · 2.24 Impact Factor
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ABSTRACT: Within the CNS and under normal conditions, nitric oxide (•NO) appears to be an important physiological signalling molecule. Its ability to increase cyclic GMP concentration suggests that •NO is implicated in the regulation of important metabolic pathways in the brain. Under certain circumstances •NO synthesis may be excessive and •NO may become neurotoxic. Excessive glutamate-receptor stimulation may lead to neuronal death through a mechanism implicating synthesis of both •NO and superoxide (O2•−) and hence peroxynitrite (ONOO−) formation. In response to lipopolysaccharide and cytokines, glial cells may also be induced to synthesize large amounts of •NO, which may be deleterious to the neighbouring neurones and oligodendrocytes. The precise mechanism of •NO neurotoxicity is not fully understood. One possibility is that it may involve neuronal energy deficiency. This may occur by ONOO− interfering with key enzymes of the tricarboxylic acid cycle, the mitochondrial respiratory chain, mitochondrial calcium metabolism, or DNA damage with subsequent activation of the energy-consuming pathway involving poly(ADP-ribose) synthetase. Possible mechanisms whereby ONOO− impairs the mitochondrial respiratory chain and the relevance for neurotoxicity are discussed. The intracellular content of reduced glutathione also appears important in determining the sensitivity of cells to ONOO− production. It is concluded that neurotoxicity elicited by excessive •NO production may be mediated by mitochondrial dysfunction leading to an energy deficiency state.
Journal of Neurochemistry 11/2002; 68(6):2227 - 2240. · 4.06 Impact Factor
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ABSTRACT: Excessive nitric oxide/peroxynitrite generation has been implicated in the pathogenesis of multiple sclerosis, and the demonstration of increased astrocytic nitric oxide synthase activity in the postmortem brain of multiple sclerosis patients supports this hypothesis. Exposure of astrocytes, in primary culture, to interferon-γ results in stimulation of nitric oxide synthase activity and increased nitric oxide release. In contrast to interferon-γ, interferon-α/β had a minimal effect on astrocytic nitric oxide formation. Furthermore, pretreatment of astrocytes with interferon-α/β inhibited (∼65%) stimulation by interferon-γ of nitric oxide synthase activity and nitric oxide release. Treatment with interferon-α/β at a concentration as low as 10 U/ml caused inhibition of mitochondrial cytochrome c oxidase. Furthermore, the damage to cytochrome c oxidase was prevented by the putative interferon-α/β receptor antagonist oxyphenylbutazone. In view of these observations, our current hypothesis is that the mitochondrial damage caused by exposure to interferon-α/β may impair the ability of astrocytes to induce nitric oxide synthase activity on subsequent interferon-γ exposure. These results may have implications for our understanding of the mechanisms responsible for the therapeutic effects of interferon-α/β preparations in multiple sclerosis.
Journal of Neurochemistry 11/2002; 68(6):2547 - 2551. · 4.06 Impact Factor
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ABSTRACT: Excessive nitric oxide/peroxynitrite generation has been implicated in the pathogenesis of multiple sclerosis, and the demonstration of increased astrocytic nitric oxide synthase activity in the postmortem brain of multiple sclerosis patients supports this hypothesis. Interferon-β is used for the treatment of multiple sclerosis, but currently little is known regarding its mode of action. Exposure of astrocytes in culture to interferon-γ plus lipopolysaccharide results in stimulation of nitric oxide release. Using a coculture system, we have been able to use astrocytes as a source of nitric oxide/peroxynitrite in an attempt to “model” the effects of raised cytokine levels observed in multiple sclerosis and to monitor the effect on neurones. Our results indicate that stimulation of astrocytic nitric oxide synthase activity causes significant damage to the mitochondrial activities of complexes II/III and IV of neighbouring neurones. This damage was prevented by a nitric oxide synthase inhibitor, suggesting that the damage was nitric oxide-mediated. Furthermore, interferon-α/β also prevented this damage. In view of these results, we suggest that a possible mechanism of action of interferon-β in the treatment of multiple sclerosis is that it prevents astrocytic nitric oxide production, thereby limiting damage to neighbouring cells, such as neurones.
Journal of Neurochemistry 12/1997; 70(1):432 - 434. · 4.06 Impact Factor
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ABSTRACT: 1. The effects of phenylpyruvate, a metabolite produced in phenylketonuria, on the pyruvate dehydrogenase-complex activity were investigated in rat brain mitochondria. 2. Pyruvate dehydrogenase activity was measured by two methods, one measuring the release of (14)CO(2) from [1-(14)C]pyruvate and the other measuring the acetyl-CoA formed by means of the coupling enzyme, pigeon liver arylamine acetyltransferase (EC 2.3.1.5). In neither case was there significant inhibition of the pyruvate dehydrogenase complex by phenylpyruvate at concentrations below 2mm. 3. However, phenylpyruvate acted as a classical competitive inhibitor of the coupling enzyme arylamine acetyltransferase, with a K(i) of 100mum. 4. It was concluded that the inhibition of pyruvate dehydrogenase by phenylpyruvate is unlikely to be a primary enzyme defect in phenylketonuria.
Biochemical Journal 07/1973; 134(2):539-44. · 4.90 Impact Factor
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ABSTRACT: 1. The activities of, and the effects of phenylpyruvate on, citrate synthase (EC 4.1.3.7), acetyl-CoA carboxylase (EC 6.4.1.2) and fatty acid synthetase derived from the brains of 14-day-old and adult rats were investigated. 2. The brain citrate synthase from 14-day-old rats had a K(m) for oxaloacetate of 2.38mum and for acetyl-CoA of 16.9mum, and a V(max.) of 838nmol of acetyl-CoA incorporation/min per mg of mitochondrial protein. From adult rat brain this enzyme had a K(m) for oxaloacetate of 2.5mum and for acetyl-CoA of 16.6mum and a V(max.) of 1070nmol of acetyl-CoA incorporated/min per mg of mitochondrial protein. Phenylpyruvate inhibited the enzyme from adult and young rat brains in a competitive fashion with respect to acetyl-CoA, with a K(i) of 700mum. 3. The brain acetyl-CoA carboxylase from 14-day-old rats had a K(m) for acetyl-CoA of 21mum and a V(max.) of 0.248nmol/min per mg of protein, and from adult rats a K(m) for acetyl-CoA of 21mum and a V(max.) of 0.173nmol/min per mg of protein. The enzyme from young and adult rats required citrate (K(a)=3mm) for activation and were inhibited non-competitively by phenylpyruvate, with a K(i) of 10mm. 4. The brain fatty acid synthetase from 14-day-old rats had a K(m) for acetyl-CoA of 7.58mum and a V(max.) of 1.1 nmol of malonyl-CoA incorporated/min per mg of protein, and from adult rats a K(m) for acetyl-CoA of 4.9mum and a V(max.) of 0.48nmol of malonyl-CoA incorporated/min per mg of protein. Phenylpyruvate acted as a competitive inhibitor with respect to acetyl-CoA with a K(i) of 250mum for the enzyme from 14-day-old rats. 5. These results are discussed with respect to phenylketonuria, and it is suggested that the inhibition of the brain fatty acid synthetase and possibly the citrate synthetase by phenylpyruvate could explain the defective myelination characteristic of this condition.
Biochemical Journal 07/1973; 134(2):545-55. · 4.90 Impact Factor
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ABSTRACT: Some hereditary ataxias are treatable and the insight required for this has come from an in depth knowledge of the phenotypes and clinical biochemistry of the conditions. This has required both fundamental and translational clinical research. Prof John Blass was fortunate to begin his career at what we can now recognise as a golden era for such studies and he worked upon two important conditions; Refsum's disease and Friedreich's ataxia. More recently the mitochondrial encephalomyopathies have been described and similar investigative work has been undertaken upon them. Ubiquinone, CoQ(10), deficiency is the most recently recognised encephalomyopathy and is itself treatable. Though rare, it is becoming increasingly recognised and patients are benefiting from the same scholarly approach to its investigation as was afforded Refsums' disease and Friedreich's ataxia.
Neurochemical Research 32(4-5):837-43. · 2.24 Impact Factor
