ubiquinone and Phenylketonurias

Mevalonic aciduria (MVA) and phenylketonuria (PKU) are inborn errors of metabolism caused by deficiencies in the enzymes mevalonate kinase and phenylalanine 4-hydroxylase, respectively. Despite numerous studies the factors responsible for the pathogenicity of these disorders remain to be fully characterised. In common with MVA, a deficit in coenzyme Q10 (CoQ10) concentration has been implicated in the pathophysiology of PKU. In MVA the decrease in CoQ10 concentration may be attributed to a deficiency in mevalonate kinase, an enzyme common to both CoQ10 and cholesterol synthesis. However, although dietary sources of cholesterol cannot be excluded, the low/normal cholesterol levels in MVA patients suggests that some other factor may also be contributing to the decrease in CoQ10.The main factor associated with the low CoQ10 level of PKU patients is purported to be the elevated phenylalanine level. Phenylalanine has been shown to inhibit the activities of both 3-hydroxy-3-methylglutaryl-CoA reductase and mevalonate-5-pyrophosphate decarboxylase, enzymes common to both cholesterol and CoQ10 biosynthesis. Although evidence of a lowered plasma/serum CoQ10 level has been reported in MVA and PKU, few studies have assessed the intracellular CoQ10 concentration of patients. Plasma/serum CoQ10 is influenced by dietary intake as well as its lipoprotein content and therefore may be limited as a means of assessing intracellular CoQ10 concentration. Whether the pathogenesis of MVA and PKU are related to a loss of CoQ10 has yet to be established and further studies are required to assess the intracellular CoQ10 concentration of patients before this relationship can be confirmed or refuted.

Topics: Amino Acid Metabolism, Inborn Errors; Animals; Antioxidants; Coenzymes; Humans; Hydroxymethylglutaryl CoA Reductases; Metabolic Networks and Pathways; Mevalonic Acid; Mitochondrial Diseases; Models, Biological; Oxidative Stress; Phenylalanine; Phenylketonurias; Ubiquinone

Coenzyme Q10 (CoQ10) serves as an electron carrier within the mitochondrial respiratory chain (MRC), where it is integrally involved in oxidative phosphorylation and consequently ATP production. It has recently been suggested that phenylketonuria (PKU) patients may be susceptible to a CoQ10 deficiency as a consequence of their phenylalanine-restricted diet, which avoids foods rich in CoQ10 and its precursors. Furthermore, the high phenylalanine level in PKU patients not on dietary restriction may also result in impaired endogenous CoQ10 production, as previous studies have suggested an inhibitory effect of phenylalanine on HMG-CoA reductase, the rate-controlling enzyme in CoQ10 biosynthesis. We investigated the effect of both dietary restriction and elevated plasma phenylalanine concentration on blood mononuclear cell CoQ10 concentration and the activity of MRC complex II + III (succinate:cytochrome-c reductase; an enzyme that relies on endogenous CoQ10) in a PKU patient population. The concentrations of CoQ10 and MRC complex II + III activity were not found to be significantly different between the PKU patients on dietary restriction, PKU patients off dietary restriction and the control group, although plasma phenylalanine levels were markedly different. The results from this investigation suggest that dietary restriction and the elevated plasma phenylalanine levels of PKU patients do not effect mononuclear cell CoQ10 concentration and consequently the activity of complex II + III of the MRC.

Topics: Adolescent; Adult; Chromatography, High Pressure Liquid; Citrate (si)-Synthase; Coenzymes; Female; Humans; Hydroxymethylglutaryl CoA Reductases; Male; Middle Aged; Mitochondrial Diseases; Monocytes; Phenylalanine; Phenylketonurias; Succinate Cytochrome c Oxidoreductase; Ubiquinone

Identifying diseases displaying chronic low plasma Coenzyme Q

Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Mucopolysaccharidoses; Mutation; Nervous System Diseases; Phenylketonurias; Retrospective Studies; Sequence Analysis, DNA; Ubiquinone; Young Adult

Phenylketonuria (PKU) is an autosomal recessive disorder resulting in neurological and intellectual disability when untreated. However, even in treated patients there may be residual neurological impairment such as tremor. It has been suggested that the hyperphenylalaninaemia in patients with PKU reduces complex I (NADH:ubiquinone reductase) activity of the mitochondrial respiratory chain (MRC) and/or biosynthesis of coenzyme Q(10) (CoQ(10)), which acts as an electron carrier in the MRC, leading to impaired energy metabolism in the brain of patients with PKU and hence the neurological pathology. The aim of this study was to elucidate the mechanism of phenylalanine (Phe) toxicity on the MRC. We compared mean plasma and blood-spot Phe and mononuclear CoQ(10) levels in 17 patients with PKU and a tremor compared to 22 patients without tremor. Human 1321N1 astrocytoma cells were exposed to hyperphenylalaninaemia by the addition of 300 or 900 micromol/L of Phe to the cell culture medium. Following 96 h of culture we measured complex I and citrate synthase activities and CoQ(10) level. Results showed no significant difference in Phe or CoQ(10) levels in patients with tremor compared to those without tremor. Further, hyperphenylalaninaemia did not cause a significant reduction in complex I activity or CoQ(10) biosynthesis, even when taking into account the mitochondrial enrichment of the cell samples by expressing complex I and CoQ(10) as a ratio to citrate synthase. In conclusion, the results of this study suggest that hyperphenylalaninaemia does not contribute to the pathophysiology of PKU by causing a decrease in MRC complex I activity and/or CoQ(10) biosynthesis.

Topics: Adult; Amino Acid Metabolism, Inborn Errors; Cell Line, Tumor; Cells, Cultured; Culture Media; Electron Transport; Female; Humans; Lactic Acid; Male; Middle Aged; Mitochondrial Diseases; Phenylalanine; Phenylketonurias; Pyruvic Acid; Tremor; Tyrosine; Ubiquinone; Young Adult

To investigate the implications of the three main factors of the antioxidant system reported in relation to oxidative damage in phenylketonuric patients: selenium, ubiquinone-10 (Q10) and antioxidant enzymes over 3 years of metabolic follow-up.. Longitudinal study of 46 phenylketonuric patients (age range: 6 months-34 years). Antioxidants were measured by atomic absorption spectrophotometric, chromatographic and spectrophotometric procedures.. Plasma selenium concentrations in phenylketonuria (PKU) were not different from those of a healthy population. Decreased plasma Q10 concentrations were mainly related to the dietary control and the age of patients. Erythrocyte catalase activity was significantly decreased in PKU while the other enzyme activities were not different from those of a healthy population.. Selenium status is not impaired in phenylketonuric patients under dietary treatment. Q10 values tend to decrease with increased patient age. Catalase activity was negatively associated with plasma phenylalanine values.

Topics: Adolescent; Adult; Antioxidants; Child; Child, Preschool; Coenzymes; Humans; Infant; Linear Models; Longitudinal Studies; Phenylketonurias; Selenium; Statistics, Nonparametric; Ubiquinone

Low serum ubiquinone-10 concentrations have been described in phenylketonuric patients fed natural-protein-restricted diets. Such low concentrations may be related to increased free radical damage.. We evaluated the relation between low serum ubiquinone-10 concentrations and other lipophilic antioxidants (tocopherol and retinol), selenium, glutathione peroxidase activity, and malondialdehyde concentrations as a marker of lipid peroxidation.. This was a cross-sectional study of 58 patients with phenylketonuria (aged 2-36 y; median: 13 y) under dietary treatment, 58 age-matched control subjects, and 30 children with moderate hyperphenylalaninemia fed unrestricted diets (aged 3-17 y; median: 7.5 y). Serum ubiquinone-10 concentrations were analyzed by HPLC with electrochemical detection. Serum retinol, serum tocopherol, and plasma malondialdehyde were analyzed by HPLC with ultraviolet detection.. A significant positive correlation was observed between ubiquinone-10 and tocopherol (r = 0.510, P < 0.001) in the patients with phenylketonuria. After the patients were stratified into 2 groups according to ubiquinone-10 values, significantly lower concentrations of tocopherol were observed in group 1 (low ubiquinone values) than in group 2 (normal ubiquinone values), the hyperphenylalaninemic children, and the control group. Plasma malondialdehyde concentrations were significantly higher in group 1 than in the other groups. No significant differences between groups 1 and 2 were observed in daily intakes of selenium, ascorbate, tocopherol, or retinol.. Plasma lipid peroxidation seems to be increased in phenylketonuria. Low concentrations of ubiquinone-10 could be associated with either excessive tocopherol consumption or high malondialdehyde concentrations in patients with phenylketonuria.

Topics: Adolescent; Adult; Antioxidants; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Lipid Peroxidation; Male; Oxidative Stress; Phenylketonurias; Tocopherols; Ubiquinone

Topics: Coenzymes; Humans; Monocytes; Phenylketonurias; Ubiquinone

To investigate the ubiquinone-10 content in lymphocytes from phenylketonuric patients.. We compared 23 patients with 25 age-matched controls. Ubiquinone-10 was analyzed by HPLC with electrochemical detection.. Ubiquinone-10 concentrations were significantly lower in patients (77-270 nmol/g of protein) compared with controls (190-550) (p < 0.001). Significantly negative correlation was observed between ubiquinone-10 and phenylalanine (r = -0.441; p < 0.05).. Ubiquinone-10 concentrations are decreased in lymphocytes from phenylketonuric patients. This deficiency is associated with high plasma phenylalanine concentrations.

Topics: Adolescent; Adult; Child; Chromatography, High Pressure Liquid; Coenzymes; Diet; Female; Humans; Lymphocytes; Male; Phenylalanine; Phenylketonurias; Ubiquinone

Decreased serum ubiquinone-10 concentrations is a common condition in patients with phenylketonuria (PKU) under dietary treatment. Our aim was to investigate the implication of the metabolic abnormalities of PKU (low concentrations of tyrosine and high concentrations of phenylalanine) and the effect of treatment with phenylalanine-restricted diets in decreased ubiquinone-10 concentrations in PKU patients. We studied 30 PKU patients (age range 5 months to 35 years; median age 7 years) under dietary treatment. Correlation between plasma tyrosine or phenylalanine and serum ubiquinone-10 concentrations was investigated. Daily cholesterol intake was calculated from the data obtained through a dietary questionnaire. The index of dietary control (IDC) was calculated as the average of the medians of plasma phenylalanine concentrations obtained every 6 months in the metabolic control of patients. Negative correlations were observed between serum ubiquinone and the IDC (r=-0.46; p<0.01) in PKU patients. No correlation was observed between tyrosine or daily cholesterol intake and serum ubiquinone concentrations. After adjustment for daily cholesterol intake by multiple linear regression analysis, for each 113 units of increase in IDC values serum ubiquinone decreased 0.1 micromol/L. According to our results, the main factor associated with the decreased serum ubiquinone concentrations was high plasma phenylalanine values. Although daily cholesterol intake seems to be associated with ubiquinone concentrations, it may not be relevant if we take into account the low intake of cholesterol in treated PKU patients.

Topics: Adolescent; Adult; Child; Child, Preschool; Cholesterol; Cholesterol, Dietary; Humans; Infant; Linear Models; Phenylalanine; Phenylketonurias; Tyrosine; Ubiquinone

Ubiquinone-10 is a lipid with important metabolic functions that may be decreased in phenylketonuria (PKU) because patients with PKU consume diets restricted in natural proteins.. We studied serum ubiquinone-10 concentrations in PKU patients.. This was a retrospective, transversal study in which we compared serum ubiquinone-10, plasma cholesterol, plasma tyrosine, and plasma phenylalanine concentrations in 43 PKU patients with concentrations in a reference population (n = 102). Serum ubiquinone-10 concentrations were analyzed by HPLC with ultraviolet detection. Plasma tyrosine and phenylalanine were measured by ion-exchange chromatography.. Serum ubiquinone-10 concentrations in PKU patients were significantly lower than in the reference population (P < 0.01 for patients aged 1 mo to <8 y and P < 0.00005 for patients aged 8-33 y). Moreover, 5 of 18 PKU patients (28%) in the younger age group and 10 of 23 (43%) in the older age group had serum ubiquinone-10 concentrations below the reference interval.. Serum ubiquinone-10 deficiency appears to be related to the restricted diet of PKU patients. Because serum ubiquinone-10 plays a major antioxidant role in the protection of circulating lipoproteins, the correction of ubiquinone-10 concentrations should be considered in PKU patients. Further investigation seems advisable to elucidate whether the deficiency in serum ubiquinone-10 status is clinically significant.

Topics: Adolescent; Adult; Antidotes; Child; Child, Preschool; Cholesterol; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Diet; Female; Humans; Infant; Male; Phenylalanine; Phenylketonurias; Reference Values; Retrospective Studies; Tyrosine; Ubiquinone

Topics: Body Fluids; Child; Chromatography; Humans; Phenylketonurias; Spectrum Analysis; Ubiquinone; Urine