Decreased serum ubiquinone-10 concentrations in phenylketonuria

Artuch, Rafael; Vilaseca, M-Antònia; Moreno, Juan Antonio; Lambruschini, Nilo; Cambra, Francisco José; Campistol, Jaume

doi:10.1093/ajcn/70.5.892

Cited by 56 publications

(40 citation statements)

References 20 publications

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“…Numerous studies have provided experimental evidence demonstrating oxidative stress in human PKU patients and animal models (Artuch et al, 2001(Artuch et al, ,2004Colome et al, 2003;Ercal et al, 2002;Martinez-Cruz et al, 2002;Sierra et al, 1998;Sirtori et al, 2005). Our laboratory previously demonstrated increased inducible nitric oxide synthase production by infiltrative cd11b macrophage cells in the mesencephalon and hypothalamus of PKU mice (Embury et al, 2005), providing further evidence of oxidative processes occurring in these regions.…”

Section: Discussionmentioning

confidence: 73%

“…Ercal et al (2002) provided experimental evidence of oxidative damage in Pah enu2 mice that included increased concentration of the lipid peroxidation by-product malon-dialdehyde in brain tissue, decreased glutathione/glutathione disulfide also in brain and increased catalase and glucose-6-phosphate dehydrogenase in erythrocytes of these animals. Other studies indicating the role of oxidative stress in PKU include human studies by Artuch et al (2001Artuch et al ( , 2004; Colome et al (2003);and Sierra et al (1998). Sirtori et al (2005) demonstrated the involvement of oxidative stress in human PKU patients through increased levels of thiobarbituric acid reactive species (indicative of lipid peroxidation) and decreased total antioxidant reactivity, suggestive of deficient capacity to handle increases in reactive species.…”

Section: Discussionmentioning

confidence: 99%

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PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

et al. 2007

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Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah enu2 mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah enu2 mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah enu2 mice and corresponded to rapid reduction of serum Phe levels.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

et al. 2007

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“…Furthermore, the normal glutathione values observed in our PKU patients would further support the beneficial effects of low tHcy and cysteine concentrations. However, this hypothesis should be considered with caution because other factors present in PKU patients may increase oxidative stress, such as selenium deficiency in patients with poor dietary adherence (Van Bakel et al, 2000), or the decreased ubiquinone-10 values observed in serum (Artuch et al, 1999) and cells (Colomé et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In PKU, deficiencies in two important antioxidants, selenium (Van Bakel et al, 2000) and coenzyme Q10 (Artuch et al, 1999), have been reported. These deficiencies were mainly related to poor dietary compliance, and might cause an increase in peroxidative damage manifested in high malondialdehyde (MDA, a product of lipid peroxidation) values, low reduced glutathione concentrations and/or low normal tocopherol concentrations.…”

Section: Introductionmentioning

confidence: 99%

Plasma thiols and their determinants in phenylketonuria

et al. 2003

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Objective: Treatment of phenylketonuria (PKU) patients consists of a phenylalanine-restricted diet supplemented with a tyrosine-, vitamin-and oligoelement-enriched amino-acid mixture. Vitamins and oligoelements may be deficient when compliance with the supplemented special formula is poor. Plasma thiol concentrations (especially homocysteine) depend mainly on B-vitamin intake. Our aim was to evaluate the plasma thiol concentrations (homocysteine, cysteine and glutathione) and their determinants (methionine, cobalamin and folate) in PKU patients under dietary treatment compared with agematched controls. Design and setting: Cross-sectional study performed in a tertiary care Hospital. Subjects: PKU (42) patients under dietary treatment compared with 42 age-matched controls. Interventions: Plasma total homocysteine, cysteine and glutathione were analyzed by HPLC with fluorescence detection. Plasma phenylalanine and methionine were analyzed by ion exchange chromatography. Serum folate and cobalamin were analyzed by radioimmunoassay procedures. Results: Total homocysteine concentrations were significantly lower in the PKU patients compared with the control group (Students t-test; Po0.0001). Serum folate and cobalamin were significantly higher in the PKU group (t-Student; Po0.0001) compared with controls. A significantly negative correlation was observed between total homocysteine and folate (r ¼ À0.378; P ¼ 0.016), and between cobalamin and phenylalanine concentrations (r ¼ À0.367; P ¼ 0.022) in the PKU group. Conclusions: Plasma total homocysteine values are lower in the PKU group than in the controls, probably because of high folate values. High phenylalanine values, an indicator of poor dietary compliance, are negatively associated with cobalamin, which might be deficient in some cases.

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“…Nowadays, apart from the bioenergetic function, quinones are considered to be engaged in a variety of cellular functions that are not only associated with their redox properties but also with the capability to change the fluidity of the lipid bilayers (48,96,256). The later point is supported by the fact that occurrence of quinones is not restricted to mitochondrial membrane (91), and the changes in their content is also correlated with age and with several diseases (10,86,87,138,156,167,263).…”

Section: Quinones and The Q Poolmentioning

confidence: 99%

Electronic Connection Between the Quinone and CytochromecRedox Pools and Its Role in Regulation of Mitochondrial Electron Transport and Redox Signaling

Sarewicz

Osyczka

2015

Physiological Reviews

140

141

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Physiol Rev 95: 219 -243, 2015; doi:10.1152/physrev.00006.2014.-Mitochondrial respiration, an important bioenergetic process, relies on operation of four membranous enzymatic complexes linked functionally by mobile, freely diffusible elements: quinone molecules in the membrane and water-soluble cytochromes c in the intermembrane space. One of the mitochondrial complexes, complex III (cytochrome bc 1 or ubiquinol: cytochrome c oxidoreductase), provides an electronic connection between these two diffusible redox pools linking in a fully reversible manner two-electron quinone oxidation/reduction with one-electron cytochrome c reduction/oxidation. Several features of this homodimeric enzyme implicate that in addition to its well-defined function of contributing to generation of proton-motive force, cytochrome bc 1 may be a physiologically important point of regulation of electron flow acting as a sensor of the redox state of mitochondria that actively responds to changes in bioenergetic conditions. These features include the following: the opposing redox reactions at quinone catalytic sites located on the opposite sides of the membrane, the inter-monomer electronic connection that functionally links four quinone binding sites of a dimer into an H-shaped electron transfer system, as well as the potential to generate superoxide and release it to the intermembrane space where it can be engaged in redox signaling pathways. Here we highlight recent advances in understanding how cytochrome bc 1 may accomplish this regulatory physiological function, what is known and remains unknown about catalytic and side reactions within the quinone binding sites and electron transfers through the cofactor chains connecting those sites with the substrate redox pools. We also discuss the developed molecular mechanisms in the context of physiology of mitochondria.

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Decreased serum ubiquinone-10 concentrations in phenylketonuria

Cited by 56 publications

References 20 publications

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice

Plasma thiols and their determinants in phenylketonuria

Electronic Connection Between the Quinone and CytochromecRedox Pools and Its Role in Regulation of Mitochondrial Electron Transport and Redox Signaling

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