Effects of Phenylalanine and its Metabolites on Cytoplasmic Free Calcium in Cortical Neurons

In a previous work, we observed that mandelonitrile (MD), which controls cyanogenic glycoside turnover, is involved in salicylic acid (SA) biosynthesis in peach plants. In order to gain knowledge about the possible roles of this SA biosynthetic pathway, this current study looks at the effect of MD and phenylalanine (Phe; MD precursor) treatments on peach plant performance from an agronomic point of view. Abiotic (2 g·l NaCl) and biotic (Plum pox virus, PPV) stresses were assayed. We recorded the following chlorophyll fluorescence parameters: quantum yield of photochemical energy conversion in PSII [Y(II)], photochemical quenching (qP) and quantum yield of regulated non-photochemical energy loss in PSII and its coefficient [Y(NPQ) and qN]. In addition, considering that environmental stresses lead to nutritional disorders, we determined the soluble K , Ca , Na and Cl concentrations in NaCl-stressed seedlings. In PPV-infected seedlings, we recorded the Ca level, which has been suggested to play critical roles in regulating SA-related plant defence responses against pathogens. The MD treatment lessened the effect of both stresses on plant development. In addition, an increase in non-photochemical quenching parameters was observed in MD-treated seedlings, suggesting a safer dissipation of excess energy under stress conditions. In NaCl-stressed peach seedlings both treatments stimulated the accumulation of phytotoxic ions in roots, whereas in PPV-infected seedlings MD increased Ca content. Our results suggest that MD and Phe influence the response of peach seedlings to the deleterious effects of salt and PPV infection stresses.

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“…Moreover, Phe treatment can decrease free Ca 2+ (Yu et al . ). This situation was different in the peach plants used for PPV assays.…”

Section: Discussionmentioning

confidence: 97%

The effect of mandelonitrile, a recently described salicylic acid precursor, on peach plant response against abiotic and biotic stresses

et al. 2018

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“…Rat models of hyperphenylalaninemia have demonstrated that Phe can directly inhibit enzyme activity within all energetic pathways in the brain, including glycolysis, tricarboxylic acid cycle, respiratory transport chain, phosphocreatine-creatine metabolism, and ketone body synthesis and utilization. Alternately, sustained elevations of blood Phe could indirectly trigger the aforementioned bioenergetic changes by enhancing the production of reactive oxygen species ( 26 ) and modulating the activity of the plasma membrane Ca 2+ -ATPase ( 27 ). The resulting accumulation of reactive oxygen species and calcium not only enhances cellular vulnerability to oxidative damage ( 28 ), but can also change the activity of key enzymes involved in energy metabolism ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…Alternately, sustained elevations of blood Phe could indirectly trigger the aforementioned bioenergetic changes by enhancing the production of reactive oxygen species ( 26 ) and modulating the activity of the plasma membrane Ca 2+ -ATPase ( 27 ). The resulting accumulation of reactive oxygen species and calcium not only enhances cellular vulnerability to oxidative damage ( 28 ), but can also change the activity of key enzymes involved in energy metabolism ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Plasma metabolomic profile changes in females with phenylketonuria following a camp intervention

Schoen

Singh

2022

The American Journal of Clinical Nutrition

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Background There remains a limited understanding of the metabolic perturbations, beyond phenylalanine (Phe) metabolism, that contribute to phenotypic variability in phenylketonuria (PKU). Objective This study aimed to characterize changes in the PKU plasma metabolome following a five-day Metabolic Camp intervention and to compare PKU profiles with those of matched healthy controls. Design In 28 females (12–57 years of age), fasting plasma samples were collected on the first (day one) and final (day five) days of camp to measure metabolic control and to complete untargeted metabolomic profiling. Three-day dietary records were collected to assess changes in dietary adherence and composition. Univariate (Wilcoxon Signed-Rank and Mann Whitney U Test) and multivariate (random forest, hierarchical clustering) analyses were performed to identify clinical and metabolic features that were associated with the intervention and disease state. Results Relative to healthy controls, Phe catabolites, ketones, and carnitine- and glycine-conjugated fatty acids were elevated in females with PKU at baseline, while fatty acylcholine metabolites were substantially lower. After the camp intervention, plasma Phe concentrations decreased [median change (IQR): –173 µmol/L (–325, –28)] and 70% of PKU participants demonstrated improved dietary adherence by decreasing Phe intake and/or increasing medical food consumption. This was accompanied by a shift in abundance for 223 metabolites (q < 0.05). Compounds associated with the metabolism of Phe, fatty acids, and choline contributed most to profile differences between camp days one and five. Conclusions In females with PKU, untargeted metabolomics identified prominent perturbations in amino acid and lipid metabolites associated with bioenergetic impairment and oxidative stress. Choline-conjugated lipids may have fundamental roles in these pathways and have not been previously evaluated in PKU. A short-term camp intervention was effective for improving or fully normalizing the abundance of the identified discriminatory metabolites.

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“…These alterations were not reverted by Phe-restricted diet [99]. In another study, Yu and colleagues [100] demonstrated that Phe alters intracellular free calcium concentrations by modulating plasma membrane Ca 2+ -ATPase in cortical neurons.…”

Section: Calcium Homeostasismentioning

confidence: 99%

Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

Schuck¹,

Malgarin²,

Cararo³

et al. 2015

Aging and disease

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Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition.

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Effects of Phenylalanine and its Metabolites on Cytoplasmic Free Calcium in Cortical Neurons

Cited by 12 publications

References 43 publications

The effect of mandelonitrile, a recently described salicylic acid precursor, on peach plant response against abiotic and biotic stresses

The effect of mandelonitrile, a recently described salicylic acid precursor, on peach plant response against abiotic and biotic stresses

Plasma metabolomic profile changes in females with phenylketonuria following a camp intervention

Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

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