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Insights from Animal Models on the Pathophysiology of Hyperphenylalaninemia: Role of Mitochondrial Dysfunction, Oxidative Stress and Inflammation

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Abstract

Phenylketonuria (PKU) is an inborn error of metabolism caused by phenylalanine hydroxylase (PAH) deficiency and characterized by elevated plasma levels of phenylalanine (hyperphenylalaninemia-HPA). In severe cases, PKU patients present with neurological dysfunction and hepatic damage, but the underlying mechanisms are not fully elucidated. Other forms of HPA also characterized by neurological symptoms occur in rare instances due to defects in the metabolism of the PAH cofactor tetrahydrobiopterin. This review aims to gather the knowledge acquired on the phenylalanine-induced toxicity focusing on findings obtained from pre-clinical studies. Mounting evidence obtained from PKU genetic mice, rats submitted to different HPA models, and cell cultures exposed to phenylalanine has shown that high levels of this amino acid impair mitochondrial bioenergetics, provoke changes in oxidative and inflammatory status, and induce apoptosis. Noteworthy, some data demonstrated that phenylalanine-induced oxidative stress occurs specifically in mitochondria. Further studies have shown that the metabolites derived from phenylalanine, namely phenylpyruvate, phenyllactate, and phenylacetate, also disturb oxidative status. Therefore, it may be presumed that mitochondrial damage is one of the most important mechanisms responsible for phenylalanine toxicity. It is expected that the findings reviewed here may contribute to the understanding of PKU and HPA pathophysiology and to the development of novel therapeutic strategies for these disorders.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Angela T. S. Wyse, Tiago M. dos Santos, Bianca Seminotti & Guilhian Leipnitz

  2. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, CEP 90035-003, Brazil

    Angela T. S. Wyse & Guilhian Leipnitz

  3. Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Guilhian Leipnitz

Authors
  1. Angela T. S. Wyse
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  2. Tiago M. dos Santos
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  3. Bianca Seminotti
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  4. Guilhian Leipnitz
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Contributions

ATSW, TMS, BS, and GL conceived, wrote, and revised the manuscript. TMS and BS designed and created the figures.

Corresponding author

Correspondence to Guilhian Leipnitz.

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Wyse, A.T.S., dos Santos, T.M., Seminotti, B. et al. Insights from Animal Models on the Pathophysiology of Hyperphenylalaninemia: Role of Mitochondrial Dysfunction, Oxidative Stress and Inflammation. Mol Neurobiol 58, 2897–2909 (2021). https://doi.org/10.1007/s12035-021-02304-1

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