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Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Mitochondrial trifunctional protein (MTP) deficiency caused by HADHA or HADHB gene mutations exhibits substantial molecular, biochemical, and clinical heterogeneity and ranks among the more severe fatty acid oxidation (FAO) disorders, without pharmacological treatment. Since bezafibrate has been shown to potentially correct other FAO disorders in patient cells, we analyzed its effects in 26 MTP-deficient patient fibroblasts representing 16 genotypes. Overall, the patient cell lines exhibited variable, complex, biochemical profiles and pharmacological responses. HADHA-deficient fibroblasts showed markedly reduced alpha subunit protein levels together with decreased beta-subunit abundance, exhibited a −86 to −96 % defect in LCHAD activity, and produced large amounts of C14 and C16 hydroxyacylcarnitines. In control fibroblasts, exposure to bezafibrate (400 μM for 48 h) increased the abundance of HADHA and HADHB mRNAs, immune-detectable alpha and beta subunit proteins, activities of LCHAD and LCKAT, and stimulated FAO capacities, clearly indicating that MTP is pharmacologically up-regulated by bezafibrate in human fibroblasts. In MTP-deficient patient fibroblasts, which were found markedly FAO-deficient, bezafibrate improved FAO capacities in six of 26 (23 %) cases, including three cell lines heterozygous for the common c1528G > C mutation. Altogether, our results strongly suggest that, due to variable effects of HADHA and HADHB mutations on MTP abundance and residual activity, improvement of MTP deficiency in response to bezafibrate was achieved in a subset of responsive genotypes.

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Acknowledgments

This study was supported by grants of the Association Française contre les Myopathies (AFM).

Compliance with ethics guidelines

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. INSERM UMR-1124, Université Paris Descartes, Centre Universitaire des Saints Pères, 45 rue des Saints Pères, 75006, Paris, France

    Fatima Djouadi, Florence Habarou, Carole Le Bachelier & Jean Bastin

  2. Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Sacha Ferdinandusse & Ronald J. A. Wanders

  3. Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Biochimie-Hormonologie, Hôpital Robert Debré, 48 bd Sérurier, 75019, Paris, France

    Dimitri Schlemmer & Jean François Benoist

  4. Service de Biochimie, Hôpital Bicêtre, 78 rue du Général Leclerc, 94270, Le Kremlin Bicêtre, France

    Audrey Boutron

  5. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230, Odense M, Denmark

    Brage S. Andresen

  6. Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Lundlaan 6, 3584 EA, Utrecht, The Netherlands

    Gepke Visser

  7. INSERM U781, Institut Imagine des Maladies Génétiques, Université Paris Descartes et Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker, 149 rue de Sèvres, 75015, Paris, France

    Pascale de Lonlay

  8. Department of Clinical Chemistry, Sheffield Children’s Hospital, Western Bank, Sheffield, South Yorkshire, S10 2TH, UK

    Simon Olpin

  9. Department of Pediatrics, Graduate School of Medicine, Gifu University, Yanagido 1-1, Gifu, 501-1194, Japan

    Toshiyuki Fukao

  10. Department of Pediatrics, Shimane University School of Medicine, 89-1 Enya-Cho, Izumo, 693-8501, Japan

    Seiji Yamaguchi

  11. Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA

    Arnold W. Strauss

Authors
  1. Fatima Djouadi
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  2. Florence Habarou
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  3. Carole Le Bachelier
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  4. Sacha Ferdinandusse
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  5. Dimitri Schlemmer
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  6. Jean François Benoist
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  7. Audrey Boutron
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  8. Brage S. Andresen
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  9. Gepke Visser
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  10. Pascale de Lonlay
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  11. Simon Olpin
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  12. Toshiyuki Fukao
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  13. Seiji Yamaguchi
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  14. Arnold W. Strauss
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  15. Ronald J. A. Wanders
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  16. Jean Bastin
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Corresponding author

Correspondence to Jean Bastin.

Additional information

Communicated by: Jörn Oliver Sass

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Djouadi, F., Habarou, F., Le Bachelier, C. et al. Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate. J Inherit Metab Dis 39, 47–58 (2016). https://doi.org/10.1007/s10545-015-9871-3

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  • DOI: https://doi.org/10.1007/s10545-015-9871-3

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