Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology - Université d'Angers Accéder directement au contenu
Article Dans Une Revue Nature Communications Année : 2020

Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

Hϋlya Kayserili
  • Fonction : Auteur
Peter Bauer
  • Fonction : Auteur
Catarina Pereira
  • Fonction : Auteur
Antoine Muchir
Lisa Martino
  • Fonction : Auteur
Song-Hua Lee
  • Fonction : Auteur
Bruno Reversade

Résumé

Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mito-chondrial membrane protein, in patients presenting with a severe laminopathy-like mandi-buloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients' primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.
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Licence : CC BY - Paternité
Licence : CC BY - Paternité

Dates et versions

hal-02942760 , version 1 (21-09-2020)

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Paternité

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Sahar Elouej, Karim Harhouri, Morgane Le Mao, Genevieve Baujat, Sheela Nampoothiri, et al.. Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology. Nature Communications, 2020, 11 (4589), ⟨10.1038/s41467-020-18146-9⟩. ⟨hal-02942760⟩
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