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ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine

Author

Listed:
  • Diletta Fontana

    (University of Milano - Bicocca)

  • Mario Mauri

    (University of Milano - Bicocca)

  • Rossella Renso

    (University of Milano - Bicocca)

  • Mattia Docci

    (University of Milano - Bicocca)

  • Ilaria Crespiatico

    (University of Milano - Bicocca)

  • Lisa M. Røst

    (Norwegian University of Science and Technology)

  • Mi Jang

    (Norwegian University of Science and Technology)

  • Antonio Niro

    (University of Milano - Bicocca)

  • Deborah D’Aliberti

    (University of Milano - Bicocca)

  • Luca Massimino

    (University of Milano - Bicocca)

  • Mayla Bertagna

    (University of Milano - Bicocca)

  • Giovanni Zambrotta

    (University of Milano - Bicocca)

  • Mario Bossi

    (University of Milano - Bicocca)

  • Stefania Citterio

    (University of Milano - Bicocca)

  • Barbara Crescenzi

    (University of Perugia)

  • Francesca Fanelli

    (University of Modena and Reggio Emilia
    University of Modena and Reggio Emilia)

  • Valeria Cassina

    (University of Milano - Bicocca)

  • Roberta Corti

    (University of Milano - Bicocca)

  • Domenico Salerno

    (University of Milano - Bicocca)

  • Luca Nardo

    (University of Milano - Bicocca)

  • Clizia Chinello

    (University of Milano - Bicocca)

  • Francesco Mantegazza

    (University of Milano - Bicocca)

  • Cristina Mecucci

    (University of Perugia)

  • Fulvio Magni

    (University of Milano - Bicocca)

  • Guido Cavaletti

    (University of Milano - Bicocca)

  • Per Bruheim

    (Norwegian University of Science and Technology)

  • Delphine Rea

    (Hôpital Saint-Louis)

  • Steen Larsen

    (University of Copenhagen
    Medical University of Bialystok)

  • Carlo Gambacorti-Passerini

    (University of Milano - Bicocca
    San Gerardo Hospital)

  • Rocco Piazza

    (University of Milano - Bicocca
    San Gerardo Hospital
    University of Milano - Bicocca)

Abstract

Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype.

Suggested Citation

  • Diletta Fontana & Mario Mauri & Rossella Renso & Mattia Docci & Ilaria Crespiatico & Lisa M. Røst & Mi Jang & Antonio Niro & Deborah D’Aliberti & Luca Massimino & Mayla Bertagna & Giovanni Zambrotta &, 2020. "ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19721-w
    DOI: 10.1038/s41467-020-19721-w
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