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

• DOI: 10.1038/s41467-020-19721-w
• Publication Date: 2020-11-23T11:08:30Z
• Authors: 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; Mario Bossi; Stefania Citterio; Barbara Crescenzi; Francesca Fanelli; Valeria Cassina; Roberta Corti; Domenico Salerno; Luca Nardo; Clizia Chinello; Francesco Mantegazza; Cristina Mecucci; Fulvio Magni; Guido Cavaletti; Per Bruheim; Delphine Rea; Steen Larsen; Carlo Gambacorti-...; Rocco Piazza
• Keywords: Hyperactivation

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