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.

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

Bossi M.;Citterio S.;Corti R.;Salerno D.;Nardo L.;Piazza R.
2020-01-01

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.
2020
Cell Line; Cell Respiration; DNA Breaks; Electron Transport Complex II; Ethanolamines; Humans; Leukemia, Myeloid; Mitochondria; Mutation; Phenotype; Phosphotransferases (Alcohol Group Acceptor); Reactive Oxygen Species; Succinic Acid; Tigecycline
Fontana, D.; Mauri, M.; Renso, R.; Docci, M.; Crespiatico, I.; Rost, L. M.; Jang, M.; Niro, A.; D'Aliberti, D.; Massimino, L.; Bertagna, M.; Zambrotta...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2133888
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