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 / 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, G.; Bossi, M.; Citterio, S.; Crescenzi, B.; Fanelli, F.; Cassina, V.; Corti, R.; Salerno, D.; Nardo, L.; Chinello, C.; Mantegazza, F.; Mecucci, C.; Magni, F.; Cavaletti, G.; Bruheim, P.; Rea, D.; Larsen, S.; Gambacorti-Passerini, C.; Piazza, R.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020), pp. 5938-5938. [10.1038/s41467-020-19721-w]
ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine
Fanelli F.;
2020
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.File | Dimensione | Formato | |
---|---|---|---|
NatCommun_2020.pdf
Open access
Tipologia:
Versione pubblicata dall'editore
Dimensione
2.93 MB
Formato
Adobe PDF
|
2.93 MB | Adobe PDF | Visualizza/Apri |
Pubblicazioni consigliate
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris