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00925njm 22002777a 4500 dc González-Recio, Irene author Simón, Jorge author Goikoetxea-Usandizaga, Naroa author Serrano-Maciá, Marina author Mercado-Gómez, Maria author Rodríguez-Agudo, Rubén author Lachiondo-Ortega, Sofía author Gil-Pitarch, Clàudia author Fernández-Rodríguez, Carmen author Castellana, Donatello author Latasa, Maria U author Abecia, Leticia author Anguita, Juan author Delgado, Teresa C author Iruzubieta, Paula author Crespo, Javier author Hardy, Serge author Petrov, Petar D author Jover, Ramiro author Avila, Matías A author Martín, César author Schaeper, Ute author Tremblay, Michel L author Dear, James W author Masson, Steven author McCain, Misti Vanette author Reeves, Helen L author Andrade, Raul J author Lucena, M Isabel author Buccella, Daniela author Martínez-Cruz, Luis Alfonso author Martínez-Chantar, Maria L author 2022-11-25 Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury. http://hdl.handle.net/10668/19549 http://hdl.handle.net/20.500.12105/18857 36433951 10.1038/s41467-022-34262-0 2041-1723 Nature communications Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage.