Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage
Irene González-Recio 1, Jorge Simón 1 2, Naroa Goikoetxea-Usandizaga 1, Marina Serrano-Maciá 1, Maria Mercado-Gómez 1, Rubén Rodríguez-Agudo 1, Sofía Lachiondo-Ortega 1, Clàudia Gil-Pitarch 1, Carmen Fernández-Rodríguez 1, Donatello Castellana 3, Maria U Latasa 4, Leticia Abecia 5 6, Juan Anguita 5 7, Teresa C Delgado 1, Paula Iruzubieta 8, Javier Crespo 8, Serge Hardy 9 10, Petar D Petrov 2 11, Ramiro Jover 2 11, Matías A Avila 2 4, César Martín 12, Ute Schaeper 13, Michel L Tremblay 9 10, James W Dear 14, Steven Masson 15 16, Misti Vanette McCain 15, Helen L Reeves 15 16, Raul J Andrade 2 17, M Isabel Lucena 2 18, Daniela Buccella 19, Luis Alfonso Martínez-Cruz 20, Maria L Martínez-Chantar 21 22
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.