Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage

Drug induced liver injury (DILI) is an important cause acute liver failure. Here the authors report that serum Mg2+ serum levels decrease in patients with DILI as well as in preclinical animal models treated with acetaminophen overdose, and that early intervention targeting the Mg2+ transporter Cycl...

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Detalhes bibliográficos
Autores: González Recio, Irene, Simón Espinosa, Jorge, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Mercado Gómez, María, Rodríguez Agudo, Rubén, Lachiondo Ortega, Sofía, Gil Pitarch, Clàudia, Fernández Rodríguez, Carmen, Castellana, Donatello, Latasa, María Ujué, Abecia Aliende, Leticia, Anguita Castillo, Juan de Dios, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín Plágaro, César Augusto, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti Vanette, Reeves, Helen L., Andrade, Raúl, Lucena, M. Isabel, Buccella, Daniela, Martínez de la Cruz, Alfonso, Martínez Chantar, María Luz
Formato: artículo
Fecha de publicación:2022
País:España
Recursos:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/59482
Acesso em linha:http://hdl.handle.net/10810/59482
Access Level:acceso abierto
Palavra-chave:intracellular Magnesium
n-acetylcysteine
hepatotoxicity
mitochondrial
inhibition
Calcium
Mg2+
mice
thapsigargin
inflammation
Descrição
Resumo:Drug induced liver injury (DILI) is an important cause acute liver failure. Here the authors report that serum Mg2+ serum levels decrease in patients with DILI as well as in preclinical animal models treated with acetaminophen overdose, and that early intervention targeting the Mg2+ transporter Cyclin M4 may be beneficial for acetaminophen overdose in preclinical models. 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.

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