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

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...

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Detalles Bibliográficos
Autores: González-Recio, Irene, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Gil-Pitarch, Clàudia, Fernández-Rodríguez, Carmen, Castellana, Donatello, Latasa, Maria U., Abecia, Leticia, Anguita, Juan, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín, César, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti, Reeves, Helen L., Andrade, Raúl J., Lucena, María Isabel, Buccella, Daniela, Martínez-Cruz, Luis Alfonso, Martínez-Chantar, María Luz
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/296821
Acceso en línea:http://hdl.handle.net/10261/296821
Access Level:acceso abierto
Palabra clave:Gastroenterology
Hepatology
Descripción
Sumario: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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