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

Irene González-recio; Jorge Simón; Naroa Goikoetxea-usandizaga; Marina Serrano-maciá; Maria Mercado-gómez; Rubén Rodríguez-agudo; Sofía Lachiondo-ortega; Clàudia Gil-pitarch; Carmen Fernández-rodríguez; Donatello Castellana; Maria U. Latasa; Leticia Abecia; Juan Anguita; Teresa C. Delgado; Paula Iruzubieta; Javier Crespo; Serge Hardy; Petar D. Petrov; Ramiro Jover; Matías A. Avila; César Martín; Ute Schaeper; Michel L. Tremblay; James W. Dear; Steven Masson; Misti Vanette Mccain; Helen L. Reeves; Raul J. Andrade; M. Isabel Lucena; Daniela Buccella; Luis Alfonso Martínez-cruz; Maria L Martínez-chantar

doi:10.1038/s41467-022-34262-0

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

Irene González-recio, Jorge Simón, Naroa Goikoetxea-usandizaga, Marina Serrano-maciá, Maria Mercado-gómez, Rubén Rodríguez-agudo, Sofía Lachiondo-ortega, Clàudia Gil-pitarch, Carmen Fernández-rodríguez, Donatello Castellana, Maria U. Latasa, Leticia Abecia, Juan Anguita, Teresa C. Delgado, Paula Iruzubieta, Javier Crespo, Serge Hardy, Petar D. Petrov, Ramiro Jover, Matías A. AvilaCésar Martín, Ute Schaeper, Michel L. Tremblay, James W. Dear, Steven Masson, Misti Vanette Mccain, Helen L. Reeves, Raul J. Andrade, M. Isabel Lucena, Daniela Buccella, Luis Alfonso Martínez-cruz, Maria L Martínez-chantar

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Abstract / Description of output

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.

Original language	English
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34262-0
Publication status	Published - 25 Nov 2022

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González-recio, I., Simón, J., Goikoetxea-usandizaga, N., Serrano-maciá, M., Mercado-gómez, M., Rodríguez-agudo, R., Lachiondo-ortega, S., Gil-pitarch, C., Fernández-rodríguez, C., Castellana, D., Latasa, M. U., Abecia, L., Anguita, J., Delgado, T. C., Iruzubieta, P., Crespo, J., Hardy, S., Petrov, P. D., Jover, R., ... Martínez-chantar, M. L. (2022). Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-34262-0

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title = "Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage",

abstract = "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.",

author = "Irene Gonz{\'a}lez-recio and Jorge Sim{\'o}n and Naroa Goikoetxea-usandizaga and Marina Serrano-maci{\'a} and Maria Mercado-g{\'o}mez and Rub{\'e}n Rodr{\'i}guez-agudo and Sof{\'i}a Lachiondo-ortega and Cl{\`a}udia Gil-pitarch and Carmen Fern{\'a}ndez-rodr{\'i}guez and Donatello Castellana and Latasa, {Maria U.} and Leticia Abecia and Juan Anguita and Delgado, {Teresa C.} and Paula Iruzubieta and Javier Crespo and Serge Hardy and Petrov, {Petar D.} and Ramiro Jover and Avila, {Mat{\'i}as A.} and C{\'e}sar Mart{\'i}n and Ute Schaeper and Tremblay, {Michel L.} and Dear, {James W.} and Steven Masson and Mccain, {Misti Vanette} and Reeves, {Helen L.} and Andrade, {Raul J.} and Lucena, {M. Isabel} and Daniela Buccella and Mart{\'i}nez-cruz, {Luis Alfonso} and Mart{\'i}nez-chantar, {Maria L}",

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doi = "10.1038/s41467-022-34262-0",

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González-recio, I, Simón, J, Goikoetxea-usandizaga, N, Serrano-maciá, M, Mercado-gómez, M, Rodríguez-agudo, R, Lachiondo-ortega, S, Gil-pitarch, C, Fernández-rodríguez, C, Castellana, D, Latasa, MU, Abecia, L, Anguita, J, Delgado, TC, Iruzubieta, P, Crespo, J, Hardy, S, Petrov, PD, Jover, R, Avila, MA, Martín, C, Schaeper, U, Tremblay, ML, Dear, JW, Masson, S, Mccain, MV, Reeves, HL, Andrade, RJ, Lucena, MI, Buccella, D, Martínez-cruz, LA & Martínez-chantar, ML 2022, 'Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage', Nature Communications, vol. 13, no. 1. https://doi.org/10.1038/s41467-022-34262-0

TY - JOUR

T1 - Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage

AU - González-recio, Irene

AU - Simón, Jorge

AU - Goikoetxea-usandizaga, Naroa

AU - Serrano-maciá, Marina

AU - Mercado-gómez, Maria

AU - Rodríguez-agudo, Rubén

AU - Lachiondo-ortega, Sofía

AU - Gil-pitarch, Clàudia

AU - Fernández-rodríguez, Carmen

AU - Castellana, Donatello

AU - Latasa, Maria U.

AU - Abecia, Leticia

AU - Anguita, Juan

AU - Delgado, Teresa C.

AU - Iruzubieta, Paula

AU - Crespo, Javier

AU - Hardy, Serge

AU - Petrov, Petar D.

AU - Jover, Ramiro

AU - Avila, Matías A.

AU - Martín, César

AU - Schaeper, Ute

AU - Tremblay, Michel L.

AU - Dear, James W.

AU - Masson, Steven

AU - Mccain, Misti Vanette

AU - Reeves, Helen L.

AU - Andrade, Raul J.

AU - Lucena, M. Isabel

AU - Buccella, Daniela

AU - Martínez-cruz, Luis Alfonso

AU - Martínez-chantar, Maria L

PY - 2022/11/25

Y1 - 2022/11/25

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-022-34262-0

DO - 10.1038/s41467-022-34262-0

M3 - Article

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

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