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

Lookup NU author(s): Dr Steven MassonORCiD, Misti McCainORCiD, Professor Helen ReevesORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022, The Author(s).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.

Publication metadata

Author(s): Gonzalez-Recio I, Simon J, Goikoetxea-Usandizaga N, Serrano-Macia M, Mercado-Gomez M, Rodriguez-Agudo R, Lachiondo-Ortega S, Gil-Pitarch C, Fernandez-Rodriguez C, Castellana D, Latasa MU, Abecia L, Anguita J, Delgado TC, Iruzubieta P, Crespo J, Hardy S, Petrov PD, Jover R, Avila MA, Martin C, Schaeper U, Tremblay ML, Dear JW, Masson S, McCain MV, Reeves HL, Andrade RJ, Lucena MI, Buccella D, Martinez-Cruz LA, Martinez-Chantar ML

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2022

Volume: 13

Issue: 1

Online publication date: 25/11/2022

Acceptance date: 17/10/2022

Date deposited: 16/06/2023

ISSN (electronic): 2041-1723

Publisher: Nature Research

URL: https://doi.org/10.1038/s41467-022-34262-0

DOI: 10.1038/s41467-022-34262-0

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