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

Author

Listed:
  • Irene González-Recio

    (Bizkaia Technology Park)

  • Jorge Simón

    (Bizkaia Technology Park
    Carlos III National Health Institute)

  • Naroa Goikoetxea-Usandizaga

    (Bizkaia Technology Park)

  • Marina Serrano-Maciá

    (Bizkaia Technology Park)

  • Maria Mercado-Gómez

    (Bizkaia Technology Park)

  • Rubén Rodríguez-Agudo

    (Bizkaia Technology Park)

  • Sofía Lachiondo-Ortega

    (Bizkaia Technology Park)

  • Clàudia Gil-Pitarch

    (Bizkaia Technology Park)

  • Carmen Fernández-Rodríguez

    (Bizkaia Technology Park)

  • Donatello Castellana

    (Bizkaia Technology Park)

  • Maria U. Latasa

    (Universidad de Navarra)

  • Leticia Abecia

    (Basque Research and Technology Alliance (BRTA)
    Facultad de Medicina y Enfermería. Universidad del País Vasco/ Euskal Herriko Unibertsitatea (UPV/EHU))

  • Juan Anguita

    (Basque Research and Technology Alliance (BRTA)
    Basque Foundation for Science)

  • Teresa C. Delgado

    (Bizkaia Technology Park)

  • Paula Iruzubieta

    (Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL)

  • Javier Crespo

    (Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL)

  • Serge Hardy

    (McGill University
    McGill Unversity)

  • Petar D. Petrov

    (Carlos III National Health Institute
    IIS Hospital La Fe & Dep. Biochemistry, University of Valencia)

  • Ramiro Jover

    (Carlos III National Health Institute
    IIS Hospital La Fe & Dep. Biochemistry, University of Valencia)

  • Matías A. Avila

    (Carlos III National Health Institute
    Universidad de Navarra)

  • César Martín

    (University of the Basque Country (UPV/EHU))

  • Ute Schaeper

    (Silence Therapeutics GmbH, Berlin)

  • Michel L. Tremblay

    (McGill University
    McGill Unversity)

  • James W. Dear

    (University of Edinburgh)

  • Steven Masson

    (Newcastle-upon-Tyne Hospitals NHS Foundation Trust
    Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University)

  • Misti Vanette McCain

    (Newcastle-upon-Tyne Hospitals NHS Foundation Trust)

  • Helen L. Reeves

    (Newcastle-upon-Tyne Hospitals NHS Foundation Trust
    Newcastle University Translational and Clinical Research Institute, The Medical School, Newcastle University)

  • Raul J. Andrade

    (Carlos III National Health Institute
    Hospital Universitario Virgen de la Victoria, Universidad de Málaga)

  • M. Isabel Lucena

    (Carlos III National Health Institute
    Hospital Universitario Virgen de la Victoria, UICEC SCReN, Universidad de Málaga)

  • Daniela Buccella

    (New York University)

  • Luis Alfonso Martínez-Cruz

    (Bizkaia Technology Park)

  • Maria L Martínez-Chantar

    (Bizkaia Technology Park
    Carlos III National Health Institute)

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.

Suggested Citation

  • 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-, 2022. "Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34262-0
    DOI: 10.1038/s41467-022-34262-0
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    References listed on IDEAS

    as
    1. Yu-Ping Lin & Daniel Bakowski & Gary R. Mirams & Anant B. Parekh, 2019. "Selective recruitment of different Ca2+-dependent transcription factors by STIM1-Orai1 channel clusters," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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