Antioxidants (Apr 2022)

Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen

  • Rubén Rodríguez-Agudo,
  • Naroa Goikoetxea-Usandizaga,
  • Marina Serrano-Maciá,
  • Pablo Fernández-Tussy,
  • David Fernández-Ramos,
  • Sofía Lachiondo-Ortega,
  • Irene González-Recio,
  • Clàudia Gil-Pitarch,
  • María Mercado-Gómez,
  • Laura Morán,
  • Maider Bizkarguenaga,
  • Fernando Lopitz-Otsoa,
  • Petar Petrov,
  • Miren Bravo,
  • Sebastiaan Martijn Van Liempd,
  • Juan Manuel Falcon-Perez,
  • Amaia Zabala-Letona,
  • Arkaitz Carracedo,
  • Jose Vicente Castell,
  • Ramiro Jover,
  • Luis Alfonso Martínez-Cruz,
  • Teresa Cardoso Delgado,
  • Francisco Javier Cubero,
  • María Isabel Lucena,
  • Raúl Jesús Andrade,
  • Jon Mabe,
  • Jorge Simón,
  • María Luz Martínez-Chantar

DOI
https://doi.org/10.3390/antiox11050897
Journal volume & issue
Vol. 11, no. 5
p. 897

Abstract

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Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.

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