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

• Main Authors: Rubén Rodríguez-Agudo (Author), Naroa Goikoetxea-Usandizaga (Author), Marina Serrano-Maciá (Author), Pablo Fernández-Tussy (Author), David Fernández-Ramos (Author), Sofía Lachiondo-Ortega (Author), Irene González-Recio (Author), Clàudia Gil-Pitarch (Author), María Mercado-Gómez (Author), Laura Morán (Author), Maider Bizkarguenaga (Author), Fernando Lopitz-Otsoa (Author), Petar Petrov (Author), Miren Bravo (Author), Sebastiaan Martijn Van Liempd (Author), Juan Manuel Falcon-Perez (Author), Amaia Zabala-Letona (Author), Arkaitz Carracedo (Author), Jose Vicente Castell (Author), Ramiro Jover (Author), Luis Alfonso Martínez-Cruz (Author), Teresa Cardoso Delgado (Author), Francisco Javier Cubero (Author), María Isabel Lucena (Author), Raúl Jesús Andrade (Author), Jon Mabe (Author), Jorge Simón (Author), María Luz Martínez-Chantar (Author)
• Format: Book
• Published: MDPI AG, 2022-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

10.3390/antiox11050897
2076-3921