RT Journal Article
T1 Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.
A1 Rodríguez-Agudo, Rubén
A1 Goikoetxea-Usandizaga, Naroa
A1 Serrano-Maciá, Marina
A1 Fernández-Tussy, Pablo
A1 Fernández-Ramos, David
A1 Lachiondo-Ortega, Sofía
A1 González-Recio, Irene
A1 Gil-Pitarch, Clàudia
A1 Mercado-Gómez, María
A1 Morán, Laura
A1 Bizkarguenaga, Maider
A1 Lopitz-Otsoa, Fernando
A1 Petrov, Petar
A1 Bravo, Miren
A1 Van Liempd, Sebastiaan Martijn
A1 Falcon-Perez, Juan Manuel
A1 Zabala-Letona, Amaia
A1 Carracedo, Arkaitz
A1 Castell, Jose Vicente
A1 Jover, Ramiro
A1 Martínez-Cruz, Luis Alfonso
A1 Delgado, Teresa Cardoso
A1 Cubero, Francisco Javier
A1 Lucena, María Isabel
A1 Andrade, Raúl Jesús
A1 Mabe, Jon
A1 Simón, Jorge
A1 Martínez-Chantar, María Luz
K1 acetaminophen (APAP)
K1 ammonia
K1 drug-induced liver injury (DILI)
K1 methionine cycle
K1 miR-873-5p
K1 mitochondria
K1 polyamines
K1 therapy
AB 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.
SN 2076-3921
YR 2022
FD 2022-04-30
LK http://hdl.handle.net/10668/20781
UL http://hdl.handle.net/10668/20781
LA en
DS RISalud
RD Aug 13, 2025