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 Bizkarguenaga, Maider
A1 Lopitz-Otsoa, Fernando
A1 Petrov, Petar
A1 Bravo, Miren
A1 Martijn Van Liempd, Sebastiaan
A1 Falcón-Pérez, Juan Manuel
A1 Zabala-Letona, Amaia
A1 Carracedo, Arkaitz
A1 Vicente Castell, Jose
A1 Jover, Ramiro
A1 Martínez-Cruz, Luis Alfonso
A1 Cardoso Delgado, Teresa
A1 Cubero, Francisco Javier
A1 Lucena-González, María Isabel
A1 Andrade-Bellido, Raúl Jesús
A1 Mabe, Jon
A1 Simón, Jorge
A1 Martínez-Chantar, María Luz
K1 Paracetamol
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.
PB IOAP-MPDI
YR 2022
FD 2022-04-30
LK https://hdl.handle.net/10630/24364
UL https://hdl.handle.net/10630/24364
LA eng
NO Rodríguez-Agudo R, Goikoetxea-Usandizaga N, Serrano-Maciá M, Fernández-Tussy P, Fernández-Ramos D, Lachiondo-Ortega S, González-Recio I, Gil-Pitarch C, Mercado-Gómez M, Morán L, Bizkarguenaga M, Lopitz-Otsoa F, Petrov P, Bravo M, Van Liempd SM, Falcon-Perez JM, Zabala-Letona A, Carracedo A, Castell JV, Jover R, Martínez-Cruz LA, Delgado TC, Cubero FJ, Lucena MI, Andrade RJ, Mabe J, Simón J, Martínez-Chantar ML. Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen. Antioxidants. 2022; 11(5):897. https://doi.org/10.3390/antiox11050897
NO We thank Ministerio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019-007125-1 (for J.S. and M.L.M.-C.); Instituto de Salud Carlos III: Proyectos de Investigación en SaludDTS20/00138 (for J.S. and M.L.M.-C.), PI20/00690 (for R.J.) and PT20/000127 (for M.I.L.); CIBERehd:EHD21TRF01/2022 (to M.L.M.-C.); Departamento de Industria del Gobierno Vasco (for M.L.M.-C.);Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00 and RTI2018-096759-1-100 integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación, cofinanciado con Fondos FEDER (for M.L.M.-C. and T.C.D., respectively); BIOEF (Basque Foundationfor Innovation and Health Research); Asociación Española contra el Cáncer (AECC) (to M.L.M.-C.,T.C.D.); AECC: GCTRA18006CARR (to A.C.); Fundación Científica de la Asociación Española Contrael Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (for M.L.M.); La Caixa Foundation Program (for M.L.M.); BFU2015-70067-REDC, BFU2016-77408-R and BES-2017-080435 (MINECO/FEDER,UE); Ministerio de Ciencia, Innovación y universidades PID2019-108787RB-100 (to A.C.), PID2019-109055RB-I00 (L.A.M.-C.), PID2020-117941RB-100 (to F.J.C.); Spanish Ministry of Economy and Competitiveness Grants BFU2013-47531-R and BFU2016-77408-R (L.A.M.-C.) and the FIGHT-CNNM2project from the EJP RD Joint Transnational Call (JTC2019) (Ref. AC19/00073) (for L.A.M.-C.); Comunidad de Madrid: EXOHEP-CM S2017/BMD-3727 and NanoLiver-CM Y2018/NMT-4949 co-fundedby European Structural and Investment Fund and COST Action CA17112 (to F.J.C.); Vencer el CáncerFoundation (to A.C.); European Research Council: Consolidator Grant 819242 (to A.C.); CIBERONCand CIBERehd were funded by the Instituto de Salud Carlos III and Cofunded by FEDER funds. Partial funding for open access charge: Universidad de Málaga
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 19 ene 2026