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

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

doi:10.3390/antiox11050897

Open AccessArticle

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

by

Rubén Rodríguez-Agudo

^1,†

,

Naroa Goikoetxea-Usandizaga

^1,†,

Marina Serrano-Maciá

¹,

Pablo Fernández-Tussy

¹,

David Fernández-Ramos

^1,2,3,

Sofía Lachiondo-Ortega

¹

,

Irene González-Recio

¹,

Clàudia Gil-Pitarch

¹,

María Mercado-Gómez

¹,

Laura Morán

⁴,

Maider Bizkarguenaga

^1,3,

Fernando Lopitz-Otsoa

^1,3

,

Petar Petrov

^1,2,5,6,

Miren Bravo

¹,

Sebastiaan Martijn Van Liempd

⁷,

Juan Manuel Falcon-Perez

^7,8

,

Amaia Zabala-Letona

^9,10,

Arkaitz Carracedo

^8,9,10,11

,

Jose Vicente Castell

^2,5,6

,

Ramiro Jover

^2,5,6

,

Luis Alfonso Martínez-Cruz

¹

,

Teresa Cardoso Delgado

¹

,

Francisco Javier Cubero

^2,4

,

María Isabel Lucena

^2,12,13

,

Raúl Jesús Andrade

^2,14

,

Jon Mabe

¹⁵,

Jorge Simón

^1,2,*

and

María Luz Martínez-Chantar

^1,2,*

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¹

Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

²

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain

³

Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

⁴

Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), 28040 Madrid, Spain

⁵

Unidad de Hepatología Experimental, Health Research Institute Hospital La Fe, Av. Fernando Abril Martorell, 46026 Valencia, Spain

⁶

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Av. de Blasco Ibáñez 15, 46010 Valencia, Spain

⁷

Metabolomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

⁸

Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain

⁹

Cancer Cell Signaling and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

¹⁰

Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Carlos III, 28029 Madrid, Spain

¹¹

Traslational prostate cancer Research Lab, CIC bioGUNE-Basurto, Biocruces Bizkaia Research Health Institute, 48903 Barakaldo, Spain

¹²

Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga—IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Malaga, Spain

¹³

UICEC IBIMA, Plataforma ISCiii de Investigación Clínica, 28020 Madrid, Spain

¹⁴

Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Malaga, Spain

¹⁵

IK4-Tekniker, 20600 Eibar, Spain

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^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Antioxidants 2022, 11(5), 897; https://doi.org/10.3390/antiox11050897

Submission received: 29 March 2022 / Revised: 27 April 2022 / Accepted: 27 April 2022 / Published: 30 April 2022

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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Abstract

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.

Keywords: drug-induced liver injury (DILI); acetaminophen (APAP); ammonia; methionine cycle; miR-873-5p; therapy; polyamines; mitochondria

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MDPI and ACS Style

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.; et al. Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen. Antioxidants 2022, 11, 897. https://doi.org/10.3390/antiox11050897

AMA Style

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, et al. 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

Chicago/Turabian Style

Rodríguez-Agudo, Rubén, 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, and et al. 2022. "Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen" Antioxidants 11, no. 5: 897. https://doi.org/10.3390/antiox11050897

APA Style

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, S. M., Falcon-Perez, J. M., Zabala-Letona, A., Carracedo, A., Castell, J. V., ... Martínez-Chantar, M. L. (2022). Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen. Antioxidants, 11(5), 897. https://doi.org/10.3390/antiox11050897

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

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