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1. The lipopolysaccharide-TLR4 axis regulates hepatic glutaminase 1 expression promoting liver ammonia build-up as steatotic liver disease progresses to steatohepatitis

Author

Mercado-Gómez, Maria, Goikoetxea-Usandizaga, Naroa, Kerbert, Annarein J.C., Gracianteparaluceta, Leire Uraga, Serrano-Maciá, Marina, Lachiondo-Ortega, Sofia, Rodriguez-Agudo, Rubén, Gil-Pitarch, Clàudia, Simón, Jorge, González-Recio, Irene, Fondevila, Marcos F., Santamarina-Ojeda, Pablo, Fraga, Mario F., Nogueiras, Rubén, Heras, Javier de las, Jalan, Rajiv, Martínez-Chantar, María Luz, and Delgado, Teresa C.

Published
2024
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2. SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer

Author

Lachiondo-Ortega, Sofia, Rejano-Gordillo, Claudia M., Simon, Jorge, Lopitz-Otsoa, Fernando, C. Delgado, Teresa, Mazan-Mamczarz, Krystyna, Goikoetxea-Usandizaga, Naroa, Zapata-Pavas, L. Estefanía, García-del Río, Ana, Guerra, Pietro, Peña-Sanfélix, Patricia, Hermán-Sánchez, Natalia, Al-Abdulla, Ruba, Fernandez-Rodríguez, Carmen, Azkargorta, Mikel, Velázquez-Cruz, Alejandro, Guyon, Joris, Martín, César, Zalamea, Juan Diego, Egia-Mendikute, Leire, Sanz-Parra, Arantza, Serrano-Maciá, Marina, González-Recio, Irene, Gonzalez-Lopez, Monika, Martínez-Cruz, Luis Alfonso, Pontisso, Patrizia, Aransay, Ana M., Barrio, Rosa, Sutherland, James D., Abrescia, Nicola G.A., Elortza, Félix, Lujambio, Amaia, Banales, Jesus M., Luque, Raúl M., Gahete, Manuel D., Palazón, Asís, Avila, Matias A., G. Marin, Jose J., De, Supriyo, Daubon, Thomas, Díaz-Quintana, Antonio, Díaz-Moreno, Irene, Gorospe, Myriam, Rodríguez, Manuel S., and Martínez-Chantar, María Luz

Published
2024
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3. Anti-miR-873-5p improves alcohol-related liver disease by enhancing hepatic deacetylation via SIRT1

Author

Rodríguez-Agudo, Rubén, González-Recio, Irene, Serrano-Maciá, Marina, Bravo, Miren, Petrov, Petar, Blaya, Delia, Herranz, Jose María, Mercado-Gómez, María, Rejano-Gordillo, Claudia María, Lachiondo-Ortega, Sofía, Gil-Pitarch, Clàudia, Azkargorta, Mikel, Van Liempd, Sebastiaan Martijn, Martinez-Cruz, Luis Alfonso, Simão, A.L., Elortza, Félix, Martín, César, Nevzorova, Yulia A., Cubero, Francisco Javier, Delgado, Teresa C., Argemi, Josepmaria, Bataller, Ramón, Schoonjans, Kristina, Banales, Jesús M., Castro, Rui E., Sancho-Bru, Pau, Avila, Matías A., Julve, Josep, Jover, Ramiro, Mabe, Jon, Simon, Jorge, Goikoetxea-Usandizaga, Naroa, and Martínez-Chantar, María L.

Published
2024
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4. Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting

Author

Capelo-Diz, Alba, Lachiondo-Ortega, Sofía, Fernández-Ramos, David, Cañas-Martín, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, González-Rellan, Maria J., Mosca, Laura, Blazquez-Vicens, Joan, Tinahones-Ruano, Alberto, Fondevila, Marcos F., Buyan, Mason, Delgado, Teresa C., Gutierrez de Juan, Virginia, Ayuso-García, Paula, Sánchez-Rueda, Alejandro, Velasco-Avilés, Sergio, Fernández-Susavila, Héctor, Riobello-Suárez, Cristina, Dziechciarz, Bartlomiej, Montiel-Duarte, Cristina, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Bilbao-García, Jon, Bernardo-Seisdedos, Ganeko, Senra, Ana, Soriano-Navarro, Mario, Millet, Oscar, Díaz-Lagares, Ángel, Crujeiras, Ana B., Bao-Caamano, Aida, Cabrera, Diana, van Liempd, Sebastiaan, Tamayo-Caro, Miguel, Borzacchiello, Luigi, Gomez-Santos, Beatriz, Buqué, Xabier, Sáenz de Urturi, Diego, González-Romero, Francisco, Simon, Jorge, Rodríguez-Agudo, Rubén, Ruiz, Asier, Matute, Carlos, Beiroa, Daniel, Falcon-Perez, Juan M., Aspichueta, Patricia, Rodríguez-Cuesta, Juan, Porcelli, Marina, Pajares, María A., Ameneiro, Cristina, Fidalgo, Miguel, Aransay, Ana M., Lama-Díaz, Tomas, Blanco, Miguel G., López, Miguel, Villa-Bellosta, Ricardo, Müller, Timo D., Nogueiras, Rubén, Woodhoo, Ashwin, Martínez-Chantar, María Luz, and Varela-Rey, Marta

Published
2023
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5. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via the DEPTOR-mTOR axis

Author

Serrano-Maciá, Marina, Simón, Jorge, González-Rellan, Maria J., Azkargorta, Mikel, Goikoetxea-Usandizaga, Naroa, Lopitz-Otsoa, Fernando, De Urturi, Diego Saenz, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofia, Mercado-Gomez, Maria, Gutiérrez de Juan, Virginia, Bizkarguenaga, Maider, Fernández-Ramos, David, Buque, Xabier, Baselli, Guido A., Valenti, Luca V.C., Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Banales, Jesus M., Avila, Matias A., Marin, Jose J.G., Aspichueta, Patricia, Sutherland, James, Barrio, Rosa, Mayor, Ugo, Elortza, Félix, Xirodimas, Dimitris P., Nogueiras, Rubén, Delgado, Teresa C., and Martínez-Chantar, María Luz

Published
2021
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6. Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage

Author

González-Recio, Irene, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Mercado-Gómez, Maria, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Gil-Pitarch, Clàudia, Fernández-Rodríguez, Carmen, Castellana, Donatello, Latasa, Maria U., Abecia, Leticia, Anguita, Juan, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Avila, Matías A., Martín, César, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti Vanette, Reeves, Helen L., Andrade, Raul J., Lucena, M. Isabel, Buccella, Daniela, Martínez-Cruz, Luis Alfonso, and Martínez-Chantar, Maria L

Published
2022
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7. Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH

Author

Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Fernández-Ramos, David, Sáenz de Urturi, Diego, Gruskos, Jessica J., Fernández-Tussy, Pablo, Lachiondo-Ortega, Sofía, González-Recio, Irene, Rodríguez-Agudo, Rubén, Gutiérrez-de-Juan, Virginia, Rodríguez-Iruretagoyena, Begoña, Varela-Rey, Marta, Gimenez-Mascarell, Paula, Mercado-Gomez, María, Gómez-Santos, Beatriz, Fernandez-Rodriguez, Carmen, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martin, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta, Patricia, Chu, Kevan H.-Y., Buccella, Daniela, Martín, César, Delgado, Teresa Cardoso, Martínez-Cruz, Luis Alfonso, and Martínez-Chantar, María Luz

Published
2021
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8. Boosting mitochondria activity by silencing MCJ overcomes cholestasis-induced liver injury

Author

Iruzubieta, Paula, Goikoetxea-Usandizaga, Naroa, Barbier-Torres, Lucía, Serrano-Maciá, Marina, Fernández-Ramos, David, Fernández-Tussy, Pablo, Gutiérrez-de-Juan, Virginia, Lachiondo-Ortega, Sofia, Simon, Jorge, Bravo, Miren, Lopitz-Otsoa, Fernando, Robles, Mercedes, Ferre-Aracil, Carlos, Varela-Rey, Marta, Elguezabal, Natalia, Calleja, José Luis, Lu, Shelly C., Milkiewicz, Malgorzata, Milkiewicz, Piotr, Anguita, Juan, Monte, María J., Marin, José J.G., López-Hoyos, Marcos, Delgado, Teresa C., Rincón, Mercedes, Crespo, Javier, and Martínez-Chantar, María Luz

Published
2021
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9. The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent

Author

Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, European Commission, Eusko Jaurlaritza, National Institutes of Health (US), National Institute on Alcohol Abuse and Alcoholism (US), Junta de Castilla y León, Junta de Andalucía, European Research Council, German Research Foundation, Ministerio de Educación, Cultura y Deporte (España), Fundació La Marató de TV3, Universidad del País Vasco, Asociación Española Contra el Cáncer, Fundación la Caixa, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Goikoetxea-Usandizaga, Naroa, Bravo, Miren, Egia-Mendikute, Leire, Abecia, Leticia, Serrano-Maciá, Marina, Urdinguio, Rocío G., Clos-García, Marc, Rodríguez-Agudo, Rubén, Araujo-Legido, Raquel, López-Bermudo, Lucía, Delgado, Teresa C., Lachiondo-Ortega, Sofía, González-Recio, Irene, Gil-Pitarch, Clàudia, Peña-Cearra, Ainize, Simón, Jorge, Benedé-Ubieto, Raquel, Ariño, Silvia, Herranz, Jose M., Azkargorta, Mikel, Salazar-Bermeo, Julio, Martí, Nuria, Varela-Rey, Marta, Falcón-Pérez, Juan M., Lorenzo, Óscar, Nogueiras, Rubén, Elortza, Félix, Nevzorova, Yulia, Cubero, Francisco J., Saura, Domingo, Martínez-Cruz, Luis Alfonso, Sabio, Guadalupe, Palazón, Asís, Sancho-Bru, Pau, Elguezabal, Natalia, Fraga, Mario F., Ávila, Matías A., Bataller, Ramón, Marín, José J. G., Martín, Franz, Martínez-Chantar, María Luz, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía, Industria y Competitividad (España), Instituto de Salud Carlos III, European Commission, Eusko Jaurlaritza, National Institutes of Health (US), National Institute on Alcohol Abuse and Alcoholism (US), Junta de Castilla y León, Junta de Andalucía, European Research Council, German Research Foundation, Ministerio de Educación, Cultura y Deporte (España), Fundació La Marató de TV3, Universidad del País Vasco, Asociación Española Contra el Cáncer, Fundación la Caixa, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), Goikoetxea-Usandizaga, Naroa, Bravo, Miren, Egia-Mendikute, Leire, Abecia, Leticia, Serrano-Maciá, Marina, Urdinguio, Rocío G., Clos-García, Marc, Rodríguez-Agudo, Rubén, Araujo-Legido, Raquel, López-Bermudo, Lucía, Delgado, Teresa C., Lachiondo-Ortega, Sofía, González-Recio, Irene, Gil-Pitarch, Clàudia, Peña-Cearra, Ainize, Simón, Jorge, Benedé-Ubieto, Raquel, Ariño, Silvia, Herranz, Jose M., Azkargorta, Mikel, Salazar-Bermeo, Julio, Martí, Nuria, Varela-Rey, Marta, Falcón-Pérez, Juan M., Lorenzo, Óscar, Nogueiras, Rubén, Elortza, Félix, Nevzorova, Yulia, Cubero, Francisco J., Saura, Domingo, Martínez-Cruz, Luis Alfonso, Sabio, Guadalupe, Palazón, Asís, Sancho-Bru, Pau, Elguezabal, Natalia, Fraga, Mario F., Ávila, Matías A., Bataller, Ramón, Marín, José J. G., Martín, Franz, and Martínez-Chantar, María Luz

Abstract

Background and Aims: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. Approach and Results: C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD+/NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. Conclusions: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.

Published
2023

10. Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression

Author

Juárez‐Fernández, María, primary, Goikoetxea‐Usandizaga, Naroa, additional, Porras, David, additional, García‐Mediavilla, María Victoria, additional, Bravo, Miren, additional, Serrano‐Maciá, Marina, additional, Simón, Jorge, additional, Delgado, Teresa C., additional, Lachiondo‐Ortega, Sofía, additional, Martínez‐Flórez, Susana, additional, Lorenzo, Óscar, additional, Rincón, Mercedes, additional, Varela‐Rey, Marta, additional, Abecia, Leticia, additional, Rodríguez, Héctor, additional, Anguita, Juan, additional, Nistal, Esther, additional, Martínez‐Chantar, María Luz, additional, and Sánchez‐Campos, Sonia, additional

Published
2023
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11. The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent

Author

Goikoetxea-Usandizaga, Naroa, primary, Bravo, Miren, additional, Egia-Mendikute, Leire, additional, Abecia, Leticia, additional, Serrano-Maciá, Marina, additional, Urdinguio, Rocío G., additional, Clos-García, Marc, additional, Rodríguez-Agudo, Rubén, additional, Araujo-Legido, Raquel, additional, López-Bermudo, Lucía, additional, Delgado, Teresa C., additional, Lachiondo-Ortega, Sofía, additional, González-Recio, Irene, additional, Gil-Pitarch, Clàudia, additional, Peña-Cearra, Ainize, additional, Simón, Jorge, additional, Benedé-Ubieto, Raquel, additional, Ariño, Silvia, additional, Herranz, Jose M., additional, Azkargorta, Mikel, additional, Salazar-Bermeo, Julio, additional, Martí, Nuria, additional, Varela-Rey, Marta, additional, Falcón-Pérez, Juan M., additional, Lorenzo, Óscar, additional, Nogueiras, Rubén, additional, Elortza, Félix, additional, Nevzorova, Yulia A., additional, Cubero, Francisco J., additional, Saura, Domingo, additional, Martínez-Cruz, Luis Alfonso, additional, Sabio, Guadalupe, additional, Palazón, Asís, additional, Sancho-Bru, Pau, additional, Elguezabal, Natalia, additional, Fraga, Mario F., additional, Ávila, Matías A., additional, Bataller, Ramón, additional, Marín, José J.G., additional, Martín, Franz, additional, and Martínez-Chantar, María Luz, additional

Published
2023
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12. Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals

Author

Inmunología, microbiología y parasitología, Immunologia, mikrobiologia eta parasitologia, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Delgado, Teresa C., Simón Espinosa, Jorge, Fernández Ramos, David, Barriales, Diego, Cornide, María E., Jiménez, Mónica, Pérez Redondo, Marina, Lachiondo Ortega, Sofía, Rodríguez Agudo, Rubén, Bizkarguenaga, Maider, Diego Zalamea, Juan, Pasco, Samuel T., Caballero Díaz, Daniel, Alfano, Benedetta, Bravo Garmendia, Miren, González Recio, Irene, Mercado Gómez, María, Gil Pitarch, Clàudia, Mabe Alvarez, Jon, Gracia Sancho, Jordi, Abecia Aliende, Leticia, Lorenzo, Oscar, Martín Sanz, Paloma, Abrescia, Nicola A.G., Sabio, Guadalupe, Rincón, Mercedes, Anguita Castillo, Juan de Dios, Miñambres, Eduardo, Martín, César, Berenguer, Marina, Fabregat, Isabel, Casado, Marta, Peralta, Carmen, Varela Rey, Marta, Martínez Chantar, María Luz, Inmunología, microbiología y parasitología, Immunologia, mikrobiologia eta parasitologia, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Delgado, Teresa C., Simón Espinosa, Jorge, Fernández Ramos, David, Barriales, Diego, Cornide, María E., Jiménez, Mónica, Pérez Redondo, Marina, Lachiondo Ortega, Sofía, Rodríguez Agudo, Rubén, Bizkarguenaga, Maider, Diego Zalamea, Juan, Pasco, Samuel T., Caballero Díaz, Daniel, Alfano, Benedetta, Bravo Garmendia, Miren, González Recio, Irene, Mercado Gómez, María, Gil Pitarch, Clàudia, Mabe Alvarez, Jon, Gracia Sancho, Jordi, Abecia Aliende, Leticia, Lorenzo, Oscar, Martín Sanz, Paloma, Abrescia, Nicola A.G., Sabio, Guadalupe, Rincón, Mercedes, Anguita Castillo, Juan de Dios, Miñambres, Eduardo, Martín, César, Berenguer, Marina, Fabregat, Isabel, Casado, Marta, Peralta, Carmen, Varela Rey, Marta, and Martínez Chantar, María Luz

Abstract

[EN] Background and Aims Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models. Approach and Results Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G(1)/S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations. Conclusions Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible o

Published
2022

13. Hu Antigen R (HuR) Protein Structure, Function and Regulation in Hepatobiliary Tumors

Author

Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Junta de Andalucía, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Ministerio de Educación, Cultura y Deporte (MECD). España, Lachiondo Ortega, Sofía, Cardoso Delgado, Teresa, Baños Jaime, Blanca, Velázquez Cruz, Alejandro, Díaz Moreno, Irene, Martínez Chantar, María Luz, Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, Junta de Andalucía, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Ministerio de Educación, Cultura y Deporte (MECD). España, Lachiondo Ortega, Sofía, Cardoso Delgado, Teresa, Baños Jaime, Blanca, Velázquez Cruz, Alejandro, Díaz Moreno, Irene, and Martínez Chantar, María Luz

Abstract

Hepatobiliary tumors are a group of primary malignancies encompassing the liver, the intra- and extra-hepatic biliary tracts, and the gall bladder. Within the liver, hepatocellular carcinoma (HCC) is the most common type of primary cancer, which is, also, representing the third-most recurrent cause of cancer-associated death and the sixth-most prevalent type of tumor worldwide, nowadays. Although less frequent, cholangiocarcinoma (CCA) is, currently, a fatal cancer with limited therapeutic options. Here, we review the regulatory role of Hu antigen R (HuR), a ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), in the pathogenesis, progression, and treatment of HCC and CCA. Overall, HuR is proposed as a valuable diagnostic and prognostic marker, as well as a therapeutic target in hepatobiliary cancers. Therefore, novel therapeutic approaches that can selectively modulate HuR function appear to be highly attractive for the clinical management of these types of tumors.

Published
2022

14. Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage

Author

Bioquímica y biología molecular, Inmunología, microbiología y parasitología, Biokimika eta biologia molekularra, Immunologia, mikrobiologia eta parasitologia, González Recio, Irene, Simón Espinosa, Jorge, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Mercado Gómez, María, Rodríguez Agudo, Rubén, Lachiondo Ortega, Sofía, Gil Pitarch, Clàudia, Fernández Rodríguez, Carmen, Castellana, Donatello, Latasa, María Ujué, Abecia Aliende, Leticia, Anguita Castillo, Juan de Dios, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín Plágaro, César Augusto, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti Vanette, Reeves, Helen L., Andrade, Raúl, Lucena, M. Isabel, Buccella, Daniela, Martínez de la Cruz, Alfonso, Martínez Chantar, María Luz, Bioquímica y biología molecular, Inmunología, microbiología y parasitología, Biokimika eta biologia molekularra, Immunologia, mikrobiologia eta parasitologia, González Recio, Irene, Simón Espinosa, Jorge, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Mercado Gómez, María, Rodríguez Agudo, Rubén, Lachiondo Ortega, Sofía, Gil Pitarch, Clàudia, Fernández Rodríguez, Carmen, Castellana, Donatello, Latasa, María Ujué, Abecia Aliende, Leticia, Anguita Castillo, Juan de Dios, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín Plágaro, César Augusto, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti Vanette, Reeves, Helen L., Andrade, Raúl, Lucena, M. Isabel, Buccella, Daniela, Martínez de la Cruz, Alfonso, and Martínez Chantar, María Luz

Abstract

Drug induced liver injury (DILI) is an important cause acute liver failure. Here the authors report that serum Mg2+ serum levels decrease in patients with DILI as well as in preclinical animal models treated with acetaminophen overdose, and that early intervention targeting the Mg2+ transporter Cyclin M4 may be beneficial for acetaminophen overdose in preclinical models. Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.

Published
2022

15. Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Comisión Asesora de Investigación Científica y Técnica, CAICYT (España), Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, European Joint Programme on Rare Diseases, Instituto de Salud Carlos III, National Institutes of Health (US), Newcastle Biobanks, Cancer Research UK, González-Recio, Irene, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Gil-Pitarch, Clàudia, Fernández-Rodríguez, Carmen, Castellana, Donatello, Latasa, Maria U., Abecia, Leticia, Anguita, Juan, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín, César, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti, Reeves, Helen L., Andrade, Raúl J., Lucena, María Isabel, Buccella, Daniela, Martínez-Cruz, Luis Alfonso, Martínez-Chantar, María Luz, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Comisión Asesora de Investigación Científica y Técnica, CAICYT (España), Ministerio de Economía y Competitividad (España), Asociación Española Contra el Cáncer, Fundación Científica Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, European Joint Programme on Rare Diseases, Instituto de Salud Carlos III, National Institutes of Health (US), Newcastle Biobanks, Cancer Research UK, González-Recio, Irene, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Gil-Pitarch, Clàudia, Fernández-Rodríguez, Carmen, Castellana, Donatello, Latasa, Maria U., Abecia, Leticia, Anguita, Juan, Delgado, Teresa C., Iruzubieta, Paula, Crespo, Javier, Hardy, Serge, Petrov, Petar D., Jover, Ramiro, Ávila, Matías A., Martín, César, Schaeper, Ute, Tremblay, Michel L., Dear, James W., Masson, Steven, McCain, Misti, Reeves, Helen L., Andrade, Raúl J., Lucena, María Isabel, Buccella, Daniela, Martínez-Cruz, Luis Alfonso, and Martínez-Chantar, María Luz

Abstract

Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.

Published
2022

16. Mitochondrial bioenergetics boost macrophage activation, promoting liver regeneration in metabolically compromised animals

Author

Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Delgado, Teresa C., Simón, Jorge, Fernández-Ramos, David, Barriales, Diego, Cornide, Maria E., Jiménez, Mónica, Pérez-Redondo, Marina, Lachiondo-Ortega, Sofía, Rodríguez-Agudo, Rubén, Bizkarguenaga, Maider, Zalamea, Juan Diego, Pasco, Samuel T., Caballero-Díaz, Daniel, Alfano, Benedetta, Bravo, Miren, González-Recio, Irene, Mercado-Gomez, María, Gil-Pitarch, Clàudia, Mabe, Jon, Gracia-Sancho, Jordi, Abecia, Leticia, Lorenzo, Óscar, Martín-Sanz, Paloma, Abrescia, Nicola G. A., Sabio, Guadalupe, Rincón, Mercedes, Anguita, Juan, Miñambres, Eduardo, Martín, César, Berenguer, Marina, Fabregat, Isabel, Casado, Marta, Peralta, Carmen, Varela-Rey, Marta, Martínez-Chantar, María Luz, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Delgado, Teresa C., Simón, Jorge, Fernández-Ramos, David, Barriales, Diego, Cornide, Maria E., Jiménez, Mónica, Pérez-Redondo, Marina, Lachiondo-Ortega, Sofía, Rodríguez-Agudo, Rubén, Bizkarguenaga, Maider, Zalamea, Juan Diego, Pasco, Samuel T., Caballero-Díaz, Daniel, Alfano, Benedetta, Bravo, Miren, González-Recio, Irene, Mercado-Gomez, María, Gil-Pitarch, Clàudia, Mabe, Jon, Gracia-Sancho, Jordi, Abecia, Leticia, Lorenzo, Óscar, Martín-Sanz, Paloma, Abrescia, Nicola G. A., Sabio, Guadalupe, Rincón, Mercedes, Anguita, Juan, Miñambres, Eduardo, Martín, César, Berenguer, Marina, Fabregat, Isabel, Casado, Marta, Peralta, Carmen, Varela-Rey, Marta, and Martínez-Chantar, María Luz

Abstract

[Background and aims ]Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early posttransplantation organ failure as mitochondrial respiration and ATP production are affected. A shortage of donors has extended liver donor criteria, including aged or steatotic livers, which are more susceptible to IRI. Given the lack of an effective treatment and the extensive transplantation waitlist, we aimed at characterizing the effects of an accelerated mitochondrial activity by silencing methylation-controlled J protein (MCJ) in three preclinical models of IRI and liver regeneration, focusing on metabolically compromised animal models., [Approach and results] Wild-type (WT), MCJ knockout (KO), and Mcj silenced WT mice were subjected to 70% partial hepatectomy (Phx), prolonged IRI, and 70% Phx with IRI. Old and young mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in preclinical models of Phx with or without vascular occlusion and in donor livers. Mice lacking MCJ initiate liver regeneration 12 h faster than WT and show reduced ischemic injury and increased survival. MCJ knockdown enables a mitochondrial adaptation that restores the bioenergetic supply for enhanced regeneration and prevents cell death after IRI. Mechanistically, increased ATP secretion facilitates the early activation of Kupffer cells and production of TNF, IL-6, and heparin-binding EGF, accelerating the priming phase and the progression through G1 /S transition during liver regeneration. Therapeutic silencing of MCJ in 15-month-old mice and in mice fed a high-fat/high-fructose diet for 12 weeks improves mitochondrial respiration, reduces steatosis, and overcomes regenerative limitations., [Conclusions] Boosting mitochondrial activity by silencing MCJ could pave the way for a protective approach after major liver resection or IRI, especially in metabolically compromised, IRI-susceptible organs.

Published
2022

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

Author

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

Published
2022
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18. FRI-466-YI Implications and therapeutic potential of neddylation for pediatric liver cancer: hepatoblastoma

Author

Zapata-Pavas, Leidy Estefanía, Serrano-Macía, Marina, Rodrigo, Miguel Angel Merlos, Peña-Sanfelix, Patricia, Gil-Pitarch, Claudia, Goikoetxea-Usandizaga, Naroa, Michalkova, Hana, Heger, Zbynek, del Río-Álvarez, Alvaro, Royo, Laura, Rejano-Gordillo, Claudia M., Barrenechea-Barrenechea, Jon Ander, Mercado-Gómez, Maria, Lachiondo-Ortega, Sofia, Delgado, Teresa C., Xirodimas, Dimitris, Marin, Jose J.G., Fernandez-Barrena, Maite G., Avila, Matías A., Armengol, Carolina, and Martínez-Chantar, María Luz

Published
2024
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19. Anti-miR-518d-5p Overcomes Liver Tumor Cell Death Resistance Through Mitochondrial Activity

Author

Medicina, Medikuntza, Fernández Tussy, Pablo, Rodríguez Agudo, Rubén, Fernández Ramos, David, Barbier Torres, Lucía, Zubiete Franco, Imanol, López de Davalillo, Sergio, Herráez Aguilar, Elisa, Goikoetxea Usandizaga, Naroa, Lachiondo Ortega, Sofía, Simón Espinosa, Jorge, Lopitz Otsoa, Fernando, Gutiérrez de Juan, Virginia, McCain, Misti V., Perugorria Montiel, María Jesús, Mabe Alvarez, Jon, Navasa, Nicolás, Rodrigues, Cecilia M. P., Fabregat, Isabel, Boix, Loreto, Sapena, Victor, Anguita Castillo, Juan de Dios, Lu, Shelly C., Mato de la Paz, José María, Bañales Asurmendi, Jesús María, Villa, Erica, Reeves, Helen L., Bruix, Jordi, Reig, María, Marín, José J. G., Cardoso Delgado, Teresa de Jesús, Martínez Chantar, María Luz, Medicina, Medikuntza, Fernández Tussy, Pablo, Rodríguez Agudo, Rubén, Fernández Ramos, David, Barbier Torres, Lucía, Zubiete Franco, Imanol, López de Davalillo, Sergio, Herráez Aguilar, Elisa, Goikoetxea Usandizaga, Naroa, Lachiondo Ortega, Sofía, Simón Espinosa, Jorge, Lopitz Otsoa, Fernando, Gutiérrez de Juan, Virginia, McCain, Misti V., Perugorria Montiel, María Jesús, Mabe Alvarez, Jon, Navasa, Nicolás, Rodrigues, Cecilia M. P., Fabregat, Isabel, Boix, Loreto, Sapena, Victor, Anguita Castillo, Juan de Dios, Lu, Shelly C., Mato de la Paz, José María, Bañales Asurmendi, Jesús María, Villa, Erica, Reeves, Helen L., Bruix, Jordi, Reig, María, Marín, José J. G., Cardoso Delgado, Teresa de Jesús, and Martínez Chantar, María Luz

Abstract

Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n=16 and n=20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n=100), where miR-518d-5p was analyzed in relation to treatment duration and patient's overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n=16) and in an additional cohort of tumor/non-tumor paired samples (n=20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.

Published
2021

20. Neddylation inhibition ameliorates steatosis in NAFLD by boosting hepatic fatty acid oxidation via DEPTOR-mTOR axis

Author

Bioquímica y biología molecular, Filosofía, Biokimika eta biologia molekularra, Fisiologia, Serrano Maciá, Marina, Simon, Jorge, González Rellán, María Jesús, Azkargorta, Mikel, Goikoetxea Usandizaga, Naroa, Lopitz Otsoa, Fernando, Saenz de Urturi Indart, Diego, Rodríguez Agudo, Rubén, Lachiondo Ortega, Sofía, Mercado Gómez, María, Gutiérrez de Juan, Virginia, Bizkarguenaga, Maider, Fernández Ramos, David, Buqué García, Xabier, Baselli, Guido A., Valenti, Luca, Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Bañales Asurmendi, Jesús María, Avila, Matias A., Marin, José J. G., Aspichueta Celaá, Patricia, Sutherland, James D., Barrio Olano, María Rosa, Mayor Martínez, Ugo, Elortza, Felix, Xirodimas, Dimitri, Nogueiras Pozo, Rubén, Delgado, Teresa C., Martínez Chantar, María Luz, Bioquímica y biología molecular, Filosofía, Biokimika eta biologia molekularra, Fisiologia, Serrano Maciá, Marina, Simon, Jorge, González Rellán, María Jesús, Azkargorta, Mikel, Goikoetxea Usandizaga, Naroa, Lopitz Otsoa, Fernando, Saenz de Urturi Indart, Diego, Rodríguez Agudo, Rubén, Lachiondo Ortega, Sofía, Mercado Gómez, María, Gutiérrez de Juan, Virginia, Bizkarguenaga, Maider, Fernández Ramos, David, Buqué García, Xabier, Baselli, Guido A., Valenti, Luca, Iruzubieta, Paula, Crespo, Javier, Villa, Erica, Bañales Asurmendi, Jesús María, Avila, Matias A., Marin, José J. G., Aspichueta Celaá, Patricia, Sutherland, James D., Barrio Olano, María Rosa, Mayor Martínez, Ugo, Elortza, Felix, Xirodimas, Dimitri, Nogueiras Pozo, Rubén, Delgado, Teresa C., and Martínez Chantar, María Luz

Abstract

[EN] Objective: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. Methods: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. Results: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models

Published
2021

21. Magnesium Accumulation Upon Cyclin M4 Silencing Activates Microsomal Triglyceride Transfer Protein Improving NASH

Author

Bioquímica y biología molecular, Fisiología, Biokimika eta biologia molekularra, Fisiologia, Simón Espinosa, Jorge, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Fernández Ramos, David, Sáenz de Urturi Indart, Diego, Gruskos, Jessica J., Fernández Tussy, Pablo, Lachiondo Ortega, Sofía, González Recio, Irene, Rodríguez Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez Iruretagoyena, Begoña, Varela Rey, Marta, Giménez Mascarell, Paula, Mercado Gómez, María, Gómez Santos, Beatriz, Fernández Rodríguez, Carmen, Lopitz Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martin, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta Celaá, Patricia, Chu, Kevan H. Y., Buccella, Daniela, Martín Plágaro, César Augusto, Cardoso Delgado, Teresa de Jesús, Martínez de la Cruz, Alfonso, Martínez Chantar, María Luz, Bioquímica y biología molecular, Fisiología, Biokimika eta biologia molekularra, Fisiologia, Simón Espinosa, Jorge, Goikoetxea Usandizaga, Naroa, Serrano Maciá, Marina, Fernández Ramos, David, Sáenz de Urturi Indart, Diego, Gruskos, Jessica J., Fernández Tussy, Pablo, Lachiondo Ortega, Sofía, González Recio, Irene, Rodríguez Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez Iruretagoyena, Begoña, Varela Rey, Marta, Giménez Mascarell, Paula, Mercado Gómez, María, Gómez Santos, Beatriz, Fernández Rodríguez, Carmen, Lopitz Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martin, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta Celaá, Patricia, Chu, Kevan H. Y., Buccella, Daniela, Martín Plágaro, César Augusto, Cardoso Delgado, Teresa de Jesús, Martínez de la Cruz, Alfonso, and Martínez Chantar, María Luz

Abstract

Background & Aims: Perturbations of intracellular magnesium (Mg2+) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg2+ across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). Methods: Serum Mg2+ levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine (R) or conjugated to N-acetylgalactosamine. Results: Patients with NASH showed hepatic CNNM4 over-expression and dysregulated Mg2+ levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg2+ accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. Conclusions: CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg2+ transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. Lay summary: Cyclin M4 (CNNM4) is overexpressed in nonalcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein.

Published
2021

22. Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Eusko Jaurlaritza, European Commission, Fundación Vasca de Innovación e Investigación Sanitarias, Radio Televisión Pública Vasca, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, Ministerio de Economía y Competitividad (España), National Institutes of Health (US), Junta de Andalucía, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Fernández-Ramos, David, Sáenz de Urturi, Diego, Gruskos, Jessica J., Fernández-Tussy, Pablo, Lachiondo-Ortega, Sofía, González-Recio, Irene, Rodríguez-Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez-Iruretagoyena, Begoña, Varela-Rey, Marta, Gimenez-Mascarell, Paula, Mercado-Gomez, María, Gómez-Santos, Beatriz, Fernández-Rodríguez, Carmen, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martín, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta, Patricia, Chu, Kevan H.-Y., Buccella, Daniela, Martín, César, Cardoso Delgado, Teresa de Jesús, Martínez-Cruz, Luis Alfonso, Martínez-Chantar, María Luz, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Eusko Jaurlaritza, European Commission, Fundación Vasca de Innovación e Investigación Sanitarias, Radio Televisión Pública Vasca, Asociación Española Contra el Cáncer, Fundación la Caixa, Fundación BBVA, Ministerio de Economía y Competitividad (España), National Institutes of Health (US), Junta de Andalucía, Simón, Jorge, Goikoetxea-Usandizaga, Naroa, Serrano-Maciá, Marina, Fernández-Ramos, David, Sáenz de Urturi, Diego, Gruskos, Jessica J., Fernández-Tussy, Pablo, Lachiondo-Ortega, Sofía, González-Recio, Irene, Rodríguez-Agudo, Rubén, Gutiérrez de Juan, Virginia, Rodríguez-Iruretagoyena, Begoña, Varela-Rey, Marta, Gimenez-Mascarell, Paula, Mercado-Gomez, María, Gómez-Santos, Beatriz, Fernández-Rodríguez, Carmen, Lopitz-Otsoa, Fernando, Bizkarguenaga, Maider, Dames, Sibylle, Schaeper, Ute, Martín, Franz, Sabio, Guadalupe, Iruzubieta, Paula, Crespo, Javier, Aspichueta, Patricia, Chu, Kevan H.-Y., Buccella, Daniela, Martín, César, Cardoso Delgado, Teresa de Jesús, Martínez-Cruz, Luis Alfonso, and Martínez-Chantar, María Luz

Abstract

Background & Aims: Perturbations of intracellular magnesium (Mg) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). Methods: Serum Mg levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine® or conjugated to N-acetylgalactosamine. Results: Patients with NASH showed hepatic CNNM4 overexpression and dysregulated Mg levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. Conclusions: CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. Lay summary: Cyclin M4 (CNNM4) is overexpressed in non-alcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein.

Published
2021

23. SAT-247 - Pediatric liver cancer: Hepatoblastoma and Neddylation post-translational modification

Author

Zapata-Pavas, Leidy Estefanía, Serrano-Macia, Marina, Merlos Rodrigo, Miguel Angel, Felix, Patricia Peña-San, Gil-Pitarch, Claudia, Goikoetxea, Naroa, Michalkova, Hana, Heger, Zbynek, del Rio, Alvaro, Domingo-Sàbat, Montserrat, Royo, Laura, Barrenechea-Barrenechea, Jon Ander, Mercado-Gómez, Maria, Lachiondo-Ortega, Sofia, Delgado, Teresa Cardoso, Xirodimas, Dimitris, Marin, Jose, Fernandez-Barrena, Maite G, Avila, Matías A, Armengol, Carolina, and Martínez-Chantar, María Luz

Published
2023
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24. SAT-244 - Silencing CNNM4 in cholangiocarcinoma inhibits tumoral progression by means of non-canonical ferroptosis

Author

Mercado-Gómez, Maria, Giné, Alvaro Eguilero, Bravo, Miren, Azkargorta, Mikel, Serrano-Macia, Marina, Goikoetxea, Naroa, González-Recio, Irene, Lachiondo-Ortega, Sofia, Gil-Pitarch, Claudia, Romero, Marta, Omella, Judit Domenech, Agudo, Rubén Rodríguez, Zapata-Pavas, Leidy Estefanía, Felix, Patricia Peña-San, Olaizola, Paula, Rodrigues, Pedro Miguel, Martinez-Cruz, Luis Alfonso, Lamarca, Angela, Moreno, Victor, Banales, Jesus Maria, Delgado, Teresa Cardoso, Elortza, Felix, Avila, Matías A, Cubero, Francisco Javier, Martín, Cesar Augusto, Merlos Rodrigo, Miguel Angel, Calvisi, Diego, Marin, Jose, and Martínez-Chantar, María Luz

Published
2023
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25. SAT-221 - Metabolic rewiring by increased mitochondrial respiration drives immunosuppression in liver cancer

Author

Goikoetxea, Naroa, Egia-Mendikute, Leire, Bravo, Miren, Serrano-Macia, Marina, Delgado, Teresa Cardoso, Ladero, Iraia, Molina, Elena, Lachiondo-Ortega, Sofia, Agudo, Rubén Rodríguez, Castelo, Janire, Barriales, Diego, Iruretagoyena, Begoña Rodriguez, Santamaria, Eva, Mercado-Gómez, Maria, González-Recio, Irene, Rincón, Mercedes, Avila, Matías A, Anguita, Juan, Elguezabal, Natalia, Palazón, Asís, and Martínez-Chantar, María Luz

Published
2023
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26. SAT-216 - MAP17 promotes an epithelial-mesenchymal-amoeboid transition in hepatocellular carcinoma by switching one-carbon metabolism

Author

Gil-Pitarch, Claudia, Uriarte, Iker, Bertran, Esther, Hermán-Sánchez, Natalia, García-Heredia, José Manuel, Agudo, Rubén Rodríguez, Goikoetxea, Naroa, Lachiondo-Ortega, Sofia, Mercado-Gómez, Maria, González-Recio, Irene, Delgado, Teresa Cardoso, Vivanco, Maria, Martinez-Cruz, Luis Alfonso, Martín, Cesar Augusto, Artuch, Rafael, Fernández, Mario, Ortiz, Manuel Gahete, Fabregat, Isabel, Avila, Matías A, Carnero, Amancio, and Martínez-Chantar, María Luz

Published
2023
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27. FRI-399 - Neddylation inhibition recovers drug-induced liver injury through the stabilization of Tamm41

Author

Gil-Pitarch, Claudia, Serrano-Macia, Marina, Espinosa, Jorge Simón, Agudo, Rubén Rodríguez, Lachiondo-Ortega, Sofia, Mercado-Gómez, Maria, González-Recio, Irene, Goikoetxea, Naroa, Delgado, Teresa Cardoso, Martinez-Cruz, Luis Alfonso, Nogueiras, Ruben, Iruzubieta, Paula, Crespo, Javier, Masson, Steven, McCain, Misti, Reeves, Helen Louise, and Martínez-Chantar, María Luz

Published
2023
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29. Correction to “Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Antifibrotic Activity”

Author

Panyain, Nattawadee, primary, Godinat, Aurélien, additional, Lanyon-Hogg, Thomas, additional, Lachiondo-Ortega, Sofía, additional, Will, Edward J., additional, Soudy, Christelle, additional, Mondal, Milon, additional, Mason, Katie, additional, Elkhalifa, Sarah, additional, Smith, Lisa M., additional, Harrigan, Jeanine A., additional, and Tate, Edward W., additional

Published
2020
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30. Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Antifibrotic Activity

Author

Panyain, Nattawadee, primary, Godinat, Aurélien, additional, Lanyon-Hogg, Thomas, additional, Lachiondo-Ortega, Sofía, additional, Will, Edward J., additional, Soudy, Christelle, additional, Mondal, Milon, additional, Mason, Katie, additional, Elkhalifa, Sarah, additional, Smith, Lisa M., additional, Harrigan, Jeanine A., additional, and Tate, Edward W., additional

Published
2020
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31. Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis

Author

Bioquímica y biología molecular, Biokimika eta biologia molekularra, Mercado Gómez, María, Lopitz Otsoa, Fernando, Azkargorta, Mikel, Serrano Maciá, Marina, Lachiondo Ortega, Sofía, Goikoetxea Usandizaga, Naroa, Rodríguez Agudo, Rubén, Fernández Ramos, David, Bizkarguenaga, Maider, Gutiérrez de Juan, Virginia, Lectez, Benoit, Aloria Escolastico, Kerman, Arizmendi Bastarrika, Jesús María, Simón Espinosa, Jorge, Alonso, Cristina, Lozano, Juan José, Avila, Matias A., Bañales Asurmendi, Jesús María, Marin, Jose J. G., Beraza, Naiara, Mato, José M., Elortza, Felix, Barrio Olano, María Rosa, Sutherland, James D., Mayor Martínez, Ugo, Martínez Chantar, María Luz, Cardoso Delgado, Teresa de Jesús, Bioquímica y biología molecular, Biokimika eta biologia molekularra, Mercado Gómez, María, Lopitz Otsoa, Fernando, Azkargorta, Mikel, Serrano Maciá, Marina, Lachiondo Ortega, Sofía, Goikoetxea Usandizaga, Naroa, Rodríguez Agudo, Rubén, Fernández Ramos, David, Bizkarguenaga, Maider, Gutiérrez de Juan, Virginia, Lectez, Benoit, Aloria Escolastico, Kerman, Arizmendi Bastarrika, Jesús María, Simón Espinosa, Jorge, Alonso, Cristina, Lozano, Juan José, Avila, Matias A., Bañales Asurmendi, Jesús María, Marin, Jose J. G., Beraza, Naiara, Mato, José M., Elortza, Felix, Barrio Olano, María Rosa, Sutherland, James D., Mayor Martínez, Ugo, Martínez Chantar, María Luz, and Cardoso Delgado, Teresa de Jesús

Abstract

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.

Published
2020

34. FRI453 - Magnesium accumulation by CNNM4 GalNAc-siRNA mediated silencing reduces cholestasis-associated liver fibrosis

Author

Serrano-Macia, Marina, Goikoetxea, Naroa, Agudo, Rubén Rodríguez, Bravo, Miren, Lachiondo-Ortega, Sofia, Fondevila, Marcos Fernandez, Petrov, Petar, González-Recio, Irene, Mercado-Gómez, Maria, Gil-Pitarch, Claudia, Romero, Marta, Delgado, Teresa Cardoso, Martinez-Cruz, Luis Alfonso, Nogueiras, Ruben, Martin, Cesar, Milkiewicz, Piotr, Milkiewicz, Malgorzata, Schaeper, Ute, Buccella, Daniela, Marin, Jose Juan G., Espinosa, Jorge Simón, and Martínez-Chantar, María Luz

Published
2022
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35. OS122 - Magnesium modulation by CNNM4 silencing in DIAMOND mice via GalNAc-siRNA therapy: a new and effective therapeutic approach against MAFLD

Author

Agudo, Rubén Rodríguez, Goikoetxea, Naroa, Bravo, Miren, Lachiondo-Ortega, Sofia, Serrano-Macia, Marina, Mercado-Gómez, Maria, Fondevila, Marcos Fernandez, Delgado, Teresa Cardoso, Martinez-Cruz, Luis Alfonso, Martin-Bermudo, Franz, Nogueiras, Ruben, Martín, Cesar Augusto, Schaeper, Ute, Buccella, Daniela, Simón, Jorge, and Martínez-Chantar, María Luz

Published
2022
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37. OS060 - MAP17 promotes metastasis in hepatocellular carcinoma by modulating the epithelial-mesenchymal-amoeboid transition

Author

Gil-Pitarch, Claudia, Bertran, Esther, Uriarte, Iker, Hermán-Sánchez, Natalia, García-Heredia, José Manuel, Goikoetxea, Naroa, Serrano-Macia, Marina, Agudo, Rubén Rodríguez, Lachiondo-Ortega, Sofia, Mercado-Gómez, Maria, Rábano, Miriam, Delgado, Teresa Cardoso, Espinosa, Jorge Simón, Martinez-Cruz, Luis Alfonso, Martín, Cesar Augusto, Vivanco, Maria, Avila, Matías A., Ortiz, Manuel Gahete, Fabregat, Isabel, Carnero, Amancio, and Martínez-Chantar, María Luz

Published
2022
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39. Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Anti-Fibrotic Activity

Author

Panyain, Nattawadee, primary, Godinat, Aurélien, primary, Lanyon-Hogg, Thomas, primary, Lachiondo-Ortega, Sofía, primary, Will, Edward J., primary, Soudy, Christelle, primary, Mason, Katie, primary, Elkhalifa, Sarah, primary, Smith, Lisa M., primary, Harrigan, Jeanine A., primary, and Tate, Edward, primary

Published
2019
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40. Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway

Author

Gil-Pitarch, Clàudia, Serrano-Maciá, Marina, Simon, Jorge, Mosca, Laura, Conter, Carolina, Rejano-Gordillo, Claudia M., Zapata-Pavas, L. Estefanía, Peña-Sanfélix, Patricia, Azkargorta, Mikel, Rodríguez-Agudo, Rubén, Lachiondo-Ortega, Sofía, Mercado-Gómez, Maria, Delgado, Teresa C., Porcelli, Marina, Aurrekoetxea, Igor, Sutherland, James D., Barrio, Rosa, Xirodimas, Dimitris, Aspichueta, Patricia, Elortza, Felix, Martínez-Cruz, Luis Alfonso, Nogueiras, Rubén, Iruzubieta, Paula, Crespo, Javier, Masson, Steven, McCain, Misti Vanette, Reeves, Helen L., Andrade, Raul J., Lucena, M. Isabel, Mayor, Ugo, Goikoetxea-Usandizaga, Naroa, González-Recio, Irene, and Martínez-Chantar, María L.

Abstract

Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.

Published
2024
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41. Role of the mitochondrial protein MCJ in the development of non-alcoholic fatty liver disease (NAFLD)

Author

Lachiondo Ortega, Sofía, Gómez Muñoz, Antonio, F. CIENCIA Y TECNOLOGIA, ZIENTZIA ETA TEKNOLOGIA F., and Grado en Bioquímica y Biología Molecular

Subjects
NAFLD, nutritional and metabolic diseases, digestive system diseases, MCJ
Abstract

[EN] Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western world, affecting 20-30% of the general population. NAFLD comprises a broad range of clinical disorders from pure steatosis and non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. However, the molecular mechanisms underlying NAFLD progression are not completely understood and the tools for its early diagnosis are limited. Notably, mitochondrial alterations have been described in a variety of chronic liver diseases, including NAFLD. Recently, MCJ, an inner mitochondrial membrane protein, has emerged as the first endogenous inhibitor of the electron transport chain complex I. In this project, we studied the role of MCJ in the pathogenesis of NAFLD and investigated the effect that the absence of MCJ exerts in the progression of the disease. Interestingly, we found that MCJ expression is increased during NAFLD. Moreover, MCJ silencing protected against hepatic lipid accumulation, liver injury and inflammation in the methionine-choline deficient mouse model of NASH. Apparently, loss of MCJ led to increased fatty acid β- oxidation, Krebs cycle function, and glycolysis rate, which maintained mitochondrial respiration and ATP production through oxidative phosphorylation. In other words, these metabolic adaptations were able to counteract the cytotoxic effects of fat accumulation on mitochondria and ultimately on hepatocytes. Altogether, MCJ arises as a key regulator of NAFLD paving the way for new promising therapeutic approaches.

Published
2017

43. THU185 - Novel therapy with anti-miR-873-5p at late stages of acetaminophen overdose

Author

Agudo, Rubén Rodríguez, Fernández-Tussy, Pablo, Ballesteros, Gorka, Ramos, David Fernández, Otsoa, Fernando Lopitz, Simón, Jorge, Mabe, Jon, Blanco, Laura Moran, Goikoetxea, Naroa, Serrano-Macia, Marina, Lachiondo-Ortega, Sofia, Mercado-Gómez, Maria, Bizkarguenaga, Maider, de Juan, Virginia Gutiérrez, González-Recio, Irene, Varela-Rey, Marta, Cubero, Francisco Javier, Mato, José M., Andrade, Raul J., Lucena, Maria Isabel, Martinez-Cruz, Luis Alfonso, Delgado, Teresa Cardoso, and Martínez-Chantar, María Luz

Published
2020
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44. AS110 - MCJ deficiency results in gut barrier dysfunction and macrophage-elicited inflammation following ethanol consumption, facilitating alcoholic endotoxemia

Author

Goikoetxea-Usandizaga, Naroa, Clos, Marc, Abecia, Leticia, Ramos, David Fernández, Itoiz, Miguel Pascual, Cearra, Ainize Peña, Iruretagoyena, Begoña Rodriguez, Bizkarguenaga, Maider, Barriales, Diego, Serrano-Macia, Marina, Lachiondo-Ortega, Sofia, Agudo, Rubén Rodríguez, Mercado-Gómez, Maria, Lorenzo, Oscar, Rincón, Mercedes, Falcon-Perez, Juan, Varela-Rey, Marta, Martin-Bermudo, Franz, Anguita, Juan, and Martínez-Chantar, María Luz

Published
2020
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45. Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probeElectronic supplementary information (ESI) available: Additional results and materials and methods for biochemical assay, cell-based experiment, chemical proteomic sample preparation, data analysis, chemical synthesis, data files of protein identification and quantification from the proteomic experiments. See DOI: 10.1039/d1md00218j

Author

Panyain, Nattawadee, Godinat, Aurélien, Thawani, Aditya Raymond, Lachiondo-Ortega, Sofía, Mason, Katie, Elkhalifa, Sarah, Smith, Lisa M., Harrigan, Jeanine A., and Tate, Edward W.

Abstract

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme (DUB), is a potential drug target in various cancers, and liver and lung fibrosis. However, bona fidefunctions and substrates of UCHL1 remain poorly understood. Herein, we report the characterization of UCHL1 covalent inhibitor MT16-001based on a thiazole cyanopyrrolidine scaffold. In combination with chemical proteomics, a closely related activity-based probe (MT16-205) was used to generate a comprehensive quantitative profile for on- and off-targets at endogenous cellular abundance. Both compounds are selective for UCHL1 over other DUBs in intact cells but also engage a range of other targets with good selectivity over the wider proteome, including aldehyde dehydrogenases, redox-sensitive Parkinson's disease related protein PARK7, and glutamine amidotransferase. Taken together, these results underline the importance of robust profiling of activity-based probes as chemical tools and highlight the cyanopyrrolidine warhead as a versatile platform for liganding diverse classes of protein with reactive cysteine residues which can be used for further inhibitor screening, and as a starting point for inhibitor development.

Published
2021
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46. Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression

Author

Fisiologia, Juárez‐Fernández, María, Goikoetxea‐Usandizaga, Naroa, Porras, David, García Mediavilla, María Victoria, Bravo, Miren, Serrano‐Maciá, Marina, Simón, Jorge, Delgado, Teresa C., Lachiondo‐Ortega, Sofía, Martínez‐Flórez, Susana, Lorenzo, Óscar, Rincón, Mercedes, Varela‐Rey, Marta, Abecia, Leticia, Rodríguez, Héctor, Anguita, Juan, Nistal González, Maria Esther, Martínez‐Chantar, María Luz, Sánchez Campos, Sonia, Fisiologia, Juárez‐Fernández, María, Goikoetxea‐Usandizaga, Naroa, Porras, David, García Mediavilla, María Victoria, Bravo, Miren, Serrano‐Maciá, Marina, Simón, Jorge, Delgado, Teresa C., Lachiondo‐Ortega, Sofía, Martínez‐Flórez, Susana, Lorenzo, Óscar, Rincón, Mercedes, Varela‐Rey, Marta, Abecia, Leticia, Rodríguez, Héctor, Anguita, Juan, Nistal González, Maria Esther, Martínez‐Chantar, María Luz, and Sánchez Campos, Sonia

Abstract

[EN] Background and Aims: Recent studies suggest that mitochondrial dysfunction promotes progression to NASH by aggravating the gut-liver status. However, the underlying mechanism remains unclear. Herein, we hypothesized that enhanced mitochondrial activity might reshape a specific microbiota signature that, when transferred to germ-free (GF) mice, could delay NASH progression. Approach and Results: Wild-type and methylation-controlled J protein knockout (MCJ-KO) mice were fed for 6 weeks with either control or a choline-deficient, L-amino acid–defined, high-fat diet (CDA-HFD). One mouse of each group acted as a donor of cecal microbiota to GF mice, who also underwent the CDA-HFD model for 3 weeks. Hepatic injury, intestinal barrier, gut microbiome, and the associated fecal metabolome were then studied. Following 6 weeks of CDA-HFD, the absence of methylation-controlled J protein, an inhibitor of mitochondrial complex I activity, reduced hepatic injury and improved gut-liver axis in an aggressive NASH dietary model. This effect was transferred to GF mice through cecal microbiota transplantation. We suggest that the specific microbiota profile of MCJ-KO, characterized by an increase in the fecal relative abundance of Dorea and Oscillospira genera and a reduction in AF12, Allboaculum, and [Ruminococcus], exerted protective actions through enhancing short-chain fatty acids, nicotinamide adenine dinucleotide (NAD+) metabolism, and sirtuin activity, subsequently increasing fatty acid oxidation in GF mice. Importantly, we identified Dorea genus as one of the main modulators of this microbiota-dependent protective phenotype. Conclusions: Overall, we provide evidence for the relevance of mitochondria–microbiota interplay during NASH and that targeting it could be a valuable therapeutic approach.

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