RT Journal Article
T1 The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent
A1 Goikoetxea Usandizaga, Naroa
A1 Bravo, Miren
A1 Egia Mendikute, Leire
A1 Abecia, Leticia
A1 Serrano Maciá, Marina
A1 Urdinguio, Rocío G.
A1 Clos García, Marc
A1 Rodríguez Agudo, Rubén
A1 Araujo Legido, Raquel
A1 López Bermudo, Lucía
A1 Delgado, Teresa C.
A1 Lachiondo Ortega, Sofía
A1 González Recio, Irene
A1 Gil Pitarch, Clàudia
A1 Peña Cearra, Ainize
A1 Simón, Jorge
A1 Benede Ubieto, Raquel
A1 Ariño, Silvia
A1 Herranz, Jose M.
A1 Azkargorta, Mikel
A1 Salazar Bermeo, Julio
A1 Martí, Nuria
A1 Varela Rey, Marta
A1 Falcón Pérez, Juan M.
A1 Lorenzo, Óscar
A1 Nogueiras, Rubén
A1 Elortza, Félix
A1 Nevzorova, Yulia
A1 Cubero Palero, Francisco Javier
A1 Saura, Domingo
A1 Martínez Cruz, Luis Alfonso
A1 Sabio, Guadalupe
A1 Palazón, Asís
A1 Sancho Bru, Pau
A1 Elguezabal, Natalia
A1 Fraga, Mario F.
A1 Ávila, Matías A.
A1 Bataller, Ramón
A1 Marín, José J.G.
A1 Martín, Franz
A1 Martínez Chantar, María Luz
AB 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.
PB Wolters Kluwer Health Inc. / American Association for the Study of Liver Diseases
SN 0270-9139
YR 2023
FD 2023
LK https://hdl.handle.net/20.500.14352/121429
UL https://hdl.handle.net/20.500.14352/121429
LA eng
NO Goikoetxea-Usandizaga N, Bravo M, Egia-Mendikute L, Abecia L, SerranoMaciá M, Urdinguio RG, et al. The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent. Hepatology. 2023;78:878–895. https://doi.org/10.1097/ HEP.0000000000000303
NO This work was supported by grants from Ministerio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019-007125-1 (for Jorge Simon and Maria Luz Martinez-Chantar); Ministerio de Economía, Industria y Competitividad, Retos a la Sociedad AGL2017-86927R (for F.M.); Instituto de Salud Carlos III, Proyectos de Investigación en Salud DTS20/00138 and DTS21/00094 (for Jorge Simon and Maria Luz Martinez-Chantar, and Asis Palazon. respectively); Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-founded by European Regional Development Fund/European Social Fund, “Investing in your future” PI19/00819, “Una manera de hacer Europa” FIS PI20/00765, and PI21/01067 (for Jose J. G. Marin., Pau Sancho-Bru,. and Mario F. Fraga respectively); Departamento de Industria del Gobierno Vasco (for Maria Luz Martinez-Chantar); Asturias Government (PCTI) co-funding 2018-2023/FEDER IDI/2021/000077 (for Mario F. Fraga.); Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00, CEX2021-001136-S PID2020-117941RB-I00, PID2020-11827RB-I00 and PID2019-107956RA-100 integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación, cofinanciado con Fondos FEDER (for Maria Luz Martinez-Chantar, Francisco J Cubero., Yulia A Nevzorova and Asis Palazon); Ayudas Ramón y Cajal de la Agencia Estatal de Investigación RY2013-13666 and RYC2018-024183-I (for Leticia Abecia and Asis Palazon); European Research Council Starting Grant 804236 NEXTGEN-IO (for Asis Palazon); The German Research Foundation SFB/TRR57/P04, SFB1382-403224013/A02 and DFG NE 2128/2-1 (for Francisco J Cubero and Yulia A Nevzorova); National Institute of Health (NIH)/National Institute of Alcohol Abuse and Alcoholism (NIAAA) 1U01AA026972-01 (For Pau Sancho-Bru); Junta de Castilla y León SA074P20 (for Jose J. G. Marin); Junta de Andalucía, Grupo PAIDI BIO311 (for Franz Martin); CIBERER Acciones Cooperativas y Complementarias Intramurales ACCI20-35 (for Mario F. Fraga); Ministerio de Educación, Cultura y Deporte FPU17/04992 (for Silvia Ariño); Fundació Marato TV3 201916-31 (for Jose J. G. Marin.); Ainize Pena-Cearra is a fellow of the University of the Basque Country (UPV/EHU); BIOEF (Basque Foundation for Innovation and Health Research); Asociación Española contra el Cáncer (Maria Luz Martinez-Chantar and Teresa C. Delgado.); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (for Maria Luz Martinez-Chantar); La Caixa Foundation Program (for Maria Luz Martinez-Chantar); Proyecto Desarrollo Tecnologico CIBERehd (for Maria Luz Martinez-Chantar); Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III.
NO Ministerio de Ciencia e Innovación (España)
NO Ministerio de Economía y Competitividad (España)
NO Instituto de Salud Carlos III
NO European Commission
NO Gobierno Vasco
NO Principado de Asturias
NO German Research Foundation
NO National Institute of Health (EEUU)
NO National Institute of Alcohol Abuse and Alcoholism (EEUU)
NO Junta de Castilla y León
NO Junta de Andalucía
NO Centro de Investigación Biomédica en Red de Enfermedades Raras
NO Ministerio de Educación, Cultura y Deporte
NO Fundació Marato
NO Universidad del País Vasco
NO Fundación Vasca de Innovación e Investigación Sanitarias
NO Asociación Española contra el Cáncer
NO Fundación Científica de la Asociación Española Contra el Cáncer
NO Fundación La Caixa
DS Docta Complutense
RD 31 mar 2026