2026-04-29T16:56:07Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/163882024-10-31T11:56:07Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Goikoetxea-Usandizaga, Naroa
author
Bravo, Miren
author
Egia-Mendikute, Leire
author
Abecia, Leticia
author
Serrano-Maciá, Marina
author
Urdinguio, Rocío G
author
Clos-García, Marc
author
Rodríguez-Agudo, Rubén
author
Araujo-Legido, Raquel
author
López-Bermudo, Lucía
author
Delgado, Teresa C
author
Lachiondo-Ortega, Sofía
author
González-Recio, Irene
author
Gil-Pitarch, Clàudia
author
Peña-Cearra, Ainize
author
Simón, Jorge
author
Benedé-Ubieto, Raquel
author
Ariño, Silvia
author
Herranz, Jose M
author
Azkargorta, Mikel
author
Salazar-Bermeo, Julio
author
Martí, Nuria
author
Varela-Rey, Marta
author
Falcón-Pérez, Juan M
author
Lorenzo, Óscar
author
Nogueiras, Rubén
author
Elortza, Félix
author
Nevzorova, Yulia A
author
Cubero, Francisco J
author
Saura, Domingo
author
Martínez-Cruz, Luis Alfonso
author
Sabio, Guadalupe
author
Palazón, Asís
author
Sancho-Bru, Pau
author
Elguezabal, Natalia
author
Fraga, Mario F
author
Ávila, Matías A
author
Bataller, Ramón
author
Marín, José J G
author
Martín, Franz
author
Martínez-Chantar, María Luz
funder
Ministerio de Ciencia e Innovación (España)
funder
Ministerio de Economía, Industria y Competitividad (España)
funder
Instituto de Salud Carlos III
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Gobierno del Principado de Asturias (España)
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Agencia Estatal de Investigación (España)
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
National Institutes of Health (Estados Unidos)
funder
Centro de Investigación Biomédica en Red - CIBERER (Enfermedades Raras)
funder
Fundación La Marató TV3
funder
Asociación Española Contra el Cáncer
funder
Fundación La Caixa
2023-09-04T08:58:26Z
2023-09-04T08:58:26Z
2023-09-01
Hepatology. 2023 Sep 1;78(3):878-895
10.1097/HEP.0000000000000303
1527-3350
0270-9139
Hepatology (Baltimore, Md.)
36745935
http://hdl.handle.net/20.500.12105/16388
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.
eng
The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.
journal article
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