The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent

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 problem...

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Detalles Bibliográficos
Autores: 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, Benede 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 Palero, Francisco Javier, 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
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/121429
Acceso en línea:https://hdl.handle.net/20.500.14352/121429
Access Level:acceso abierto
Palabra clave:616.36
576.315
612.35
612.014
Medicina
Gastroenterología y hepatología
Biología celular (Biología)
Fisiología
3205 Medicina Interna
6113.01 Alcoholismo
2407 Biología Celular
2411 Fisiología Humana
Descripción
Sumario: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.

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