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Tag: MCJ

MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension

Ayelén M. Santamans, Beatriz Cicuéndez, Alfonso Mora , María Villalba-Orero, Sanela Rajlic, María Crespo, Paula Vo, Madison Jerome, Álvaro Macías, Juan Antonio López, Magdalena Leiva, Susana F. Rocha, Marta León, Elena Rodríguez, Luis Leiva, Aránzazu Pintor Chocano, Inés García Lunar, Ana García-Álvarez, Pablo Hernansanz-Agustín, Víctor I. Peinado, Joan Albert Barberá, Borja Ibañez, Jesús Vázquez, Jessica B. Spinelli, Andreas Daiber, Eduardo Oliver & Guadalupe Sabio.

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies.

MCJ stainimg in lungs of patients with chronic obstructive pulmonary disease.

Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure.

These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition

The outcome of boosting mitochondrial activity in alcoholic liver disease (ALD) is organ-dependent

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

Objective: Alcoholic 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 recovering mitochondrial fitness without collateral oxidative damage.

Design: C57BL/6 mice (Wild-type (Wt), Mcj knockout (MCJ-KO) 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, liver, gut, and pancreas where characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition.

Results: 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, i.e., 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.

Conclusion: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.

Mitochondrial bioenergetics boost macrophages activation promoting liver regeneration in metabolically compromised animals

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

BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury (IRI) is the leading cause of early post-transplantation organ failure, as mitochondrial respiration and ATP production are affected. 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 pre-clinical models of IRI and liver regeneration, focusing on metabolically compromised animal models.

Hepatic uptake of 18F-fluorodeoxyglucose (Image: Alfonso Mora).

APPROACH & RESULTS: Wt, MCJ KO and Mcj silenced Wt mice were subjected to 70% Partial hepatectomy (Phx), prolonged IRI and 70% Phx with IRI. Old and mice with metabolic syndrome were also subjected to these procedures. Expression of MCJ, an endogenous negative regulator of mitochondrial respiration, increases in pre-clinical models of Phx with or without vascular occlusion, and in donors’ livers. Mice lacking MCJ initiate liver regeneration 12h faster than WT, 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 HB-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 with 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 novel protective approach after major liver resection or IRI, specially in metabolically compromised, IRI susceptible organs.

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