Tag: MCJ (Page 2 of 2)

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.

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.