The p38 mitogen-activated kinase (MAPK) family controls cell adaptation to stress stimuli. There are four different p38 family members with different roles in relation to cardiac development and function.
The first isoform demonstrated to play an important role in cardiac development was p38α; however, all p38 family members are now known to collaborate in different aspects of cardiomyocyte differentiation and growth. p38 family members have been proposed to have protective and deleterious actions in the stressed myocardium, with the outcome of their action dependent on the model system under study and the identity of the p38 family member activated.
In this talk, we summarize current understanding of the role of the p38 pathway in cardiac physiology and discuss recent advances in the field.
Natáliada Silva Lima, Marcos F. Fondevila, Eva Nóvoa, Xabier Buqué, Maria Mercado-Gómez, Sarah Gallet, Maria J. González-Rellan, Uxia Fernandez, Anne Loyens, Maria Garcia-Vence, Maria del Pilar Chantada-Vazquez, Susana B. Bravo, Patricia Marañon, Ana Senra, Adriana Escudero, Magdalena Leiva, Diana Guallar, Miguel Fidalgo, Pedro Gomes, Marc Claret, Guadalupe Sabio, Marta Varela-Rey, Teresa C. Delgado, Rocio Montero-Vallejo, Javier Ampuero, Miguel López, Carlos Diéguez, Laura Herrero, Dolors Serra, Markus Schwaninger, Vincent Prevo, Rocio Gallego-Duran, Manuel Romero-Gomez, Paula Iruzubieta, Javier Crespo, Maria L. Martinez-Chantar, Carmelo Garcia-Monzon, Agueda Gonzalez-Rodriguez, Patricia Aspichueta & Ruben Nogueiras.
BACKGROUND & AIMS: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to nonalcoholic fatty liver disease (NAFLD) remains unknown.
METHODS: By performing a liver proteomic analysis from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples of patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the liver of mice.
RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and NASH) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoiltransferase I (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action.
CONCLUSIONS: Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis.
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.